Conditions: Multiple Myeloma Lymphoma Amyloidosis
Keywords: Drug Therapy
Allocation: NON_RANDOMIZED | Intervention model: SINGLE_GROUP
Enrollment: 32
Healthy volunteers: no

Brief summary:
The purpose of this study is to provide continued access to ixazomib and/or other study drugs from an ixazomib parent study.

Detailed description:
The drug being tested in this study is called ixazomib. This study will look at the long term safety profile of ixazomib in participants who have previously received and tolerated ixazomib in a Takeda-sponsored clinical study, and in the investigator's opinion and approved by the Takeda medical monitor, may benefit from continued ixazomib therapy.

The study will enroll approximately 250 patients.

All participants will receive ixazomib as a single agent or in combination with other study drugs at same dose and schedule that they were receiving in the parent study until they experience disease progression, clinical deterioration in the investigator's judgment, experience an unacceptable toxicity, withdraw consent, pursue an alternative therapy, meet other study-specified reasons for discontinuation of study drug, or until ixazomib is available to the participant is transitioned to ixazomib/other therapy through commercial channels, including reimbursement for the participant's indication, whichever is sooner.

This multicenter, rollover study will be conducted worldwide. The overall time to participate in this study is up to 7 years. Participants will make multiple visits to the clinic, and a final visit after 30 days of last dose of study drug for a safety assessment.

Arms:
arm 1: Participants received ixazomib capsule, orally, at same dose and schedule as they were receiving in the parent study until disease progression, clinical deterioration in the investigator's judgment, experienced an unacceptable toxicity, withdrew consent, pursued an alternative therapy, met other study-specified reasons for discontinuation of study drug, or until the participant was transitioned to ixazomib through commercial channels, including reimbursement for the participant's indication, or up to a maximum of 7 years whichever was sooner. arm 2: Participants received combination therapy with ixazomib capsule, orally and another medication(s) (1 or more of the anticancer agents dexamethasone, lenalidomide or cyclophosphamide) at same dose and schedule as they were receiving in the parent study until disease progression, clinical deterioration in the investigator's judgment, experienced an unacceptable toxicity, withdrew consent, pursued an alternative therapy, met other study-specified reasons for discontinuation of study drug, or until the participant was transitioned to ixazomib through commercial channels, including reimbursement for the participant's indication, or up to a maximum of 6.5 years whichever was sooner.

Interventions: intervention 1: Ixazomib
Intervention descriptions: intervention 1: Ixazomib Capsules

Protocol document:
Prot_000.pdf: 
For non-commercial use only


PROTOCOL
An Open-Label, Rollover Protocol for Patients Previously Enrolled in Takeda-Sponsored 
Ixazomib Studies 
Ixazomib Rollover Study
Sponsor:
Takeda Development Center Americas, Inc 
95 Hayden Avenue
Lexington, MA 02421, USA
Telephone: +1 (617) 679-7000
Study Number:
C16027
EudraCT Number:
2016-001681-28
Compound:
Ixazomib
Date:
03 June 2021
Amendment Number:
03
Amendment History:
Date
Amendment Number
Amendment Type (for regional 
Europe purposes only)
Region
30 June 2016
Initial Protocol
Not applicable
Global
23 March 2017
01
Substantial amendment
Global
08 November 2017
02
Nonsubstantial amendment
Local (Sweden)
03 June 2021
03
Substantial amendment
Global
CONFIDENTIAL PROPERTY OF TAKEDA
This document is a confidential communication of Takeda. Acceptance of this document constitutes the agreement by 
the recipient that no information contained herein will be published or disclosed without written authorization from 
Takeda except to the extent necessary to obtain informed consent from those persons to whom the drug may be 
administered. Furthermore, the information is only meant for review and compliance by the recipient, his or her staff, 
and applicable institutional review committee and regulatory agencies to enable conduct of the study.
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1.0
ADMINISTRATIVE 
1.1
Contacts 
A separate contact information list will be provided to each site.
Serious adverse event and pregnancy reporting information is presented in Section 10.0, as is 
information on reporting product complaints. 
Medical and study drug advice for this protocol is available by contacting the Medical Monitor. 
Refer to the study manual for contact information.
TDC-sponsored investigators per individual country requirements will be provided with 
emergency medical contact information cards to be carried by each subject.
General advice on protocol procedures should be obtained through the monitor assigned to the 
study site. Information on service providers is given in Section 3.1 and relevant guidelines 
provided to the site.
Contact Type/Role
North America
Contact
Europe
Contact
Asia
Contact
Serious adverse event 
and pregnancy reporting
See Section 10.2
See Section 10.2
See Section 10.2
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1.3
Protocol Amendment 03 Summary of Changes
Rationale for Amendment 03
This document describes the changes in reference to the protocol incorporating 
Amendment No. 03. Patients are eligible to enroll in this rollover study if they have previously 
received and tolerated a defined study regimen in a designated Takeda-sponsored ixazomib 
clinical study (ie, Studies C16003, C16005, C16006, C16007, C16008, C16010 Global, C16011, 
C16013, C16014 Global and Korean Continuation, C16017, C16020, C16029, and C16047) and 
if, in the investigator’s opinion, they may benefit from continued therapy with 1 or more of the 
drugs from the parent protocol. No new anticancer agents can be started or added. Note that for 
patients whose study therapy in a parent study includes a placebo, the placebo capsule will be 
discontinued; crossover to ixazomib is not permitted. The primary reason for this amendment is to 
update the protocol regarding dosing and treatment information from parent protocols.
Additionally, this amendment clarifies other elements of the study design and procedures. 
Descriptions of how to manage study procedures during the coronavirus disease 2019 
(COVID-19) pandemic have been added. Event descriptions were updated to the current program 
standards for the management of clinical events. Paper-based serious adverse event (SAE) 
reporting procedures were additionally clarified. The list of acceptable methods of contraception 
previously added in the Sweden-specific Protocol Amendment 02 has now been added to this 
global amendment (see Appendix D). See the changes below for a complete list of all changes 
included in this amendment. Minor grammatical, editorial, and formatting changes are included 
for clarification purposes only.
For specific descriptions of text changes and where the changes are located, see Appendix E. 
Changes in Amendment 03
1. Updated the legal entity of the sponsor.
2. Updated signatories for the study.
3. Clarified that ixazomib and/or combinational study drugs from the designated parent protocols 
will be provided in this study until other means of accessing treatment are available; no new 
anticancer agents can be started or added; and for patients whose study therapy in a parent 
study includes placebo, the placebo capsule will be discontinued and crossover to ixazomib is 
not permitted. 
4. Clarified the study objectives. 
5. Clarified the duration of adverse event (AE) follow-up. 
6. Updated the background information on other ixazomib clinical trials. 
7. Clarified the anticipated number of patients and sites/countries.
8. Clarified the duration of an individual patient’s study participation. 
9. Clarified the anticipated total study duration.
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10. Specified the acceptable methods of contraception to prevent pregnancy. 
11. Clarified that systemic treatment with strong cytochrome P-450 (CYP)3A inducers is 
prohibited for patients receiving ixazomib during the study.
12. Updated the management of ixazomib clinical events to align with the current program 
standards.
13. Clarified the instructions for management of combination therapy clinical events. 
14. Updated the storage, handling, and accountability text to clarify procedures and account for the 
COVID-19 pandemic. 
15. Added language regarding alternative methods for administering study 
procedures/assessments when it is not possible for the patient to come to the study site due to 
the COVID-19 pandemic.
16. Clarified that patients previously enrolled in this study who remain on study treatment upon 
implementation of Amendment 3 may need to be reconsented, according to IRB/IEC 
standards.
17. Clarified regional exceptions for assessment of carbon dioxide, depending on standard of care.
18. Updated the criteria for withdrawing patients from study. 
19. Added language to Procedures for Recording and Reporting Adverse Events and Serious 
Adverse Events.
20. Revised language regarding the statistical analyses.
21. Clarified language regarding procedures for reporting product complaints or medication 
errors.
22. Clarified language regarding quality assurance audits and Regulatory Agency inspections. 
23. Add information about alternative monitoring approaches, such as remote source data 
verification, in the event a monitor cannot visit the site in a timely manner due to the 
COVID-19 pandemic.
24. Clarify the ixazomib capsule strengths that are available.
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INVESTIGATOR AGREEMENT 
I confirm that I have read and that I understand this protocol, the Investigator’s Brochure, package 
insert and any other product information provided by the sponsor. I agree to conduct this study in 
accordance with the requirements of this protocol and also to protect the rights, safety, privacy, 
and well-being of study subjects in accordance with the following:

The ethical principles that have their origin in the Declaration of Helsinki.

International Conference on Harmonisation, E6 Good Clinical Practice: Consolidated 
Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations.

Regulatory requirements for reporting serious adverse events defined in Section 10.0 of this 
protocol.

Terms outlined in the Clinical Study Site Agreement.

Responsibilities of the Investigator (Appendix B).
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in Appendix C of this protocol.
Signature of Investigator
Date
Investigator Name (print or type)
Investigator’s Title
Location of Facility (City, State/Provence)
Location of Facility (Country)
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TABLE OF CONTENTS
1.0
ADMINISTRATIVE.......................................................................................................2
1.1
Contacts.....................................................................................................................2
1.2
Approval....................................................................................................................3
1.3
Protocol Amendment 03 Summary of Changes ..........................................................4
2.0
STUDY SUMMARY ....................................................................................................11
3.0
STUDY REFERENCE INFORMATION ......................................................................15
3.1
Study-Related Responsibilities.................................................................................15
3.2
List of Abbreviations ...............................................................................................15
4.0
INTRODUCTION.........................................................................................................17
4.1
Background .............................................................................................................17
4.1.1
Risk: Benefit Assessment.................................................................................18
4.2
Rationale for the Proposed Study.............................................................................19
5.0
STUDY OBJECTIVES AND ENDPOINTS..................................................................19
5.1
Objectives................................................................................................................19
5.1.1
Primary Objectives ..........................................................................................19
5.2
Endpoints.................................................................................................................19
5.2.1
Primary Endpoint.............................................................................................19
6.0
STUDY DESIGN..........................................................................................................19
6.1
Overview of Study Design.......................................................................................19
6.2
Number of Patients ..................................................................................................21
6.3
Duration of Study ....................................................................................................21
6.3.1
Duration of an Individual Patient’s Study Participation....................................21
6.3.2
End of Study/Study Completion Definition and Planned Reporting..................22
6.3.3
Timeframe for Primary Endpoint to Support Disclosures .................................22
6.3.4
Total Study Duration .......................................................................................22
7.0
STUDY POPULATION................................................................................................22
7.1
Inclusion Criteria .....................................................................................................22
7.2
Exclusion Criteria ....................................................................................................23
8.0
STUDY DRUG .............................................................................................................23
8.1
Study Drug Administration......................................................................................23
8.2
Reference/Control Therapy......................................................................................24
8.3
Dose Modification Guidelines..................................................................................24
8.4
Excluded Concomitant Medications and Procedures ................................................24
8.5
Permitted Concomitant Medications and Procedures................................................24
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8.6
Precautions and Restrictions ....................................................................................24
8.7
Management of Clinical Events ...............................................................................25
8.7.1
Management of Ixazomib Clinical Events........................................................25
8.7.2
Management of Combination Therapy Clinical Events ....................................27
8.8
Blinding and Unblinding..........................................................................................27
8.9
Description of Investigational Agents ......................................................................27
8.10
Preparation, Reconstitution, and Dispensation..........................................................28
8.11
Packaging and Labeling...........................................................................................28
8.12
Storage, Handling, and Accountability.....................................................................28
8.13
Combination Therapy ..............................................................................................29
8.14
Other Protocol-Specified Materials ..........................................................................29
9.0
STUDY CONDUCT......................................................................................................29
9.1
Study Personnel and Organizations..........................................................................30
9.2
Arrangements for Recruitment of Patients................................................................30
9.3
Treatment Group Assignments.................................................................................30
9.4
Study Procedures.....................................................................................................30
9.4.1
Informed Consent ............................................................................................31
9.4.2
Vital Signs.......................................................................................................31
9.4.3
Weight.............................................................................................................31
9.4.4
Pregnancy Test ................................................................................................31
9.4.5
Concomitant Medications and Procedures........................................................31
9.4.6
Adverse Events................................................................................................32
9.4.7
Enrollment.......................................................................................................32
9.4.8
Clinical Laboratory Evaluations.......................................................................32
9.4.9
Disease Assessment.........................................................................................33
9.5
Completion of Study (for Individual Patients)..........................................................33
9.6
Withdrawal of Patients From Study .........................................................................33
9.7
Study Compliance....................................................................................................33
10.0
ADVERSE EVENTS ....................................................................................................34
10.1
Definitions...............................................................................................................34
10.1.1
Adverse Event Definition.................................................................................34
10.1.2
Serious Adverse Event Definition....................................................................34
10.2
Procedures for Recording and Reporting Adverse Events and Serious 
Adverse Events........................................................................................................35
10.3
Monitoring of Adverse Events and Period of Observation........................................36
10.4
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events.........37
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10.5
Procedures for Reporting Product Complaints or Medication Errors (Including 
Overdose) ................................................................................................................37
10.6
Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities...........37
11.0
STUDY-SPECIFIC COMMITTEES .............................................................................38
12.0
DATA HANDLING AND RECORDKEEPING............................................................38
12.1
eCRFs......................................................................................................................38
12.2
Record Retention .....................................................................................................39
13.0
STATISTICAL METHODS..........................................................................................39
13.1
Statistical and Analytical Plans ................................................................................39
13.1.1
Analysis Sets ...................................................................................................39
13.1.2
Efficacy Analysis.............................................................................................39
13.1.3
Safety Analysis................................................................................................40
13.2
Interim Analysis and Criteria for Early Termination ................................................40
13.3
Determination of Sample Size..................................................................................40
14.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................40
14.1
Study-Site Monitoring Visits ...................................................................................40
14.2
Protocol Deviations..................................................................................................41
14.3
Quality Assurance Audits and Regulatory Agency Inspections ................................41
15.0
ETHICAL ASPECTS OF THE STUDY........................................................................42
15.1
IRB and/or IEC Approval ........................................................................................42
15.2
Subject Information, Informed Consent, and Subject Authorization .........................43
15.3
Subject Confidentiality ............................................................................................44
15.4
Publication, Disclosure, and Clinical Trial Registration Policy.................................44
15.4.1
Publication.......................................................................................................44
15.4.2
Clinical Trial Registration................................................................................45
15.4.3
Clinical Trial Results Disclosure......................................................................45
15.5
Insurance and Compensation for Injury....................................................................45
16.0
REFERENCES..............................................................................................................46
LIST OF IN-TEXT TABLES
Table 6.a
Primary Endpoint for Disclosures.......................................................................22
Table 9.a
Clinical Chemistry and Hematology Tests..........................................................32
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LIST OF APPENDICES
Appendix A
Schedule of Events.............................................................................................47
Appendix B
Responsibilities of the Investigator.....................................................................49
Appendix C
Investigator Consent to Use of Personal Information..........................................51
Appendix D
Acceptable Methods of Contraception................................................................52
Appendix E
Detailed Description of Amendments to Text.....................................................53
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2.0
STUDY SUMMARY 
Name of Sponsor(s):
Takeda Development Center Americas, Inc
Compound:
Ixazomib
Title of Protocol: An Open-Label, Rollover Protocol for 
Patients Previously Enrolled in Takeda-Sponsored 
Ixazomib Studies 
EudraCT No.:
2016-001681-28
Study Number: C16027
Phase: 2
Study Design:
This is an open-label, multicenter, rollover study to provide continued access to ixazomib and/or other combinational 
study drugs from the designated ixazomib parent protocols when the patient has no other means to access study 
treatment. The study will also evaluate the long-term safety profile of ixazomib. 
The patient population will consist of patients who have previously received and tolerated a defined study regimen in 
a designated Takeda-sponsored ixazomib clinical study, and in the investigator’s opinion and approved by the Takeda 
medical monitor, may benefit from continued therapy with 1 or more of the study drugs from a parent protocol (eg, 
response to therapy or stable disease without evidence of disease progression). 
Patients may be enrolled provided they have not met any of the discontinuation criteria in a parent study. Patients will 
enter this study on the same dose, schedule of study drug(s), and combination regimen that they were receiving at the 
time of rollover from the parent study, or according to the required dose modification from a parent study. For those 
patients who received ixazomib dosing based on body surface area (BSA) per the parent study, the dose may be 
rounded. The dose may also be rounded for those patients who convert from BSA-based dosing to fixed dosing with 
approval from the Medical Monitor. No new anticancer agents can be started or added. Note that for patients whose 
study therapy in a parent study includes a placebo, the placebo capsule will be discontinued; crossover to ixazomib is 
not permitted. 
Following enrollment, patients may receive study treatment until they experience disease progression, clinical 
deterioration in the investigator’s judgment, experience an unacceptable toxicity, withdraw consent, pursue an 
alternative therapy, meet other study-specified reasons for discontinuation of study drug, or until the patient is 
transitioned to ixazomib/other therapy through commercial channels. 
Patients participating in a designated parent study will enter the rollover study when they have completed the end of 
treatment (EOT) visit in the parent study and when the rollover study is active at the investigative site. Following their 
provision of informed consent to continue receiving treatment in the rollover study, patients will be provided with 
study medication. Patients should enter the study within a maximum of 8 weeks of their last dose of study drug(s) in 
the parent study or as agreed upon by the Takeda clinician/designee so to minimize any treatment disruption to the 
patient. Local safety-related laboratory evaluations and vital sign measurements will be performed according to the 
schedule of events as presented in this rollover study and accordingly will only be recorded in the electronic case 
report forms (eCRFs) prior to the first dose of ixazomib in the rollover study, at the end of study, and as spontaneously 
reported by the investigator. Electrocardiogram assessments will only be performed as clinically indicated. During 
treatment, dosing modification decisions will be made per the parent study. Systemic treatment with strong 
cytochrome P-450 (CYP)3A inducers is prohibited for patients receiving ixazomib during the study. The procedures 
prohibited in the patient’s parent study are prohibited during this study. Prohibited medications due to 
co-administration of other agents in the ixazomib regimen are prohibited as per the prescribing information for the 
co-administered agent(s).
It is recommended that disease assessments are performed per standard of care. 
At the time of discontinuation of study drug(s) in this study, an end-of-study (EOS) visit will be scheduled and will 
occur prior to the initiation of any new therapy, or within 30 days of last dose of study drug administration, whichever 
is earlier. The reason for treatment discontinuation, an overall investigator assessment of best response obtained 
during this rollover study, and the investigator assessment of date of progression will be captured in the eCRFs. 
Toxicity will be evaluated according to National Cancer Institute Common Terminology Criteria for Adverse Events, 
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Version 5.0, effective date 27 November 2017 [1]. 
The long-term safety and tolerability of ixazomib will be monitored. The following adverse events (AEs) will be 
reported from the first dose of study drug for this study through 30 days after administration of the last dose of study 
drug and recorded in the eCRFs and serious adverse events (SAEs) will also be reported directly to the Sponsor (see 
Section 10.2). The following AEs that are ongoing at the time of entry into the rollover study will be recorded in the 
eCRFs as baseline AEs.

All SAEs.

All ≥Grade 3 AEs.

≥Grade 2 peripheral neuropathy.

New primary malignancies.

Any AE resulting in dose modification or discontinuation of any study drug.

Any other AE that in the opinion of the investigator is a clinically significant event.
The above AEs will be followed until resolution, until the AE becomes chronic or stable, or is determined to be part of 
the underlying disease process, or until the patient attends the EOS visit and discontinues the study.
The transfer of patients between sites is allowed with the approval of the sponsor’s clinician/designee (eg, in the case 
of site closure, patient moves, etc).
Primary Objective:

To provide continued access to ixazomib and/or other study drugs from an ixazomib parent study. 

To evaluate the long-term safety profile of ixazomib. 
Subject Population: Patients on study drug(s) at the closure of an ixazomib parent study, and who are likely to derive 
benefit from continued study therapy.
Number of Subjects:
The estimated number of patients to be enrolled is 
approximately 250. 
Number of Sites: 
The number of countries and sites is not currently 
specified as this study is open to all countries and sites 
with qualifying patients from prior 
company-sponsored ixazomib studies
Dose Level(s):
Patients will enter this study on the same same dose, 
schedule of study drug(s), and combination regimen that 
they were receiving at the time of rollover from the parent 
study, or according to the required dose modification from a 
parent study. No new anticancer agents can be started or 
added. Note that for patients whose study therapy in a 
parent study includes a placebo, the placebo capsule will be 
discontinued; crossover to ixazomib is not permitted. 
For those patients who received ixazomib dosing based on 
body surface area (BSA) per the parent study, the dose may 
be rounded. The dose may also be rounded for those 
patients who convert from BSA-based dosing to fixed 
dosing with approval from the Medical Monitor. 
Route of Administration:
Oral
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Duration of Treatment:
The anticipated duration of treatment in this rollover study 
will be approximately 5 years. Patients may remain in the 
rollover study until they are transitioned to ixazomib/other 
therapy through commercial channels or until any of the 
other reasons for treatment discontinuation are met, 
whichever is sooner.
Period of Evaluation:
Patients will be followed for 30 days after the last dose 
of ixazomib/other study drug(s) or the start of 
subsequent alternative anticancer therapy.
Duration of Study:
The estimated time frame for study completion (first patient 
in to last patient last visit) is approximately 7 years.
Main Criteria for Inclusion:
Patients previously treated with ixazomib, background therapy, and/or comparator drugs (including placebo) in a 
Takeda-sponsored ixazomib parent study. Patients will be eligible to enter the rollover study when:
a)
The parent study is closed or planned to be closed; and
b)
The patient is on ixazomib monotherapy, a combination regimen with ixazomib and other study medication(s), 
on a placebo combination, or on an alternative arm regimen in a designated ixazomib parent study (ie, Studies 
C16003, C16005, C16006, C16007, C16008, C16010 Global, C16011, C16013, C16014 Global and Korean 
Continuation, C16017, C16020, C16029, and C16047); and
c)
In the opinion of the investigator and approved by the Takeda medical monitor, the patient may continue to 
benefit from treatment with ixazomib and/or another study drug/combination regimen (eg, response to therapy or 
stable disease without evidence of disease progression) and has no alternate means to access the study drug(s) 
(eg, commercial supply). 
Main Criteria for Exclusion:
Patients meeting any of the criteria for treatment discontinuation in the parent study.
Main Criteria for Evaluation and Analyses:
The primary endpoint is safety, as assessed by the incidence of the following AEs:

All SAEs.

All ≥Grade 3 AEs.

≥Grade 2 peripheral neuropathy.

New primary malignancies.

Any AE resulting in dose modification or discontinuation of any study drug.

Any other AE that in the opinion of the investigator is a clinically significant event.
Statistical Considerations:
The following AEs will be summarized for patients who receive at least 1 dose of ixazomib using the full analysis set: 

All SAEs.

All ≥Grade 3 AEs. 

≥Grade 2 peripheral neuropathy.

New primary malignancies. 

Any AE resulting in dose modification or discontinuation of any study drug.

Any other AE that in the opinion of the investigator is a clinically significant event. 
No formal statistical testing or inferential statistics will be generated.
All AEs will be coded using the Medical Dictionary for Regulatory Activities. Data will be summarized using 
preferred term and primary system organ class. Local laboratory assessment changes and vital sign changes from 
study entry to end of study will also be summarized.
Exposure to study drug and study regimen will be tabulated. In addition, reasons for drug discontinuation will be 
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summarized. 
The overall investigator assessment of best response obtained during this rollover study and investigator assessment of 
date of progression will be listed.
Concomitant medications and procedures related to treatment of AEs from screening through the study period will be 
classified by generic terms according to the World Health Organization drug dictionary. 
Data will be presented by the entire ixazomib Safety population, by population of monotherapy of ixazomib, and by 
population of ixazomib in combination with other anticancer agents(s), as specified in the SAP. Safety listings will be 
prepared for patients receiving other study drugs and not ixazomib. Additional safety analyses by subgroups such as 
drug indication and baseline characteristics may be performed, as specified in the SAP. 
Sample Size Justification: There is no statistical hypothesis and no power considerations in this study.
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3.0
STUDY REFERENCE INFORMATION
3.1
Study-Related Responsibilities 
The sponsor will perform all study-related activities with the exception of those identified in the 
vendor contact information. The identified vendors in the template for specific study-related 
activities will perform these activities in full or in partnership with the sponsor.
3.2
List of Abbreviations
AE
adverse event
AL amyloidosis
systemic light-chain amyloidosis
ASCT
autologous stem cell transplant
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANC
absolute neutrophil count
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
BUN
blood urea nitrogen
BSA
body surface area
CO2
carbon dioxide
eCRF
case report form (electronic or paper)
CRO
contract research organization
CYP
cytochrome P-450
ECG
electrocardiogram
EOS
end of study
EOT
end of treatment
FAS
full analysis set
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GGT
-glutamyl transferase
ICH
International Conference on Harmonisation
IEC
independent ethics committee
IRB
institutional review board
IV
intravenous
IVRS
interactive voice response system
IWRS
interactive web response system
LDH
lactate dehydrogenase
LenDex
lenalidomide plus dexamethasone
MedDRA
Medical Dictionary for Regulatory Activities
MLN2238
research name for ixazomib, the biologically active boronic acid form of the drug 
substance
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MLN9708
research name for ixazomib citrate, the stable citrate ester of ixazomib
MM
multiple myeloma
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NDMM
newly diagnosed multiple myeloma 
RRAL amyloidosis
relapsed and/or refractory systemic light-chain amyloidosis 
RRMM
relapsed and/or refractory multiple myeloma
SAE
serious adverse event
SAP
statistical analysis plan
SmPC
Summary of Product Characteristics
SUSAR
suspected unexpected serious adverse reaction
US
United States
USPI
United States Prescribing Information
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4.0
INTRODUCTION
4.1
Background
Ixazomib is an investigational, oral, inhibitor of the 20S proteasome that has been studied for the 
treatment of multiple myeloma (MM), plasma cell dyscrasias, amyloidosis, lymphoma, 
nonhematologic malignancies, and lupus nephritis. Inhibition of the 20S proteasome has been 
validated as a therapeutic target for the treatment of malignancies using VELCADE® (bortezomib) 
for Injection, Takeda’s first-in-class proteasome inhibitor [2]. 
Oral ixazomib in combination with lenalidomide and dexamethasone was first approved by the 
United States (US) Food and Drug Administration (FDA) in November 2015 for the treatment of 
patients with MM who have received at least 1 prior therapy [3,4]. It has since been approved in 
over 65 countries globally.
Ixazomib (MLN2238) refers to the biologically active boronic acid form of the drug substance. 
The drug substance is administered as a stable citrate ester, designated as ixazomib citrate 
(MLN9708). Under physiological conditions, ixazomib citrate rapidly hydrolyzes to the 
biologically active boronic acid, ixazomib. Ixazomib is a peptide boronic acid that is structurally 
different from bortezomib.
Detailed information regarding the nonclinical pharmacology and toxicology of MLN9708 may be 
found in the ixazomib IB.
Phase 1, phase 1/2, and phase 2 trials have been conducted in MM, relapsed and/or refractory 
systemic light-chain amyloidosis (RRAL), solid tumors, and lymphoma. In addition, phase 1 
studies were conducted in patients with renal impairment who had relapsed and/or refractory 
multiple myeloma (RRMM) or advanced solid tumors (Study C16015), in patients with hepatic 
impairment who had advanced solid tumors or hematologic malignancies (Study C16018), and in 
an absorption, distribution, metabolism, and excretion study in patients with advanced solid 
tumors or lymphoma (Study C16016). Phase 3 trials in RRMM (C16010), newly diagnosed 
multiple myeloma (NDMM) (C16014), and RRAL (C16011) have additionally been completed. 
Phase 3 trials of ixazomib as maintenance therapy following autologous stem cell transplantation 
(C16019) or in patients who did not receive ASCT (C16021) are ongoing.
Ixazomib had been available as an IV and oral formulation (during the early development of 
ixazomib); however, only the oral formulation is currently being developed for commercialization. 
Regardless of the route of administration, in the twice-weekly dosing schedule, ixazomib is given 
on Days 1, 4, 8, and 11 of a 21-day cycle, and in the weekly dosing schedule, ixazomib 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 have been studied during the clinical development of 
ixazomib: RRMM, NDMM, RRAL, advanced solid tumors, advanced lymphoma, and pediatric 
acute lymphoblastic leukemia. Studies are investigating both single-agent ixazomib and ixazomib 
in combination with standard treatments. 
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Further details on these studies are provided in the ixazomib IB.
4.1.1
Risk: Benefit Assessment
4.1.1.1
Risks
The risks (identified and potential) have been assessed in clinical and nonclinical studies and are 
detailed in the current version of the IB. The emerging safety profile indicates that oral ixazomib is 
generally well tolerated and, while some potential toxicities may be severe, the predominant 
toxicities are largely reversible, able to be monitored by routine clinical examination, and 
manageable by dose reductions, discontinuation, or standard supportive care. It is possible that 
ixazomib will have toxicities that were not predicted from its evaluation in nonclinical studies or 
previously observed in ongoing clinical studies. To mitigate the inherent risks in clinical studies of 
ixazomib, patients are monitored closely for anticipated toxicities. Guidance for the management 
of adverse events (AEs) and procedures for reducing doses are provided (see Section 8.3 and 
Section 8.7), and drug dosage can be reduced either by decreasing the dose administered or by 
interruption of the scheduled treatment. Further information is provided in the IB.
Risks associated with ixazomib therapy have been identified from ongoing clinical studies as well 
as the registrational trial of ixazomib plus lenalidomide and dexamethasone in the treatment of 
patients with MM who have received at least 1 prior therapy (see the current IB and the United 
States Prescribing Information (USPI) for further information). These include blood and 
lymphatic system disorders (thrombocytopenia, neutropenia and anemia [all reversible]), 
gastrointestinal toxicities (diarrhea, nausea, vomiting, and constipation), general disorders 
(fatigue, peripheral edema, and pyrexia), metabolism and nutrition disorders (decreased appetite), 
nervous system disorders (dizziness, dysgeusia, peripheral neuropathy [generally Grades 1 or 2]), 
psychiatric disorders (insomnia), skin and subcutaneous tissue disorders (rash [very common], 
severe dermal events [rare]).
Refer to the current IB for the list of potential risks of ixazomib.
4.1.1.2
Benefits
Ixazomib in combination with lenalidomide and dexamethasone was approved by the US FDA in 
November 2015 for the treatment of patients with MM who have received at least 1 prior therapy 
[3,4]. The exploration of other therapeutic areas is ongoing. To date, activity in MM has been seen 
with single-agent ixazomib and with ixazomib combined with established therapies. In addition, 
single-agent activity has been observed in relapsed amyloidosis and indolent non-Hodgkin 
lymphoma. This study will provide continued access to ixazomib and/or other combinational study 
drugs from the designated ixazomib parent protocols when the patient has no other means to access 
study treatment. Qualified patients who have been deriving benefit in an ixazomib parent protocol 
will receive treatment in this study until they are transitioned to ixazomib/other therapy through 
commercial channels or until any of the other reasons for treatment discontinuation are met, 
whichever is sooner. Based on approval by the Takeda medical monitor every 24 months, 
continued access to ixazomib and/or other study drugs will be allowed for patients who in the 
investigator’s opinion are deriving clinical benefit.
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4.2
Rationale for the Proposed Study
The primary purpose of this rollover study is to continue to provide ixazomib and/or other 
combinational study drugs to patients who have previously received and tolerated treatment in an 
ixazomib parent study, and in the investigator’s opinion may benefit from continued therapy with 
1 or more of the drugs from the parent protocol (eg, patient demonstrates response to therapy or 
stable disease without evidence of disease progression). The study will also evaluate the long-term 
safety profile of ixazomib in those patients who continue to receive ixazomib. 
5.0
STUDY OBJECTIVES AND ENDPOINTS
5.1
Objectives
5.1.1
Primary Objectives
The primary objectives are:

To provide continued access to ixazomib and/or other study drugs from an ixazomib parent 
study.

To evaluate the long-term safety profile of ixazomib.
5.2
Endpoints
5.2.1
Primary Endpoint
The primary endpoint is safety of ixazomib, as assessed by the incidence of the following AEs:

All serious adverse events (SAEs).

All ≥Grade 3 AEs.

≥Grade 2 peripheral neuropathy.

New primary malignancies.

Any AE resulting in dose modification or discontinuation of any study drug.

Any other AE that in the opinion of the investigator is a clinically significant event.
6.0
STUDY DESIGN
6.1
Overview of Study Design
This is an open-label, multicenter, rollover study to provide continued access to ixazomib and/or 
other study drugs from a designated ixazomib parent study (ie, Studies C16003, C16005, C16006, 
C16007, C16008, C16010 Global, C16011, C16013, C16014 Global and Korean Continuation, 
C16017, C16020, C16029, and C16047) when the patient has no other means to access study 
treatment. The study will also evaluate the long-term safety profile of ixazomib in those patients 
who continue to receive ixazomib. The patient population will consist of patients who have 
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previously received and tolerated treatment in a Takeda-sponsored clinical study of ixazomib, and 
in the investigator’s opinion and approved by the Takeda medical monitor, may benefit from 
continued therapy with 1 or more of the drugs from a parent protocol (eg, patient demonstrates 
response to therapy or stable disease without evidence of disease progression). 
Patients may be enrolled provided they have not met any of the discontinuation criteria in their 
parent study. Patients will enter this study on the same ixazomib dose, schedule of study drug(s), 
and combination regimen that they were receiving at the time of rollover from the parent study, or 
according to the required dose modification from a parent study (Section 8.1). For those patients 
who received ixazomib dosing based on BSA per the parent study, the dose may be rounded. The 
dose may also be rounded for those patients who convert from BSA-based dosing to fixed dosing 
with approval from the Medical Monitor. No new anticancer agents can be started or added. Note 
that for patients whose study therapy in a parent study includes a placebo, the placebo capsule will 
be discontinued; crossover to ixazomib is not permitted.
Following enrollment, patients may receive study drug(s) until they experience disease 
progression, clinical deterioration in the investigator’s judgment, experience an unacceptable 
toxicity, withdraw consent, pursue an alternative therapy, meet other study-specified reasons for 
discontinuation of study drug, or until the patient is transitioned to ixazomib/other therapy through 
commercial channels. 
Patients participating in a designated ixazomib parent study will enter the rollover study at the 
time-point when they have completed the EOT visit in the parent study and when the rollover 
study is active at an investigative site. Following their provision of informed consent to receive 
treatment in the rollover study, patients will be provided with study medication. Patients should 
enter the study within 8 weeks of their last dose of ixazomib/other study drug(s) in the parent study 
or as agreed upon by the Takeda clinician/designee so to minimize any treatment disruption to the 
patient. Local safety-related laboratory evaluations and vital sign measurements will be performed 
according to the schedule of events as presented in this study and accordingly will only be 
recorded in the electronic case report forms (eCRF) prior to the first dose of study drug in the 
rollover study, at the end of study, and as spontaneously reported by the investigator. 
Electrocardiogram (ECG) assessments will only be performed as clinically indicated. During 
treatment, dosing modification decisions will be made per the parent study. For patients receiving 
ixazomib, systemic treatment with strong cytochrome P-450 (CYP)3A inducers (rifabutin, 
carbamazepine, phenytoin, phenobarbital), or use of St. John’s wort) is prohibited during the 
study. The procedures prohibited in the patient’s parent study are prohibited during this study. 
Prohibited medications due to co-administration of other agents in the ixazomib regimen are 
prohibited as per the prescribing information for the co-administered agent(s).
It is recommended that disease assessments are performed per standard of care. 
At the time of discontinuation of study drug(s) in this study, an end-of-study (EOS) visit will be 
scheduled and will occur prior to the initiation of any new therapy, or within 30 days of last dose of 
study drug administration, whichever is earlier. The reason for treatment discontinuation, an 
overall investigator assessment of best response obtained during this rollover study, and the 
investigator assessment of date of progression will be captured in the eCRFs.
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Toxicity will be evaluated according to National Cancer Institute Common Terminology Criteria
for Adverse Events (NCI CTCAE), Version 5.0, effective date 27 November 2017 [1]. 
The long-term safety and tolerability of ixazomib/other study drug(s) will be monitored. The 
following AEs will be reported from the first dose of study drug in this study through 30 days after 
administration of the last dose of study drug and recorded in the eCRFs and SAEs will also be 
reported directly to the Sponsor (see Section 10.2). The following AEs that are ongoing at the time 
of entry into the rollover study will be recorded in the eCRFs as baseline AEs.

All SAEs.

All ≥Grade 3 AEs. 

≥Grade 2 peripheral neuropathy.

New primary malignancies. 

Any AE resulting in dose modification or discontinuation of any study drug.

Any other AE that in the opinion of the investigator is a clinically significant event.
The above AEs will be followed until resolution, until the AE becomes chronic or stable, or is 
determined to be part of the underlying disease process, or until the patient attends the EOS visit 
and discontinues the study.
The transfer of patients between sites is allowed with the approval of the sponsor’s 
clinician/designee (eg, in the case of site closure, patient moving, etc).
6.2
Number of Patients
The estimated number of patients to be enrolled is approximately 250. The number of countries 
and sites is not currently specified as this study is open to all countries and sites with qualifying 
patients from prior company-sponsored ixazomib studies.
Enrollment is defined as when the patient receives the first dose of study drug in this rollover 
study.
6.3
Duration of Study
6.3.1
Duration of an Individual Patient’s Study Participation
The anticipated duration of treatment for an individual patient in this rollover study will be 
approximately 5 years. Based on approval by the Takeda medical monitor every 24 months, 
continued access to ixazomib and/or other study drugs will be allowed for patients who in the 
investigator’s opinion are deriving clinical benefit. Patients may remain in the rollover study until 
they are transitioned to ixazomib/other therapy through commercial channels or until any of the 
other reasons for treatment discontinuation are met, whichever is sooner.
Patients will be followed for 30 days after the last dose of study drug(s). 
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Ongoing AEs meeting the criteria in Section 10.2 will be followed until resolution, until the AE 
becomes chronic or stable or is determined to be part of the underlying disease process, or until the 
patient attends the EOS visit and discontinues the study. 
6.3.2
End of Study/Study Completion Definition and Planned Reporting
Primary Completion/Study Completion
The estimated time frame for study completion (first patient in to last patient last visit) is 
approximately 7 years.
The final analyses for the primary endpoint and single final clinical study report will be conducted 
following the end of the study.
6.3.3
Timeframe for Primary Endpoint to Support Disclosures
Please refer to Table 6.a for disclosures information for the primary endpoint.
Table 6.a
Primary Endpoint for Disclosures
Endpoint
Maximum Time Frame
Primary: 
The incidence of the following AEs:

All SAEs.

All ≥Grade 3 AEs. 

≥Grade 2 peripheral neuropathy.

New primary malignancies. 

Any AE resulting in dose modification or 
discontinuation of any study drug.

Any other AE that in the opinion of the investigator is a 
clinically significant event.
Approximately 5 years of treatment with study drug(s) 
for an individual patient in this study. Overall, 
assessment of the primary endpoint will be 
approximately 7 years after the first patient is enrolled 
in the study. 
AE=adverse event; SAE=serious adverse event.
6.3.4
Total Study Duration
It is anticipated that this study will last for approximately 7 years. 
7.0
STUDY POPULATION
7.1
Inclusion Criteria
Each patient must meet all of the following inclusion criteria to be enrolled in the study:
1. Voluntary written consent must be given before performance of any study-related procedure 
not part of standard medical care. Patients should consent and enter the study within a 
maximum of 8 weeks of their last dose of treatment in the parent study or as agreed by the 
Takeda clinician/designee.
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2. Previously treated with ixazomib, background therapy, and/or comparator drugs (including 
placebo) in a Takeda-sponsored ixazomib parent study. Patients will be eligible to enter the 
rollover study when:
a) The parent study is closed or planned to be closed; and
b) The patient is on ixazomib monotherapy, a combination regimen with ixazomib and other 
study medication(s), on a placebo combination, or on an alternative arm regimen in a 
designated ixazomib parent study (ie, Studies C16003, C16005, C16006, C16007, 
C16008, C16010 Global, C16011, C16013, C16014 Global and Korean Continuation, 
C16017, C16020, C16029, and C16047); and
c) In the opinion of the investigator and approved by the Takeda medical monitor, the patient 
may continue to benefit from treatment with ixazomib and/or another study 
drug/combination regimen (eg, response to therapy or stable disease without evidence of 
disease progression) and has no alternate means to access the study drug(s) 
(eg, commercial supply).
3. Agree to continue to practice contraceptive methods as outlined in the parent study. See 
Appendix D for acceptable methods of contraception. 
7.2
Exclusion Criteria
Patients meeting any of the following exclusion criteria are not to be enrolled in the study:
1. The patient meets any of the criteria for treatment discontinuation in the parent study.
2. Female patients who are lactating and breastfeeding or have a positive serum pregnancy test 
during the eligibility period.
8.0
STUDY DRUG
8.1
Study Drug Administration
All study-specific criteria for administration of study drug must be met and documented prior to 
drug administration. Study drug will be administered only to eligible patients under the 
supervision of the investigator or identified subinvestigator(s).
Ixazomib, as a single agent or in combination with other study drugs, will be administered 
according to the dose, schedule, and combination regimen the patient was receiving at the time of 
rollover from the parent study, or according to the required dose modification from a parent study. 
For those patients who received ixazomib based on BSA dosing per the parent study, the dose may 
be rounded. The dose may also be rounded for those patients who convert from BSA-based dosing 
to fixed dosing with approval from the Medical Monitor. No new anticancer agents can be started 
or added. Note that for patients whose study therapy in a parent study includes a placebo, the 
placebo capsule will be discontinued; crossover to ixazomib is not permitted. 
Patients will be given ixazomib as a single, oral dose on a 21- or 28-day cycle according to the 
parent protocol. Patients should be instructed to swallow ixazomib capsules whole with water and 
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to not break, chew, or open the capsules. Ixazomib should be taken on an empty stomach at least 
1 hour before or no sooner than 2 hours after a meal. Each capsule should be swallowed separately 
with a sip of water. A total of approximately 8 oz (240 mL) of water should be taken with the 
capsules. 
Missed doses can be taken as soon as the patient remembers if the next scheduled dose is 72 hours 
or more away. A double dose should not be taken to make up for a missed dose. If the patient 
vomits after taking a dose, the patient should not repeat the dose but should resume dosing at the 
time of the next scheduled dose.
8.2
Reference/Control Therapy 
Patients whose study treatment in a parent study includes a placebo will discontinue the placebo 
capsule when they enter this study. Other study medication(s)/alternative arm therapies 
administered during the parent protocol will be continued according to the dose, schedule, and 
regimen the patient was receiving at the time of rollover from the parent study, or according to the 
required dose modification from a parent study.
8.3
Dose Modification Guidelines
Toxicity will be evaluated according to NCI CTCAE, Version 5.0, effective date 27 November 
2017 [1]. 
Dose modifications for the management of AEs will be made according to the parent study. 
8.4
Excluded Concomitant Medications and Procedures
The following medications are prohibited during this study: 

For patients receiving ixazomib, systemic treatment with strong CYP3A inducers (rifampin, 
rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital), or use of St. John’s wort.
The procedures prohibited in the patient’s parent study are prohibited during this study. Prohibited 
medications due to co-administration of other agents are prohibited as per the prescribing 
information for the co-administered agent(s).
8.5
Permitted Concomitant Medications and Procedures 
All necessary supportive care consistent with optimal patient care shall be available to patients as 
needed.
8.6
Precautions and Restrictions
It is not known what effects ixazomib has on human pregnancy or development of the embryo or 
fetus. Pregnancy prevention measures as per the patient’s parent study should continue to be used.
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 and male patients should use effective methods of contraception through defined periods 
during and after study treatment as specified in the parent study.
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8.7
Management of Clinical Events 
8.7.1
Management of Ixazomib Clinical Events
Prophylaxis Against Risk of Reactivation of Herpes Infection
Patients may be at an increased risk of infection, including reactivation of herpes zoster and herpes 
simplex viruses. All patients continuing to receive ixazomib in this rollover study should receive 
prophylactic antiviral therapy. Patients receiving a non-ixazomib-containing regimen should be 
guided by the physician's clinical practice.
Nausea or Vomiting
Prophylaxis with standard antiemetics, including serotonin 5-hydroxytryptamine 3 receptor 
antagonists, is recommended for emesis. Any fluid deficit occurring during treatment should be 
promptly corrected. 
Diarrhea
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. Any fluid deficit occurring during treatment should be promptly corrected.
Erythematous Rash With or Without Pruritus
Rash may range from limited erythematous areas, macular 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 
predominantly 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 and self-limiting and is typically Grade 1 or 2 in 
severity. If rash occurs, consideration should be given to alternate causes of the rash such as 
concomitant medications, infections, etc; these other causative agents should be discontinued and 
alterative agents considered if medically necessary.
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 (eg, prednisone ≤ 10 mg per day or equivalent) is permitted. 
Management of a Grade 3 rash may require IV antihistamines or corticosteroids. Administration of 
ixazomib (and other causative agent if given in combination) should be modified and re-initiated at 
a reduced level from where rash was noted (per parent study). 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). 
The rare risks of Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN), drug reaction with 
eosinophilia and systemic symptoms (DRESS syndrome), and pemphigus vulgaris have been 
reported in oncology studies when ixazomib (or placebo) was given with concomitant medications 
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that are known to cause rash (eg, Bactrim, lenalidomide, aspirin), and/or in the setting of 
confounding treatment-emergent AEs. These severe, potentially life-threatening or deadly 
conditions may involve rash with skin peeling and mouth sores and should be clinically managed 
according to standard medical practice. Punch biopsies for histopathological analysis are 
encouraged at the discretion of the investigator. Study medications should be discontinued in the 
event of severe, potentially life-threatening rash. Additional information regarding these reactions 
can be found in the IB.
Thrombocytopenia
Blood counts should be monitored regularly according to standard clinical practice. 
Thrombocytopenia may be severe but has been manageable with platelet transfusions according to 
standard clinical practice. Ixazomib administration should be modified according to dose 
modification recommendations in the parent study when thrombocytopenia occurs. Therapy can 
be reinitiated at a reduced level upon recovery of platelet counts. Thrombotic microangiopathy 
(TMA), including thrombotic thrombocytopenia purpura and hemolytic uremic syndrome, are 
rare, serious blood disorders that cause low levels of platelets and red blood cells and result in 
blood clots in small blood vessels. Symptoms may include fatigue, fever, bruising, nose bleeds, 
and decreased urination. These disorders, including fatal cases, have been reported in patients 
receiving ixazomib. If TMA is suspected, consider withdrawal of the suspected causative agent 
and manage according to standard medical practice.
Neutropenia
Blood counts should be monitored regularly with additional testing, as appropriate, according to 
standard clinical practice. Neutropenia may be severe but has been manageable. Growth factor 
support is not required but may be considered according to standard clinical practice. Ixazomib 
administration should be modified according to dose modification recommendations in the parent 
study when neutropenia occurs. Therapy can be reinitiated at a reduced level upon recovery of 
absolute neutrophil count (ANC). 
Fluid Deficit
Dehydration should be avoided because ixazomib may cause vomiting, diarrhea, and dehydration. 
Acute renal failure has been reported in patients treated with ixazomib, commonly in the setting of 
the previously noted gastrointestinal toxicities and dehydration.
Fluid deficit should be promptly corrected before administration of study drug and as needed 
during treatment to avoid dehydration.
Hypotension
Symptomatic hypotension and orthostatic hypotension with or without syncope have been 
reported with ixazomib. Blood pressure should be closely monitored as per standard of care 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 decreased appetite. 
Patients taking medications or diuretics to manage their blood pressure (for either hypotension or 
hypertension) should be managed according to standard clinical practice, including considerations 
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for dose adjustments of their concomitant medications during the course of the trial. Fluid deficit 
should be corrected before administration of study drug and as needed during treatment to avoid 
dehydration.
Posterior Reversible Encephalopathy Syndrome
Posterior reversible encephalopathy syndrome, which ultimately resolved, has been reported with 
ixazomib. This condition is usually transient and reversible. It is characterized by headache, 
seizures, and visual loss, and abrupt increase in blood pressure. Diagnosis may be confirmed by 
magnetic resonance imaging or computed tomography. 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.
Transverse Myelitis
Transverse myelitis has been reported with ixazomib. It is not known whether ixazomib causes 
transverse myelitis; however, because transverse myelitis happened to a patient receiving 
ixazomib, the possibility that ixazomib may have contributed to the transverse myelitis cannot be 
excluded. Transverse myelitis should be managed according to standard medical practice.
Overdose
An overdose is defined as a known deliberate or accidental administration of investigational drug, 
to or by a study subject, at a dose above that which is assigned to that individual subject according 
to the study protocol. Overdose has been reported in patients taking ixazomib. Symptoms of 
overdose are generally consistent with the known risks of ixazomib. Reports of accidental 
overdose have been associated with serious adverse events, such as nausea, lung infections 
including aspiration pneumonia, multiple organ failure, and death. If overdose occurs, consider 
close observation including hospitalization for hemodynamic support. Gastric lavage may be 
considered if instituted within 1 hour of ingestion of ixazomib overdose.
AEs associated with an overdose will be documented on AE eCRF according to Section 10.0, 
Adverse Events. SAEs associated with overdose should be reported according to the procedure 
outlined in Section 10.2, Collection and Reporting of SAEs.
8.7.2
Management of Combination Therapy Clinical Events
For each medication(s) used as combination therapy with or without ixazomib, please refer to the 
prescribing information and details in the parent protocol for the applicable management of 
clinical events. 
8.8
Blinding and Unblinding
This is an open-label study.
8.9
Description of Investigational Agents
The ixazomib capsule formulation consists of the drug substance (ixazomib citrate), 
microcrystalline cellulose, talc, and magnesium stearate. There are 7 capsule strengths: 0.2, 0.5, 
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2.0, 2.3, 3.0, 4.0, and 5.5 mg. Each strength is differentiated by a unique capsule size and color. 
Dosage strength is stated as ixazomib. Ixazomib capsules are individually packaged in blisters.
For additional details, please see the ixazomib IB and Pharmacy Manual.
8.10
Preparation, Reconstitution, and Dispensation
The 0.2, 0.5, and 2.0 mg ixazomib capsules (B1 formulation) are supplied in 1×4 blister strips that 
are individually perforated. The strips are placed in cartons containing 6 strips (24 total capsules) 
of the same strength. 
The 2.3, 3.0, 4.0, and 5.5 mg ixazomib capsules (B2 formulation) are individually packaged using 
cold form foil-foil blisters that are in a child-resistant carton. There are 3 capsules (of exact 
strength) in each carton. 
8.11
Packaging and Labeling
Ixazomib study drug will be provided by Takeda. The study drug labels will fulfill all requirements 
specified by governing regulations. 
8.12
Storage, Handling, and Accountability
On receipt at the investigative site, ixazomib should remain in the blister pack and carton provided 
until use or dispensation. The container should be stored as directed by the label on the packaging. 
All excursions should immediately be brought to the sponsor’s attention for assessment and 
authorization for continued use. Ensure that the drug is used before the retest expiry date provided 
by Takeda. Expiry extensions will be communicated accordingly with updated documentation to 
support the extended shelf life.
Ixazomib dispensed to the patient for take-home dosing should remain in the blister packaging and 
carton and stored as directed by the label on the packaging as noted previously until the point of 
use. Patients who are receiving take-home medication should be given a supply of study drug as 
per the parent study schedule or for up to 3 cycles at the discretion of the investigator. (Note: 
Patients in France are only permitted to receive 1 cycle of medication at a time). In case of the 
COVID-19 pandemic preventing a patient from attending the study site, sites may use alternative 
strategies to deliver study drug to patients (eg, via courier or site staff), per local standard practice 
and regulations and with prior approval from the investigator and the sponsor’s project 
clinician/designee. Comprehensive instructions should be provided to the patient to ensure 
compliance with, and understanding of, dosing procedures and to avoid the potential for incorrect 
self-administration or overdose of medication. 
Patients should be instructed to store the medication as directed by the label on the packaging. 
Patients should be instructed to return their empty or partially used cartons to the investigative site 
at their next visit, rather than discarding them, as permitted by site policy. Reconciliation will 
occur accordingly when the patient returns at their next visit for take-home medication. In case of 
the COVID-19 pandemic preventing a patient from attending the study site, drug packs and dosing 
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diaries should be returned at the next available on-site clinic visit. Any excursions in temperature 
should be reported and dealt with on a case-by-case basis. 
Ixazomib is an anticancer drug and, as with other potentially toxic compounds, caution should be 
exercised when handling the study drug. 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 clean-up and during 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 (eg, from a broken capsule), skin should be washed 
immediately with soap and copious amounts of water for at least 15 minutes. In case of contact 
with the eyes, copious amounts of water should be used to flush the eyes for at least 15 minutes. 
Medical personnel should be notified.
Patients are to be instructed on proper storage, accountability, and administration of ixazomib, 
including that study drug is to be taken as intact capsules.
Please refer to the Pharmacy Manual for this study for additional instructions.
8.13
Combination Therapy
Patients who entered the study receiving a combination therapy with ixazomib or with other study 
medications will continue to receive the combination regimen.
The medication(s) used in combination with ixazomib or the control arm treatments may be 
site-sourced from commercial supply with commercial packaging and labeling when arrangements 
have been made and agreed to by Takeda and the clinical site and when regulations allow for 
clinical site sourcing, appropriate labeling, and compliance with local and regional regulations. 
The medication(s) may be provided by the sponsor if the site is unable to obtain these drugs from 
commercial sources. 
Additional details are provided in the package insert (PI) /summary of product characteristics 
(SmPC) for the applicable medication(s) used in the parent study. 
8.14
Other Protocol-Specified Materials
No other drugs or ancillary material are supplied for use in this study.
9.0
STUDY CONDUCT
This trial will be conducted in compliance with the protocol, Good Clinical Practice (GCP), 
applicable regulatory requirements, and International Conference on Harmonisation (ICH) 
guidelines.
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9.1
Study Personnel and Organizations
The contact information for the Medical Monitor for this study, and any additional clinical 
laboratories, the coordinating investigator for each member state/country, and other vendors as 
necessary, such as the interactive voice response system (IVRS)/interactive web response system 
(IWRS) provider, and the contract research organization (CRO) team may be found in the Study 
Manual. A full list of investigators is available in the sponsor’s investigator database.
9.2
Arrangements for Recruitment of Patients
Patients will only be considered for this study if they were enrolled in 1 of the parent studies. The 
transfer of patients between sites is allowed with the approval of the sponsor’s clinician/designee 
(eg, in the case of site closure, patient moving, etc). No additional recruitment activity is needed.
9.3
Treatment Group Assignments
Patients will enter this study on the same dose, schedule of study drug(s), and combination 
regimen that they were receiving at the time of rollover from the parent study (Section 8.1), or 
according to the required dose modification from a parent study. For those patients who received 
ixazomib based on BSA dosing per the parent study, the dose may be rounded. The dose may also 
be rounded for those patients who convert from BSA-based dosing to fixed dosing with approval 
from the Medical Monitor. No new anticancer agents can be started or added. Note that for patients 
whose study therapy in a parent study includes a placebo, the placebo capsule will be discontinued; 
crossover to ixazomib is not permitted.
9.4
Study Procedures
In acknowledgement of hospital, local, state or national government restrictions, or other 
site-related factors caused by the COVID-19 pandemic that may prevent investigators from 
conducting the study according to the Schedule of Events at the clinical study site, investigators 
may continue patients in the study despite departure from the Schedule of Events. Investigators are 
expected to evaluate the impact to the safety of the study participants and site personnel for 
patients to continue. In evaluating such requests, the investigator/study site staff will give the 
highest priority to the safety and welfare of the patients. Patients must be willing and able to 
continue taking study medication and remain compliant with the protocol. For patients that are 
impacted by the COVID-19 pandemic, any procedures not conducted per the study protocol will 
be documented in the eCRF. 
Alternative methods should be considered for performing the assessments by other means than the 
patient presenting to the clinic (eg, remote assessment, having lab assessment performed at a 
facility closer to the patient’s home, etc.) If a patient misses an in-person study visit, the 
investigator/study team staff will speak directly with the patient by telephone or other medium (eg, 
a computer-based video communication) during each visit window to assess subject safety and 
overall clinical status. During this contact with the patient, the study site physician or other 
qualified site staff should at minimum conduct AE collection and an assessment of clinical 
symptoms. Other study assessments may be collected remotely as is feasible and may involve 
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audio or video recording. Assessments/procedures that cannot be completed during the 
protocol-specified window because a site visit is done remotely (eg, hematology, clinical 
chemistry, concomitant medications/procedures) are waived. 
Refer to the Schedule of Events (Appendix A) for timing of assessments. Procedures performed at 
the end of treatment (EOT)/EOS in the patient’s parent study and collected in the eCRFs within 
28 days of the study entry/Day 1 visit do not need to be repeated. 
Additional details are provided as necessary in the sections that follow.
9.4.1
Informed Consent
Each patient must provide written informed consent before any study-required procedures are 
conducted, unless those procedures are performed as part of the patient’s standard care.
Patients previously enrolled in this study who remain on study treatment upon implementation of 
Amendment 3 may need to be reconsented, according to IRB/IEC standards. Reconsenting should 
be done in person, where possible. Remote reconsenting is permitted as long as the process adheres 
to site, IRB/IEC, and GCP standards and local regulations.
9.4.2
Vital Signs
Vital sign measurements include measurements of diastolic and systolic blood pressure and heart 
rate.
9.4.3
Weight
Weight will be measured at the Study Entry/ Day 1 visit and at the EOS visit.
9.4.4
Pregnancy Test
A serum pregnancy test will be performed for women of childbearing potential at the Study Entry/ 
Day 1 visit before the first dose of study drug and at the EOS visit. The serum pregnancy test may 
be completed within 28 days of the Study Entry/Day 1 Visit. The results must be available and 
negative before the study drug regimen is administered. Pregnancy tests may also be repeated 
during the study if requested by an independent ethics committee (IEC)/institutional review board 
(IRB) or if required by local regulations or the prescribing information for any medication(s) used 
as combination therapy with ixazomib.
Pregnancy prevention measures as per the parent study should continue to be used.
9.4.5
Concomitant Medications and Procedures
Only concomitant medications and therapeutic procedures related to the treatment of AEs that are 
reported in the study eCRFs (see Section 10.2) will be recorded in the eCRFs as specified in the 
Schedule of Events Appendix A. See Section 8.4 and Section 8.5 for a list of medications and 
therapies that are prohibited and/or allowed during the study.
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9.4.6
Adverse Events
Monitoring of AEs, serious and nonserious, will be conducted throughout the study as specified in 
the Schedule of Events Appendix A. Refer to Section 10.0 for details regarding definitions, 
documentation, and reporting of AEs and SAEs.
SAEs, ≥Grade 3 AEs, ≥Grade 2 peripheral neuropathy, new primary malignancies, any AE 
resulting in dose modification or discontinuation of any study drug, or any other AE that in the 
opinion of the investigator is a clinically significant event will be recorded in the eCRFs and SAEs 
will also be reported directly to the sponsor (see Section 10.2). The AEs meeting the definitions 
above that are ongoing at the time of entry into the rollover study will be recorded in the eCRFs as 
baseline AEs.
9.4.7
Enrollment
A patient is considered to be enrolled in the study when he/she has received the first dose of study 
drug in this rollover study.
Procedures for completion of the enrollment information are described in the Study Manual.
9.4.8
Clinical Laboratory Evaluations
Clinical laboratory evaluations will be performed locally. Local laboratory normal ranges will be 
entered in the eCRFs.
9.4.8.1
Clinical Chemistry, Hematology, and Urinalysis
Blood samples for analysis of the clinical chemistry and hematological parameters shown in 
Table 9.a will be obtained and recorded in the eCRFs as specified in the Schedule of Events 
Appendix A.
Table 9.a
Clinical Chemistry and Hematology Tests
Hematology
Serum Chemistry
Hematocrit
Hemoglobin
Leukocytes with differential
Neutrophils ANC
Platelet (count)
Albumin
Alkaline phosphatase (ALP)
Alanine aminotransferase (ALT)
Aspartate aminotransferase (AST)
Bilirubin (total)
Blood urea nitrogen (BUN)
Calcium
Carbon dioxide (CO2)a
Creatinine
Chloride
Gamma glutamyl transferase (GGT)
Glucose
Lactate dehydrogenase (LDH)
Magnesium
Phosphate
Potassium
Sodium
Urate
aIf CO2 is not done as a part of standard care in the participant’s region, then this test does not need to be performed.
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9.4.9
Disease Assessment
It is recommended that disease assessments are performed per standard of care. An overall 
investigator assessment of best response obtained during this rollover study and the investigator 
assessment of date of progression will be recorded in the eCRF at the EOS visit.
9.5
Completion of Study (for Individual Patients)
Patients will be considered to have completed the study if they are discontinued from study 
treatment for any reason.
9.6
Withdrawal of Patients From Study
A patient will be withdrawn from the study for any of the following reasons:

Progressive disease (as defined in the patient’s parent study). 

Pregnancy.

Transition to commercial supply of study drug(s).

Study terminated by sponsor.

Withdrawal by subject.

Lost to follow-up.

Death.
A patient may also be withdrawn from the study for any of the following reasons:

Adverse event.

Protocol deviation. 

Clinical deterioration, in the investigator’s opinion.

Investigator’s decision.

Other.
The consequence of study withdrawal is that no new information will be collected from the 
withdrawn patient and added to the existing data or any database.
9.7
Study Compliance
Study drug will be administered or dispensed only to eligible patients under the supervision of the 
investigator or identified subinvestigator(s). The appropriate study personnel will maintain records 
of study drug receipt and dispensing.
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10.0
ADVERSE EVENTS
10.1
Definitions
10.1.1
Adverse Event Definition
AE means any untoward medical occurrence in a patient or subject administered a pharmaceutical 
product; the untoward medical occurrence does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product whether or not it is related to the medicinal product. This includes any 
newly occurring event, or a previous condition that has increased in severity or frequency since the 
administration of study drug.
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.
10.1.2
Serious Adverse Event Definition
SAE means any untoward medical occurrence that at any dose:

Results in death.

Is life-threatening (refers to an AE in which the patient was at risk of death at the time of the 
event. It does not refer to an event which hypothetically might have caused death if it were 
more severe).

Requires inpatient hospitalization or prolongation of an existing hospitalization (see 
clarification in the paragraph in Section 10.2 on planned hospitalizations).

Results in persistent or significant disability or incapacity. (Disability is defined as a 
substantial disruption of a person’s ability to conduct normal life functions).

Is a congenital anomaly/birth defect.

Is a medically important event. This refers to an AE that may not result in death, be 
immediately life threatening, or require hospitalization, but may be considered serious when, 
based on appropriate medical judgment, may jeopardize the patient, require medical or 
surgical intervention to prevent 1 of the outcomes listed above, or involves suspected 
transmission via a medicinal product of an infectious agent. Examples of such medical events 
include allergic bronchospasm requiring intensive treatment in an emergency room or at home, 
blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse; any organism, virus, or infectious particle 
(eg, prion protein transmitting transmissible spongiform encephalopathy), pathogenic or 
nonpathogenic, is considered an infectious agent.
In this study, intensity for each AE, including any lab abnormality, will be determined using the 
NCI CTCAE, Version 5.0, effective date 27 November 2017 [1]. Clarification should be made 
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between an SAE and an AE that is considered severe in intensity (Grade 3 or 4), because the terms 
serious and severe are NOT synonymous. The general term severe is often used to describe the 
intensity (severity) of a specific event; the event itself, however, may be of relatively minor 
medical significance (such as a Grade 3 headache). This is NOT the same as serious, which is 
based on patient/event outcome or action criteria described above, and is usually associated with 
events that pose a threat to a patient’s life or ability to function. A severe AE (Grade 3 or 4) does 
not necessarily need to be considered serious. For example, a white blood cell count of 1000/mm3
to less than 2000 is considered Grade 3 (severe) but may not be considered serious. Seriousness 
(not intensity) serves as a guide for defining regulatory reporting obligations.
10.2
Procedures for Recording and Reporting Adverse Events and Serious 
Adverse Events
The following AEs 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 will be recorded on the appropriate page of the eCRF (see Section 10.3 for the period 
of observation). 

All SAEs (see Section 10.1.2).

All ≥Grade 3 AEs (see Section 10.1.2).

≥Grade 2 peripheral neuropathy.

New primary malignancies. 

Any AE resulting in dose modification or discontinuation of any study drug.

Any other AE that in the opinion of the investigator is a clinically significant event. 
Any clinically relevant deterioration in laboratory assessments or other clinical finding is 
considered an AE, but should only be recorded in eCRF if meeting any of the above criteria. When 
possible, signs and symptoms indicating a common underlying pathology should be noted as 1 
comprehensive event.
Regardless of causality, SAEs (as defined in Section 10.1) must be reported (see Section 10.3 for 
the period of observation) by the investigator to the Takeda Global Pharmacovigilance department 
or designee (contact information provided below). This should be done by faxing the SAE Form 
within 24 hours after becoming aware of the event. The SAE Form, created specifically by Takeda, 
will be provided to each clinical study site. A sample of the SAE Form may be found in the Study 
Manual. Follow-up information on the SAE may be requested by Takeda. SAE report information 
must be consistent with the data provided on the eCRF.
The paper SAE forms must be submitted via fax (see fax numbers below) within 24 hours of 
awareness. In case of fax, site personnel must confirm successful transmission of all pages and 
include an e-mail address on the fax cover sheet so that an acknowledgment of receipt can be 
returned via e-mail within 1 business day. E-mail submission of paper SAE forms with a PDF 
attachment should only be used in the case where fax is not possible within 24 hours of receiving 
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the event. In case of e-mail, site personnel must confirm successful transmission by awaiting an 
acknowledgment of the receipt via e-mail within 1 business day. If SAEs are reported via fax or by 
e-mail, the EDC application must be updated as soon as possible with the appropriate information.
SAE Reporting Contact Information
Cognizant
US and Canada
Toll-Free Fax #: 1-800-963-6290
E-mail: takedaoncocases@cognizant.com
All Other Countries (Rest of World)
Fax #: 1-202-315-3560
E-mail: takedaoncocases@cognizant.com
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 (eg, surgery was performed earlier or later than planned).
For both serious and nonserious AEs, the investigator must determine both the severity (toxicity 
grade) of the event and the relationship of the event to study drug administration. 
Severity (toxicity grade) for each AE, including any laboratory abnormality, will be determined 
using the NCI CTCAE, Version 5.0, effective date 27 November 2017 [1]. The criteria are 
provided in the Study Manual.
Relationship of the event to study drug administration (ie, its causality) will be determined by the 
investigator responding yes (related) or no (unrelated) to this question: “Is there a reasonable 
possibility that the AE is associated with the study drug?”
10.3
Monitoring of Adverse Events and Period of Observation
AEs meeting the criteria in Section 10.2 must be reported to the sponsor as follows:

AEs will be reported from the first dose of study drug for this study through 30 days after 
administration of the last dose of study drug and recorded in the eCRFs. AEs meeting the 
criteria in Section 10.2 that are ongoing at the time of entry into the rollover study will be 
recorded in the eCRFs as baseline AEs.

AEs meeting the criteria in Section 10.2 will be followed until resolution, until the AE 
becomes chronic or stable, or is determined to be part of the underlying disease process, or 
until the patient attends the EOS visit and discontinues the study. 
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
SAEs
–
Related and unrelated treatment-emergent SAEs will be reported to the Takeda Global 
Pharmacovigilance department or designee from the first dose of study drug through 
30 days after administration of the last dose of study drug and recorded in the eCRF. After 
this period, only related SAEs must be reported to the Takeda Global Pharmacovigilance 
department or designee. 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).
10.4
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events
If a woman becomes pregnant or suspects that she is pregnant while participating in this study, she 
must inform the investigator immediately and permanently discontinue study drug. The sponsor 
must also be contacted immediately by faxing a completed Pregnancy Form to the Takeda Global 
Pharmacovigilance department or designee (see Section 10.2). The pregnancy must be followed 
for the final pregnancy outcome.
If a female partner of a male patient becomes pregnant during the male patient’s participation in 
this study, the sponsor must also be contacted immediately by faxing a completed Pregnancy Form 
to the Takeda Global Pharmacovigilance department or designee (see Section 10.2). Every effort 
should be made to follow the pregnancy for the final pregnancy outcome.
10.5
Procedures for Reporting Product Complaints or Medication Errors (Including 
Overdose)
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 report to: 
ctmcomplaint@takeda.com.
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 Cognizant (refer to Section 10.2).
A medication error is a preventable event that involves an identifiable patient and that leads to 
inappropriate medication use, which may result in patient harm. Whereas overdoses and 
underdoses constitute medication errors, doses missed inadvertently by a patient do not. 
Individuals who identify a potential medication error (including overdose) situation should 
immediately report this to Cognizant (refer to Section 10.2). 
10.6
Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities
The sponsor will be responsible for reporting all suspected unexpected serious adverse reactions 
(SUSARs) and any other applicable SAEs to regulatory authorities, including the European 
Medicines Agency, investigators and IRBs or IECs, as applicable, in accordance with national 
regulations in the countries where the study is conducted. Relative to the first awareness of the 
event by/or further provision to the sponsor or sponsor’s designee, SUSARs will be submitted to 
the regulatory authorities as an expedited report within 7 days for fatal and life-threatening events 
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and 15 days for other serious events, unless otherwise required by national regulations. The 
sponsor will also prepare an expedited report for other safety issues where these might materially 
alter the current benefit-risk assessment of an investigational medicinal product or that would be 
sufficient to consider changes in the investigational medicinal product’s administration or in the 
overall conduct of the trial. The investigational site also will forward a copy of all expedited 
reports to his or her IRB or IEC in accordance with national regulations. 
11.0
STUDY-SPECIFIC COMMITTEES
No steering committee, data safety monitoring committee, or clinical endpoint committee will be 
used in this study.
12.0
DATA HANDLING AND RECORDKEEPING 
The full details of procedures for data handling will be documented in the Data Management Plan. 
If selected for coding, AEs and concurrent conditions will be coded using the Medical Dictionary 
for Regulatory Activities (MedDRA). Drugs will be coded using the World Health Organization 
(WHO) Drug Dictionary.
12.1
eCRFs
Completed eCRFs are required for each subject who signs an informed consent form.
The sponsor or its designee will supply investigative sites with access to eCRFs and will make 
arrangements to train appropriate site staff in the use of the eCRF. These forms are used to transmit 
the information collected in the performance of this study to the sponsor, CRO partners, and 
regulatory authorities. Investigative sites must complete eCRFs in English.
After completion of the entry process, computer logic checks will be run to identify items, such as 
inconsistent dates, missing data, and questionable values. Queries may be issued by Takeda 
personnel (or designees) and will be answered by the site.
Any change of, modification of, or addition to the data on the eCRFs should be made by the 
investigator or appropriate site personnel. Corrections to eCRFs are recorded in an audit trail that 
captures the old information, the new information, identification of the person making the 
correction, the date the correction was made, and the reason for change.
The principal investigator must review the eCRFs for completeness and accuracy and must sign 
and date the appropriate eCRFs as indicated. Furthermore, the principal investigator must retain 
full responsibility for the accuracy and authenticity of all data entered on the eCRFs.
eCRFs will be reviewed for completeness and acceptability at the study site during periodic visits 
by study monitors. The sponsor or its designee will be permitted to review the subject’s medical 
and hospital records pertinent to the study to ensure accuracy of the eCRFs. The completed eCRFs 
are the sole property of the sponsor and should not be made available in any form to third parties, 
except for authorized representatives of appropriate governmental health or regulatory authorities, 
without written permission of the sponsor.
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12.2
Record Retention
The investigator agrees to keep the records stipulated in Section 12.1 and those documents that 
include (but are not limited to) the study-specific documents, the identification log of all 
participating subjects, medical records, temporary media such as thermal sensitive paper, source 
worksheets, all original signed and dated informed consent forms, subject authorization forms 
regarding the use of personal health information (if separate from the informed consent forms), 
electronic copy of eCRFs, including the audit trail, and detailed records of drug disposition to 
enable evaluations or audits from regulatory authorities, the sponsor or its designees. Any source 
documentation printed on degradable thermal sensitive paper should be photocopied by the site 
and filed with the original in the subject’s chart to ensure long term legibility. Furthermore, ICH 
E6 Section 4.9.5 requires the investigator to retain essential documents specified in ICH E6 
(Section 8) until at least 2 years after the last approval of a marketing application for a specified 
drug indication being investigated or, if an application is not approved, until at least 2 years after 
the investigation is discontinued and regulatory authorities are notified. In addition, ICH E6 
Section 4.9.5 states that the study records should be retained until an amount of time specified by 
applicable regulatory requirements or for a time specified in the Clinical Study Site Agreement 
between the investigator and sponsor.
Refer to the Clinical Study Site Agreement for the sponsor’s requirements on record retention. The 
investigator should contact and receive written approval from the sponsor before disposing of any 
such documents.
13.0
STATISTICAL METHODS
13.1
Statistical and Analytical Plans
A statistical analysis plan (SAP) will be prepared and finalized prior to database lock. This 
document will provide further details regarding the definition of analysis variables and analysis 
methodology to address all study objectives.
A data review will be conducted prior to database lock. This review will assess the accuracy and 
completeness of the study database, subject evaluability, and appropriateness of the planned 
statistical methods.
13.1.1
Analysis Sets
The full analysis set (FAS) will included all enrolled patients who receive at least 1 dose of study 
medication and will be used for the safety analyses.
13.1.2
Efficacy Analysis
No efficacy analyses are planned for this study as there is no statistical hypothesis testing.
The overall investigator assessment of best response obtained during this rollover study and 
investigator assessment of date of progression will be listed.
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13.1.3
Safety Analysis
The following AEs will be summarized with descriptive statistics for all patients who receive at 
least 1 dose of ixazomib using the FAS: 

All SAEs.

All ≥Grade 3 AEs. 

≥Grade 2 peripheral neuropathy.

New primary malignancies. 

Any AE resulting in dose modification or discontinuation of any study drug.

Any other AE that in the opinion of the investigator is a clinically significant event. 
No formal statistical testing or inferential statistics will be generated.
All AEs will be coded using the current MedDRA version at the time of the analysis. Data will be 
summarized using preferred term and primary system organ class. Local laboratory assessment 
changes and vital sign changes from study entry to end of study will also be summarized.
Exposure to study drug and study regimen will be tabulated. In addition, reasons for drug 
discontinuation will be summarized. 
Concomitant medications and procedures related to treatment of AEs from screening through the 
end of study will be classified by generic terms according to the WHO drug dictionary. 
Data will be presented by the entire ixazomib safety population, by population of monotherapy of 
ixazomib, and by population of ixazomib in combination with other anticancer agents(s) as 
specified in the SAP. Safety listings will be prepared for patients receiving other study drugs and 
not ixazomib. Additional safety analyses by subgroups such as drug indication and baseline 
characteristics may be performed as specified in the SAP. 
13.2
Interim Analysis and Criteria for Early Termination
No interim analysis is planned.
13.3
Determination of Sample Size
There is no statistical hypothesis and no power considerations in this study. The number of patients 
will be determined as discussed in Section 6.2.
14.0
QUALITY CONTROL AND QUALITY ASSURANCE
14.1
Study-Site Monitoring Visits
The study site will be monitored remotely by the CRO periodically during the study to ensure that 
all aspects of the protocol are followed. Monitoring will include electronic data collection, which 
has a set of automatic data checks with data queries for programmed data collection. There will be 
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monitoring of study site by telephone and email to ensure that the drug supplies have been 
provided to the site and patients and that protocol instructions are well understood and applied.
Monitoring visits to the study site will also be made periodically during the study to ensure that all 
aspects of the protocol are followed. Source documents will be reviewed for verification of data 
recorded on the eCRFs. Source documents are defined as original documents, data, and records. 
The investigator and institution guarantee access to source documents by the sponsor or its 
designee (CRO) and by the IRB or IEC.
All aspects of the study and its documentation will be subject to review by the sponsor or designee, 
including but not limited to the Investigator’s Binder, study medication, subject medical records, 
informed consent documentation, documentation of subject authorization to use personal 
information (if separate from the informed consent forms), and review of eCRFs and associated 
source documents. It is important that the investigator and other study personnel are available 
during the monitoring visits and that sufficient time is devoted to the process. 
In the event a monitor cannot visit the site in a timely manner due to the COVID-19 pandemic, 
alternative monitoring approaches such as remote source data verification (SDV) or telephone 
contact may be used to ensure data quality and integrity and maintain patient safety. Alternative 
monitoring approaches should be used only where allowed by the local Health Authority and 
permitted by the IRB/IEC.
14.2
Protocol Deviations
The investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to study subjects. Should other unexpected circumstances arise that will require 
deviation from protocol-specified procedures, the investigator should consult with the sponsor or 
designee (and IRB or IEC, as required) to determine the appropriate course of action. There will be 
no exemptions (a prospectively approved deviation) from the inclusion or exclusion criteria.
The site should document all protocol deviations in the subject’s source documents. In the event of 
a significant deviation, the site should notify the sponsor or its designee (and IRB or EC, as 
required). Significant deviations include, but are not limited to, those that involve fraud or 
misconduct, increase the health risk to the subject, or confound interpretation of primary study 
assessment. A Protocol Deviation Form or equivalent form should be completed by the site and 
signed by the sponsor or designee for any significant deviation from the protocol.
14.3
Quality Assurance Audits and Regulatory Agency Inspections
The study site also may be subject to quality assurance audits by the sponsor or designees. The 
investigator agrees to provide access to records, facilities, and personnel for conduct of any 
inspection or audit. If a quality assurance audit is requested, the sponsor-designated auditor will 
contact the site in advance to arrange an auditing visit. The auditor may ask to visit the facilities 
where laboratory samples are collected, where the medication is stored and prepared, and any 
other facility used during the study. In addition, there is the possibility that this study may be 
inspected by regulatory agencies, including those of foreign governments (eg, the FDA, the United 
Kingdom Medicines and Healthcare products Regulatory Agency, the Pharmaceuticals and 
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Medical Devices Agency of Japan). If the study site is contacted for an inspection by a regulatory 
body, the sponsor should be notified immediately. The investigator and institution guarantee 
access for quality assurance auditors to all study documents as described in Section 14.1.
15.0
ETHICAL ASPECTS OF THE STUDY
This study will be conducted with the highest respect for the individual participants (ie, subjects) 
according to the protocol, the ethical principles that have their origin in the Declaration of 
Helsinki, and the ICH Harmonised Tripartite Guideline for GCP. Each investigator will conduct 
the study according to applicable local or regional regulatory requirements and align his or her 
conduct in accordance with the “Responsibilities of the Investigator” that are listed in Appendix B. 
The principles of Helsinki are addressed through the protocol and through appendices containing 
requirements for informed consent and investigator responsibilities.
15.1
IRB and/or IEC Approval
IRBs and IECs must be constituted according to the applicable state and federal/local requirements 
of each participating region. The sponsor or designee will require documentation noting all names 
and titles of members who make up the respective IRB or IEC. If any member of the IRB or IEC 
has direct participation in this study, written notification regarding his or her abstinence from 
voting must also be obtained. Those American sites unwilling to provide names and titles of all 
members due to privacy and conflict of interest concerns should instead provide a Federal Wide 
Assurance Number or comparable number assigned by the Department of Health and Human 
Services.
The sponsor or designee will supply relevant documents for submission to the respective IRB or 
IEC for the protocol’s review and approval. This protocol, the Investigator’s Brochure, a copy of 
the informed consent form, and, if applicable, subject recruitment materials and/or advertisements 
and other documents required by all applicable laws and regulations, must be submitted to a 
central or local IRB or IEC for approval. The IRB’s or IEC’s written approval of the protocol and 
subject informed consent must be obtained and submitted to the sponsor or designee before 
commencement of the study (ie, before shipment of the sponsor-supplied drug or study specific 
screening activity). The IRB or IEC approval must refer to the study by exact protocol title, 
number, and version date; identify versions of other documents (eg, informed consent form) 
reviewed; and state the approval date. The sponsor will ship drug/notify site once the sponsor has 
confirmed the adequacy of site regulatory documentation and, when applicable, the sponsor has 
received permission from competent authority to begin the trial. Until the site receives 
drug/notification no protocol activities, including screening may occur.
Sites must adhere to all requirements stipulated by their respective IRB or IEC. This may include 
notification to the IRB or IEC regarding protocol amendments, updates to the informed consent 
form, recruitment materials intended for viewing by subjects, local safety reporting requirements, 
reports and updates regarding the ongoing review of the study at intervals specified by the 
respective IRB or IEC, and submission of the investigator’s final status report to IRB or IEC. All 
IRB and IEC approvals and relevant documentation for these items must be provided to the 
sponsor or its designee.
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Subject incentives should not exert undue influence for participation. Payments to subjects must 
be approved by the IRB or IEC and sponsor.
15.2
Subject Information, Informed Consent, and Subject Authorization
Written consent documents will embody the elements of informed consent as described in the 
Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance with all 
applicable laws and regulations. The informed consent form, subject authorization form (if 
applicable), and subject information sheet (if applicable) describe the planned and permitted uses, 
transfers, and disclosures of the subject’s personal and personal health information for purposes of 
conducting the study. The informed consent form and the subject information sheet (if applicable) 
further explain the nature of the study, its objectives, and potential risks and benefits, as well as the 
date informed consent is given. The informed consent form will detail the requirements of the 
participant and the fact that he or she is free to withdraw at any time without giving a reason and 
without prejudice to his or her further medical care.
Patients previously enrolled in this study who remain on study treatment upon implementation of 
Amendment 3 may need to be reconsented, according to IRB/IEC standards. Reconsenting should 
be done in person, where possible. Remote reconsenting is permitted as long as the process adheres 
to site, IRB/IEC, and GCP standards and local regulations.
The investigator is responsible for the preparation, content, and IRB or IEC approval of the 
informed consent form and if applicable, the subject authorization form. The informed consent 
form, subject authorization form (if applicable), and subject information sheet (if applicable) must 
be approved by both the IRB or IEC and the sponsor prior to use.
The informed consent form, subject authorization form (if applicable), and subject information 
sheet (if applicable) must be written in a language fully comprehensible to the prospective subject. 
It is the responsibility of the investigator to explain the detailed elements of the informed consent 
form, subject authorization form (if applicable), and subject information sheet (if applicable) to the 
subject. Information should be given in both oral and written form whenever possible and in the 
manner deemed appropriate by the IRB or IEC. In the event the subject is not capable of rendering 
adequate written informed consent, then the subject’s legally acceptable representative may 
provide such consent for the subject in accordance with applicable laws and regulations.
The subject, or the subject’s legally acceptable representative, must be given ample opportunity to: 
(1) inquire about details of the study and (2) decide whether or not to participate in the study. If the 
subject, or the subject’s legally acceptable representative, determines he or she will participate in 
the study, then the informed consent form and subject authorization form (if applicable) must be 
signed and dated by the subject, or the subject’s legally acceptable representative, at the time of 
consent and prior to the subject entering into the study. The subject or the subject’s legally 
acceptable representative should be instructed to sign using their legal names, not nicknames, 
using blue or black ballpoint ink. The investigator must also sign and date the informed consent 
form and subject authorization (if applicable) at the time of consent and prior to subject entering 
into the study; however, the sponsor may allow a designee of the investigator to sign to the extent 
permitted by applicable law.
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Once signed, the original informed consent form, subject authorization form (if applicable), and 
subject information sheet (if applicable) will be stored in the investigator’s site file. The 
investigator must document the date the subject signs the informed consent in the subject’s 
medical record. Copies of the signed informed consent form, the signed subject authorization form 
(if applicable), and subject information sheet (if applicable) shall be given to the subject.
All revised informed consent forms must be reviewed and signed by relevant subjects or the 
relevant subject’s legally acceptable representative in the same manner as the original informed 
consent. The date the revised consent was obtained should be recorded in the subject’s medical 
record, and the subject should receive a copy of the revised informed consent form.
15.3
Subject Confidentiality
The sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy. Throughout this study, a subject’s source data will only be linked to 
the sponsor’s clinical study database or documentation via a unique identification number. As 
permitted by all applicable laws and regulations, limited subject attributes, such as sex, age, or date 
of birth, and subject initials may be used to verify the subject and accuracy of the subject’s unique 
identification number.
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the sponsor 
requires the investigator to permit its monitor or designee’s monitor, representatives from any 
regulatory authority (eg, FDA, Medicines and Healthcare products Regulatory Agency, 
Pharmaceuticals and Medical Devices Agency), the sponsor’s designated auditors, and the 
appropriate IRBs and IECs to review the subject’s original medical records (source data or 
documents), including, but not limited to, laboratory test result reports, ECG reports, admission 
and discharge summaries for hospital admissions occurring during a subject’s study participation, 
and autopsy reports. Access to a subject’s original medical records requires the specific 
authorization of the subject as part of the informed consent process (see Section 15.2).
Copies of any subject source documents that are provided to the sponsor must have certain 
personally identifiable information removed (ie, subject name, address, and other identifier fields 
not collected on the subject’s [e]CRF).
15.4
Publication, Disclosure, and Clinical Trial Registration Policy
15.4.1
Publication 
The investigator is obliged to provide the sponsor with complete test results and all data derived by 
the investigator from the study. During and after the study, only the sponsor may make study 
information available to other study investigators or to regulatory agencies, except as required by 
law or regulation. Except as otherwise allowable in the clinical study site agreement, any public 
disclosure (including publicly accessible websites) related to the protocol or study results, other 
than study recruitment materials and/or advertisements, is the sole responsibility of the sponsor.
The sponsor may publish any data and information from the study (including data and information 
generated by the investigator) without the consent of the investigator. Manuscript authorship for 
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any peer-reviewed publication will appropriately reflect contributions to the production and 
review of the document. All publications and presentations must be prepared in accordance with 
this section and the Clinical Study Site Agreement. In the event of any discrepancy between the 
protocol and the Clinical Study Site Agreement, the Clinical Study Site Agreement will prevail.
15.4.2
Clinical Trial Registration
In order to ensure that information on clinical trials reaches the public in a timely manner and to 
comply with applicable laws, regulations and guidance, Takeda will, at a minimum register 
interventional clinical trials it sponsors anywhere in the world on ClinicalTrials.gov or other 
publicly accessible websites on or before start of study, as defined in Takeda Policy/Standard. 
Takeda contact information, along with investigator’s city, state (for Americas investigators), 
country, and recruiting status will be registered and available for public viewing. 
As needed Takeda and Investigator/site contact information may be made public to support 
participant access to trials via registries. In certain situations/registries, Takeda may assist 
participants or potential participants to find a clinical trial by helping them locate trial sites closest 
to their homes by providing the investigator name, address, and phone number via email/phone or 
other methods callers requesting trial information. Once subjects receive investigator contact 
information, they may call the site requesting enrollment into the trial. The investigative sites are 
encouraged to handle the trial inquiries according to their established subject screening process. If 
the caller asks additional questions beyond the topic of trial enrollment, they should be referred to 
the sponsor. 
Any investigator who objects to Takeda providing this information to callers must provide Takeda 
with a written notice requesting that their information not be listed on the registry site. 
15.4.3
Clinical Trial Results Disclosure
Takeda will post the results of clinical trials on ClinicalTrials.gov or other publicly accessible 
websites (including the Takeda corporate site) and registries, as required by Takeda 
Policy/Standard, applicable laws and/or regulations. 
Data Sharing
The sponsor is committed to responsible sharing of clinical data with the goal of advancing 
medical science and improving patient care. Qualified independent researchers will be permitted 
to use data collected from patients during the study to conduct additional scientific research, which 
may be unrelated to the study drug or the patient’s disease. The data provided to external 
researchers will not include information that identifies patients personally.
15.5
Insurance and Compensation for Injury
Each subject in the study must be insured in accordance with the regulations applicable to the site 
where the subject is participating. If a local underwriter is required, then the sponsor or sponsor’s 
designee will obtain clinical study insurance against the risk of injury to clinical study subjects. 
Refer to the Clinical Study Site Agreement regarding the sponsor’s policy on subject 
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compensation and treatment for injury. If the investigator has questions regarding this policy, he or 
she should contact the sponsor or sponsor’s designee.
16.0
REFERENCES
1. Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0. U.S. Department of 
Health and Human Services, National Institutes of Health, National Cancer Institute. 
November 2017.
2. VELCADE (bortezomib) for Injection, October [package insert]. Cambridge, MA: 
Millennium Pharmaceuticals, Inc., October 2012.
3. NINLARO® (ixazomib) capsules, for oral use [prescribing information]. Cambridge, MA: 
Takeda Pharmaceutical Company Limited.
4. Moreau P, Masszi T, Grzasko N, Bahlis NJ, Hansson M, Pour L, et al. Oral Ixazomib, 
Lenalidomide, and Dexamethasone for Multiple Myeloma. New England Journal of Medicine 
2016;374(17):1621-34.
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(f) At EOS, record an overall investigator assessment of best response obtained during this rollover study and 
investigator assessment of date of progression.
(g) Vital sign measurements, which include measurements of diastolic and systolic blood pressure and heart rate, will 
be obtained at Study Entry/Day 1, EOS, and as medically needed at the discretion of investigator.
(h) Only concomitant medications and therapeutic procedures related to the treatment of AEs that are collected in the 
study (see Section 10.2), will be recorded in the eCRFs.
(i) This will included collection of the following:

All SAEs.

All ≥Grade 3 AEs.

≥Grade 2 peripheral neuropathy.

New primary malignancies.

Any AE resulting in dose modification or discontinuation of study drug.

Any other AE that in the opinion of the investigator is a clinically significant event (see Section 10.2).
(j) For all patients, hematology and chemistry laboratory evaluations will be obtained at the Study Entry/Day 1 visit 
and at the EOS visit. Laboratory evaluations may be done within 4 weeks of the Study Entry/Day 1 visit. Unscheduled 
hematology and chemistry laboratory assessments may be performed if clinically indicated. Laboratory samples will 
be processed locally.
(k) A serum -hCG pregnancy test will be performed only for women of childbearing potential. The serum pregnancy 
test may be completed within 28 days of the Study Entry /Day 1 visit. See Section 9.4.4 for additional details. 
Pregnancy tests may also be repeated during the study if required by an IEC/IRB or if required by local regulations.
(l) Study drug(s) will be administered at the dose, schedule of study drug(s), and combination regimen that they were 
receiving at the time of rollover from the parent study, or according to the required dose modification from a parent 
study. For those patients who received ixazomib dosing based on body surface area (BSA) per the parent study, the 
dose may be rounded. The dose may also be rounded for those patients who convert from BSA-based dosing to fixed 
dosing with approval from the Medical Monitor. No new anticancer agents can be started or added. Note that for 
patients whose study therapy in a parent study includes a placebo, the placebo capsule will be discontinued; crossover 
to ixazomib is not permitted. Patients will continue to receive study treatment until disease progression, occurrence of 
an unacceptable toxicity, and/or other criteria as detailed in Section 9.6). Ixazomib and/or other study drug(s) will be 
dispensed at each on-study visit (up to a 3-cycle supply to the patient [eg, 21- or 28-day cycles] at the discretion of the 
investigator. Note: patients in France are only permitted to receive 1 cycle of medication at a time). The study center 
staff will check the patient’s supply of remaining ixazomib tablets at each on-study visit to ensure proper compliance 
with dosing.
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Appendix B
Responsibilities of the Investigator
Clinical research studies sponsored by the sponsor are subject to ICH GCP and all the applicable 
local laws and regulations. The responsibilities imposed on investigators by the FDA are 
summarized in the “Statement of Investigator” (Form FDA 1572), which must be completed and 
signed before the investigator may participate in this study.
The investigator agrees to assume the following responsibilities by signing a Form FDA 1572:
1. Conduct the study in accordance with the protocol.
2. Personally conduct or supervise the staff who will assist in the protocol.
3. Ensure that study related procedures, including study specific (non routine/non standard panel) 
screening assessments are NOT performed on potential subjects, prior to the receipt of written 
approval from relevant governing bodies/authorities.
4. Ensure that all colleagues and employees assisting in the conduct of the study are informed of 
these obligations.
5. Secure prior approval of the study and any changes by an appropriate IRB/IEC that conform to 
21 CFR Part 50, ICH, and local regulatory requirements.
6. Ensure that the IRB/IEC will be responsible for initial review, continuing review, and approval 
of the protocol. Promptly report to the IRB/IEC all changes in research activity and all 
anticipated risks to subjects. Make at least yearly reports on the progress of the study to the 
IRB/IEC, and issue a final report within 3 months of study completion.
7. Ensure that requirements for informed consent, as outlined in 21 CFR Part 50, ICH and local 
regulations, are met.
8. Obtain valid informed consent from each subject who participates in the study, and document 
the date of consent in the subject’s medical chart. Valid informed consent is the most current 
version approved by the IRB/IEC. Each informed consent form should contain a subject 
authorization section that describes the uses and disclosures of a subject’s personal 
information (including personal health information) that will take place in connection with the 
study. If an informed consent form does not include such a subject authorization, then the 
investigator must obtain a separate subject authorization form from each subject or the 
subject’s legally acceptable representative.
9. Prepare and maintain adequate case histories of all persons entered into the study, including 
eCRFs, hospital records, laboratory results, etc, and maintain these data for a minimum of 
2 years following notification by the sponsor that all investigations have been discontinued or 
that the regulatory authority has approved the marketing application. The investigator should 
contact and receive written approval from the sponsor before disposing of any such 
documents.
10. Allow possible inspection and copying by the regulatory authority of GCP-specified essential 
documents.
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11. Maintain current records of the receipt, administration, and disposition of sponsor-supplied 
drugs, and return all unused sponsor-supplied drugs to the sponsor.
12. Report adverse reactions to the sponsor promptly. In the event of an SAE, notify the sponsor 
within 24 hours.
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Appendix C
Investigator Consent to Use of Personal Information 
Takeda will collect and retain personal information of investigator, including his or her name, 
address, and other personally identifiable information. In addition, investigator’s personal 
information may be transferred to other parties located in countries throughout the world (eg, the 
United Kingdom, United States, and Japan), including the following:

Takeda, its affiliates, and licensing partners.

Business partners assisting Takeda, its affiliates, and licensing partners.

Regulatory agencies and other health authorities.

IRBs and IECs.
Investigator’s personal information may be retained, processed, and transferred by Takeda and 
these other parties for research purposes including the following:

Assessment of the suitability of investigator for the study and/or other clinical studies.

Management, monitoring, inspection, and audit of the study.

Analysis, review, and verification of the study results.

Safety reporting and pharmacovigilance relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to other medications used in other clinical studies that may contain 
the same chemical compound present in the study medication.

Inspections and investigations by regulatory authorities relating to the study.

Self-inspection and internal audit within Takeda, its affiliates, and licensing partners.

Archiving and audit of study records.

Posting investigator site contact information, study details and results on publicly accessible 
clinical trial registries, databases, and websites.
Investigator’s personal information may be transferred to other countries that do not have data 
protection laws that offer the same level of protection as data protection laws in investigator’s own 
country.
Investigator acknowledges and consents to the use of his or her personal information by Takeda 
and other parties for the purposes described above.
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Appendix D
Acceptable Methods of Contraception
The following information is based on (and in line with) the informed consent form for ixazomib.
Female patients: Unless the patient cannot have children because of surgery or other medical 
reasons (had an effective tubal ligation, had the ovaries or the uterus removed, or is 
postmenopausal), the patient must use 2 effective methods of birth control from the time of signing 
the informed consent form through the entire study drug treatment period (including interruptions 
in treatment) and for 90 days after completing study drug treatment. It is strongly recommended 
that at least 1 of these 2 methods be highly effective (see examples below).
Highly Effective Methods
Other Effective Methods (Barrier Methods)
Intrauterine devices
Latex or nonlatex condom with or without a 
spermicidal agent
Hormonal (birth control pills/oral contraceptives, 
injectable contraceptives, contraceptive patches, or 
contraceptive implants)
Diaphragm with spermicide; cervical cap with a 
spermicide; sponge with a spermicide
If one of the highly effective methods cannot be used, using 2 effective methods at the same time is 
recommended.
The patient must use birth control methods as directed above, unless the patient completely avoids 
having heterosexual intercourse.
Male patients: We do not know if using ixazomib will affect sperm. Therefore, because of 
potential risk, the patient should not get a partner pregnant during the study drug treatment period 
(including interruptions in treatment). Even if the patient is surgically sterilized (ie, had a 
vasectomy), the patient must agree to use an appropriate method of barrier contraception (latex or 
nonlatex condom with or without a spermicidal agent) during the entire study drug treatment 
period and for 90 days after completing study drug treatment, or the patient should completely 
avoid having heterosexual intercourse.
Highly Effective Methods
Other Effective Methods (Barrier Methods)
Vasectomy
Latex or nonlatex condom with or without a spermicidal agent
Diaphragm with spermicide; cervical cap with spermicide; sponge with 
spermicide
If one of the highly effective methods cannot be used, using 2 effective methods at the same time is 
recommended.
All patients (male or female): If the patient or a partner becomes pregnant during this study, the 
patient must tell the study doctor immediately. The doctor will advise the patient of the possible 
risks to the unborn child and discuss options for managing the pregnancy with the patient. For 
female patients who become pregnant while on this study, the study drug will be stopped 
immediately, and the pregnancy will be followed until conclusion.
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Appendix E
Detailed Description of Amendments to Text
The primary section(s) of the protocol affected by the changes in Amendment No. 03 are indicated. 
The corresponding text has been revised throughout the protocol. 
Change 1: Updated the legal entity of the sponsor.
The primary change occurs on the cover page, in the Sponsor row: 
Initial 
wording:
Millennium Pharmaceuticals, Inc, a wholly owned subsidiary of Takeda 
Pharmaceutical Company Limited
40 Landsdowne Street
Cambridge, MA USA 02139
Telephone: +1 (617) 679-7000
Please note: Millennium Pharmaceuticals, Inc, a wholly owned subsidiary of Takeda 
Pharmaceutical Company Limited, may be referred to in this protocol as 
“Millennium,” “Sponsor,” or “Takeda”.
Amended or 
new 
wording:
Millennium Pharmaceuticals, Inc, a wholly owned subsidiary of Takeda 
Pharmaceutical Company Limited Takeda Development Center Americas, Inc
40 Landsdowne Street95 Hayden Avenue
CambridgeLexington, MA USA 02139421 USA
Telephone: +1 (617) 679-7000
Please note: Millennium Pharmaceuticals, Inc, a wholly owned subsidiary of Takeda 
Pharmaceutical Company Limited, may be referred to in this protocol as 
“Millennium,” “Sponsor,” or “Takeda”.
Rationale for Change:
To reflect the new legal entity for the sponsor of Takeda Development Center Americas rather than 
Millennium. 
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The following sections also contain this change:

Section 2.0 STUDY SUMMARY

Section 3.2 List of Abbreviations

Section 3.3 Corporate Identification [removed]

Section 4.1 Background

Section 6.1 Overview of Study Design

Section 6.3.1 Duration of an Individual Patient’s Study Participation

Section 7.1 Inclusion Criteria

Section 8.11 Packaging and Labeling

Section 8.12 Storage, Handling, and Accountability

Section 8.13 Combination Therapy.
Change 2: Updated signatories for the study.
The primary change occurs in Section 1.2 Approval: 
Description 
of change:

Removed 
 and 
 as 
signatories.

Added 
 and 
 as signatories. 
Rationale for Change:
To reflect the current Takeda personnel responsible for approving the protocol. 
Change 3: Clarified that ixazomib and/or combinational study drugs from the designated parent 
protocols will be provided in this study until other means of accessing treatment are available; no 
new anticancer agents can be started or added; and for patients whose study therapy in a parent 
study includes placebo, the placebo capsule will be discontinued and crossover to ixazomib is not 
permitted.
The primary change occurs in Section 6.1 Overview of Study Design: 
Initial 
wording:
This is an open-label, multicenter, rollover study to provide continued access to 
ixazomib and evaluation of the long-term safety profile of ixazomib. The patient 
population will consist of patients who have previously received and tolerated 
ixazomib in a Millennium-sponsored clinical study, and in the investigator’s opinion 
and confirmed by the Millennium medical monitor, may benefit from continued 
ixazomib therapy (eg, patient demonstrates response to therapy or stable disease 
without evidence of disease progression). 
Patients may be enrolled provided they have not met any of the discontinuation criteria 
in the parent study. Patients will enter this study on the same ixazomib dose and 
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schedule that they were receiving in the parent study (Section 8.1). For those patients 
who received ixazomib dosing based on BSA per the parent study, the dose may be 
rounded. The dose may also be rounded for those patients who convert from 
BSA-based dosing to fixed dosing with approval from the Medical Monitor. Patients 
who enter this study receiving a combination therapy with ixazomib and another 
medication(s) will continue to receive the combination regimen (which will be 
sourced locally) until there is a need to selectively discontinue the other medication(s) 
(eg, due to cumulative toxicity, product expiry, or other factors that limit availability 
from local sources). In that situation, the patient will continue to receive ixazomib 
without the discontinued agent(s), if, in the opinion of the investigator and with 
sponsor approval, it is likely that the patient will continue to derive benefit from single 
agent ixazomib; no new anticancer agents can be started or added. Patients receiving a 
combination of ixazomib and another medication(s) will be discontinued from this 
study when ixazomib therapy is discontinued.
Following enrollment, patients may receive ixazomib until they experience disease 
progression, clinical deterioration in the investigator’s judgment, experience an 
unacceptable toxicity, withdraw consent, pursue an alternative therapy, meet other 
study-specified reasons for discontinuation of study drug, or until ixazomib is 
available to the patient through commercial channels, including reimbursement for the 
patient’s indication. 
Patients participating in eligible ixazomib parent studies will enter the rollover study 
at the time-point when the rollover study is active at an investigative site. Following 
their provision of informed consent to continue in the rollover study, patients will be 
provided with study medication. Patients should enter the study within 8 weeks of 
their last dose of ixazomib in the parent study or as agreed upon by the Millennium 
clinician/designee.
Amended 
or new 
wording:
This is an open-label, multicenter, rollover study to provide continued access to 
ixazomib and/or other study drugs from a designated ixazomib parent study (ie, 
Studies C16003, C16005, C16006, C16007, C16008, C16010 Global, C16011, 
C16013, C16014 Global and Korean Continuation, C16017, C16020, C16029, 
and C16047) when the patient has no other means to access study treatment. The 
study will also evaluatione of the long-term safety profile of ixazomib in those 
patients who continue to receive ixazomib. The patient population will consist of 
patients who have previously received and tolerated ixazomibtreatment in a 
MillenniumTakeda-sponsored clinical study of ixazomib, and in the investigator’s 
opinion and confirmedapproved by the MillenniumTakeda medical monitor, may 
benefit from continued ixazomib therapy with 1 or more of the drugs from a parent 
protocol (eg, patient demonstrates response to therapy or stable disease without 
evidence of disease progression). 
Patients may be enrolled provided they have not met any of the discontinuation criteria 
in thetheir parent study. Patients will enter this study on the same ixazomib dose and,
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schedule of study drug(s), and combination regimen that they were receiving inat 
the time of rollover from the parent study, or according to the required dose 
modification from a parent study (Section 8.1). For those patients who received 
ixazomib dosing based on BSA per the parent study, the dose may be rounded. The 
dose may also be rounded for those patients who convert from BSA-based dosing to 
fixed dosing with approval from the Medical Monitor. Patients who enter this study 
receiving a combination therapy with ixazomib and another medication(s) will 
continue to receive the combination regimen (which will be sourced locally) until 
there is a need to selectively discontinue the other medication(s) (eg, due to 
cumulative toxicity, product expiry, or other factors that limit availability from local 
sources). In that situation, the patient will continue to receive ixazomib without the 
discontinued agent(s), if, in the opinion of the investigator and with sponsor approval, 
it is likely that the patient will continue to derive benefit from single agent ixazomib; 
noNo new anticancer agents can be started or added. Patients receiving a combination 
of ixazomib and another medication(s)Note that for patients whose study therapy 
in a parent study includes a placebo, the placebo capsule will be discontinued from 
this study when; crossover to ixazomib therapy is discontinuedis not permitted.
Following enrollment, patients may receive ixazomibstudy drug(s) until they 
experience disease progression, clinical deterioration in the investigator’s judgment, 
experience an unacceptable toxicity, withdraw consent, pursue an alternative therapy, 
meet other study-specified reasons for discontinuation of study drug, or until ixazomib 
is available to the patient is transitioned to ixazomib/other therapy through 
commercial channels, including reimbursement for the patient’s indication. 
Patients participating in eligiblea designated ixazomib parent studiesstudy will enter 
the rollover study at the time-point when they have completed the EOT visit in the 
parent study and when the rollover study is active at an investigative site. Following 
their provision of informed consent to continuereceive treatment in the rollover 
study, patients will be provided with study medication. Patients should enter the study 
within 8 weeks of their last dose of ixazomib/other study drug(s) in the parent study 
or as agreed upon by the MillenniumTakeda clinician/designee so to minimize any 
treatment disruption to the patient.
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Rationale for Change:
To clarify the study drug administration and supply language to make provision for future patients 
enrolling from designated ixazomib parent protocols. 
The following sections also contain this change:

Section 2.0 STUDY SUMMARY

Section 4.1.1.2 Benefits.

Section 4.2 Rationale for the Proposed Study.

Section 7.1 Inclusion Criteria, Criterion 2.

Section 8.1 Study Drug Administration. 

Section 8.13 Combination Therapy.

Section 9.3 Treatment Group Assignments.

Appendix A Schedule of Events, footnote “l”.
Change 4: Clarified the study objectives.
The primary change occurs in Section 5.1.1 Primary Objectives: 
Initial 
wording:
The primary objective is:

To provide continued access of ixazomib and to evaluate the long-term safety 
profile of ixazomib.
Amended 
or new 
wording:
The primary objectives isare:

To provide continued access to ixazomib and/or other study drugs from an 
ixazomib parent study.

To provide continued access of ixazomib and to evaluate the long-term safety 
profile of ixazomib.
Rationale for Change:
To clarify that the study objectives in light of continued access to other study drugs from an 
ixazomib parent study.
The following sections also contain this change:

Section 2.0 STUDY SUMMARY

Section 5.2.1 Primary Endpoint
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Change 5: Clarified the duration of adverse event (AE) follow-up.
The primary change occurs in Section 6.3.1 Duration of an Individual Patient’s Study 
Participation: 
Initial 
wording:
Patients will be followed for 30 days after the last dose of study drug(s) or the start of 
subsequent alternative anticancer therapy. 
Ongoing AEs meeting the criteria in Section 10.2 will be followed until resolution, 
until the AE becomes chronic or stable, or is determined to be part of the underlying 
disease process, or until the patient starts alternative therapy.
Amended 
or new 
wording:
Patients will be followed for 30 days after the last dose of study drug(s) or the start of 
subsequent alternative anticancer therapy. 
Ongoing AEs meeting the criteria in Section 10.2 will be followed until resolution, 
until the AE becomes chronic or stable, or is determined to be part of the underlying 
disease process, or until the patient starts alternative therapyattends the EOS visit 
and discontinues the study.
Rationale for Change:
To clarify that AEs will be followed until the patient attends an EOS visit and discontinues the 
study; this will occur prior to a patient starting alternative therapy. 
The following sections also contain this change:

Section 2.0 STUDY SUMMARY

Section 6.1 Overview of Study Design. 

Section 10.3 Monitoring of Adverse Events and Period of Observation.
Change 6: Updated the background information on other ixazomib clinical trials.
The primary change occurs in Section 4.1 Background: 
Initial 
wording:
Ixazomib is an investigational, oral, inhibitor of the 20S proteasome that is under 
development for the treatment of multiple myeloma (MM), plasma cell dyscrasias, 
amyloidosis, lymphoma, nonhematologic malignancies, and lupus nephritis. 
Inhibition of the 20S proteasome has been validated as a therapeutic target for the 
treatment of malignancies using VELCADE® (bortezomib) for Injection, Millennium 
Pharmaceuticals, Inc.’s first-in-class proteasome inhibitor [2]. 
Oral ixazomib in combination with lenalidomide and dexamethasone was approved 
by the United States (US) Food and Drug Administration (FDA) in November 2015 
for the treatment of patients with MM who have received at least 1 prior therapy [3,4].
…
Phase 1, phase 1/2, and phase 2 trials are ongoing in MM, relapsed and/or refractory 
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systemic light-chain amyloidosis (RRAL), solid tumors, and lymphoma. In addition, a 
phase 1 study is ongoing in patients with renal impairment who have relapsed and/or 
refractory multiple myeloma (RRMM) or advanced solid tumors (Study C16015). 
Phase 1 studies have been completed in patients with hepatic impairment who have 
advanced solid tumors or hematologic malignancies (Study C16018) and in an 
absorption, distribution, metabolism, and excretion study in patients with advanced 
solid tumors or lymphoma (Study C16016). Phase 3 trials in RRMM, newly 
diagnosed multiple myeloma (NDMM), and RRAL are underway. As of 27 March 
2016, data are available from 929 patients known to have received at least 1 dose of 
either the intravenous (IV) or oral ixazomib formulations across the clinical 
development program; 2417 patients have been enrolled in 5 phase 3 clinical trials:

Double-blind, placebo-controlled Study C16010 and Study C16010 China 
continuation study (CCS) of ixazomib versus placebo in combination with 
lenalidomide + dexamethasone (LenDex) in patients with RRMM.

Double-blind, placebo-controlled Study C16014 and Study C16014 extension in 
South Korea (KES) of ixazomib versus placebo in combination with LenDex in 
patients with NDMM. 

Double-blind, placebo-controlled Study C16019 of ixazomib versus placebo as 
maintenance in patients with NDMM who have undergone autologous stem cell 
transplantation (ASCT) before entering the study.

Double-blind, placebo-controlled Study C16021 of ixazomib versus placebo as 
maintenance in patients with NDMM who have not undergone ASCT.

Open-label Study C16011 of ixazomib and dexamethasone versus physician’s 
choice of a dexamethasone-containing regimen in patients with RRAL. 
Ixazomib is available as an IV and oral formulation (during the early development of 
ixazomib); however, only the oral formulation is currently being developed for 
commercialization. Regardless of the route of administration, in the twice-weekly 
dosing schedule, ixazomib is given on Days 1, 4, 8, and 11 of a 21-day cycle, and in 
the weekly dosing schedule, ixazomib 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 during the clinical development 
of ixazomib: RRMM, NDMM, RRAL, advanced solid tumors, and advanced 
lymphoma. Studies are investigating both single-agent ixazomib and ixazomib in 
combination with standard treatments. However, other therapeutic areas are also being 
explored.
Amended 
or new 
wording:
Ixazomib is an investigational, oral, inhibitor of the 20S proteasome that is under 
developmenthas been studied for the treatment of multiple myeloma (MM), plasma 
cell dyscrasias, amyloidosis, lymphoma, nonhematologic malignancies, and lupus 
nephritis. Inhibition of the 20S proteasome has been validated as a therapeutic target 
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for the treatment of malignancies using VELCADE® (bortezomib) for Injection, 
MillenniumTakeda Pharmaceuticals, Inc.’s first-in-class proteasome inhibitor [2]. 
Oral ixazomib in combination with lenalidomide and dexamethasone was first 
approved by the United States (US) Food and Drug Administration (FDA) in 
November 2015 for the treatment of patients with MM who have received at least 1 
prior therapy [3,4]. It has since been approved in over 65 countries globally.
…
Phase 1, phase 1/2, and phase 2 trials are ongoinghave been conducted in MM, 
relapsed and/or refractory systemic light-chain amyloidosis (RRAL), solid tumors, 
and lymphoma. In addition, a phase 1 study is ongoingstudies were conducted in 
patients with renal impairment who havehad relapsed and/or refractory multiple 
myeloma (RRMM) or advanced solid tumors (Study C16015). Phase 1 studies have 
been completed, in patients with hepatic impairment who havehad advanced solid 
tumors or hematologic malignancies (Study C16018), and in an absorption, 
distribution, metabolism, and excretion study in patients with advanced solid tumors 
or lymphoma (Study C16016). Phase 3 trials in RRMM (C16010), newly diagnosed 
multiple myeloma (NDMM) (C16014), and RRAL are underway. As of 27 March 
2016, data are available from 929 patients known to have received at least 1 dose of 
either the intravenous (IV) or oral ixazomib formulations across the clinical 
development program; 2417 patients have been enrolled in 5 phase 3 clinical trials:
 (C16011) have additionally been completed. Phase 3 trials of ixazomib 
Double blind, placebo controlled Study C16010 and Study C16010 China 
continuation study (CCS) of ixazomib versus placebo in combination with
lenalidomide + dexamethasone (LenDex) in patients with RRMM.
 Double blind, placebo controlled Study C16014 and Study C16014 extension in 
South Korea (KES) of ixazomib versus placebo in combination with LenDex in 
patients with NDMM. 
Double blind, placebo controlled Study C16019 of ixazomib versus placebo as 
maintenance in patients with NDMM who have undergone maintenance therapy 
following autologous stem cell transplantation (ASCT) before entering the 
studyC16019) or in patients who did not receive ASCT (C16021) are ongoing.
 Double blind, placebo controlled Study C16021 of ixazomib versus placebo as 
maintenance in patients with NDMM who have not undergone ASCT.
 Open label Study C16011 of ixazomib and dexamethasone versus physician’s 
choice of a dexamethasone containing regimen in patients with RRAL. 
Ixazomib ishad been available as an IV and oral formulation (during the early 
development of ixazomib); however, only the oral formulation is currently being 
developed for commercialization. Regardless of the route of administration, in the 
twice-weekly dosing schedule, ixazomib is given on Days 1, 4, 8, and 11 of a 21-day
F
lac
For n
dy
on-commercial use only
C1
nt who
t who
6018)
18), an
y in patie
in pa
als in RR
s in R
, and RR
and R
atients
ents kn
k
rc
l ixazom
ixazom
me
atients h
tients
mm
nally be
lly b
bo contr
co
n
(CCS
(CC
y (CCS)
(CC
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no
+ dexam
+ dexam
or
plplace
a
F


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cycle, and in the weekly dosing schedule, ixazomib 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 beinghave been studied during the clinical 
development of ixazomib: RRMM, NDMM, RRAL, advanced solid tumors, and 
advanced lymphoma, and pediatric acute lymphoblastic leukemia. Studies are 
investigating both single-agent ixazomib and ixazomib in combination with standard 
treatments. However, other therapeutic areas are also being explored.
Rationale for Change:
To update the current status of the ixazomib development program.
Change 7: Clarified the anticipated number of patients and sites/countries.
The primary change occurs in Section 6.2 Number of Patients: 
Initial 
wording:
The maximum number of patients to be enrolled is estimated to be 250. The number of 
countries and sites cannot be determined as this study is open to all countries and sites 
with qualifying patients from prior company-sponsored ixazomib studies.
Amended 
or new 
wording:
The maximumestimated number of patients to be enrolled is estimated to 
beapproximately 250. The number of countries and sites cannot be determinedis not 
currently specified as this study is open to all countries and sites with qualifying 
patients from prior company-sponsored ixazomib studies.
Rationale for Change:
To provide clarification. 
Section 2.0 STUDY SUMMARY also contains this change. 
Change 8: Clarified the duration of an individual patient’s study participation.
The primary change occurs in Section 6.3.1 Duration of an Individual Patient’s Study 
Participation: 
Initial 
wording:
The anticipated duration of treatment in this rollover study will be up to 5 years.
Patients will be followed for 30 days after the last dose of ixazomib or the start of 
subsequent alternative anticancer therapy. 
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Amended 
or new 
wording:
The anticipated duration of treatment for an individual patient in this rollover study 
will be up to 5 years.approximately 5 years. Based on approval by the Takeda 
medical monitor every 24 months, continued access to ixazomib and/or other 
study drugs will be allowed for patients who in the investigator’s opinion are 
deriving clinical benefit. Patients may remain in the rollover study until they are 
transitioned to ixazomib/other therapy through commercial channels or until 
any of the other reasons for treatment discontinuation are met, whichever is 
sooner.
Patients will be followed for 30 days after the last dose of ixazomibstudy drug(s) or 
the start of subsequent alternative anticancer therapy, whichever occurs earlier. 
Rationale for Change:
To provide clarification. 
The following sections also contain this change:

Section 2.0 STUDY SUMMARY. 

Section 6.3.3 Timeframe for Primary Endpoint to Support Disclosures.
Change 9: Clarified the anticipated total study duration.
The primary change occurs in Section 6.3.2 End of Study/Study Completion Definition and 
Planned Reporting: 
Added text:The estimated time frame for study completion (first patient in to last patient last visit) 
is approximately 7 years.
Rationale for Change:
To add flexibility to the anticipated total study duration. 
The following sections also contain this change:

Section 2.0 STUDY SUMMARY. 

Section 6.3.3 Timeframe for Primary Endpoint to Support Disclosures.

Section 6.3.4 Total Study Duration.
Change 10: Specified the acceptable methods of contraception to prevent pregnancy.
The primary change occurs in Section 7.1 Inclusion Criteria and Appendix D: 
Description 
of change:
Added Appendix D to describe acceptable methods of contraception.
Added a referenced to Appendix D in Section 7.1, Inclusion Criterion 3.
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Rationale for Change:
To incorporate the acceptable methods of contraception appendix (first added to Sweden-specific 
Protocol Amendment 02) into the Global protocol. 
Change 11: Clarified that systemic treatment with strong cytochrome P-450 (CYP)3A inducers is 
prohibited for patients receiving ixazomib during the study.
The primary change occurs in Section 8.4 Excluded Concomitant Medications and Procedures: 
Initial 
wording:

Systemic treatment with strong CYP3A inducers (rifampin, rifapentine, rifabutin, 
carbamazepine, phenytoin, phenobarbital), or use of St. John’s wort.
Amended 
or new 
wording:

For patients receiving ixazomib, sSystemic treatment with strong CYP3A 
inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, 
phenobarbital), or use of St. John’s wort.
Rationale for Change:
To add clarity to this protocol. 
The following sections also contain this change:

Section 2.0 STUDY SUMMARY. 

Section 6.1 Overview of Study Design.
Change 12: Updated the management of ixazomib clinical events to align with the current 
program standards.
The primary change occurs in Section 8.7.1 Management of Ixazomib Clinical Events: 
Initial 
wording:
Prophylaxis Against Risk of Reactivation of Herpes Infection
Patients may be at an increased risk of infection, including reactivation of herpes 
zoster and herpes simplex viruses. Antiviral therapy, such as acyclovir, valacyclovir, 
or other antivirals, may be initiated as clinically indicated. 
Nausea or Vomiting
Standard anti-emetics, including serotonin 5-hydroxytryptamine 3 receptor 
antagonists, are recommended for emesis if it occurs; prophylactic anti-emetics may 
also be considered at the physician’s discretion. Fluid deficit should be corrected 
during treatment.
Diarrhea
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 during 
treatment.
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Erythematous Rash With or Without Pruritus
Rash may range from limited erythematous areas, macular 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 predominantly 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 and self-limiting and is typically Grade 1 or 2 in severity. If rash occurs, 
consideration should be given to alternate causes of the rash such as concomitant 
medications, infections, etc.
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 (eg, prednisone ≤ 10 mg per 
day or equivalent is permitted. Management of a Grade 3 rash may require IV 
antihistamines or corticosteroids. Administration of ixazomib (and other causative 
agent if given in combination) should be modified and re-initiated at a reduced level 
from where rash was noted (per parent study).
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). 
The rare risks of Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN), drug 
reaction with eosinophilia and systemic symptoms (DRESS syndrome), and 
pemphigus vulgaris have been reported in oncology studies when ixazomib (or 
placebo) was given with concomitant medications that are known to cause rash (eg, 
Bactrim, lenalidomide, aspirin), and/or in the setting of confounding 
treatment-emergent AEs. These severe, potentially life-threatening or deadly 
conditions may involve rash with skin peeling and mouth sores and should be 
clinically managed according to standard medical practice. Punch biopsies for 
histopathological analysis are encouraged at the discretion of the investigator. 
Additional information regarding these reactions can be found in the IB.
Thrombocytopenia
Blood counts should be monitored regularly according to standard clinical practice. 
Thrombocytopenia may be severe but has been manageable with platelet transfusions 
according to standard clinical practice. Ixazomib administration should be modified 
according to dose modification recommendations in the parent study when 
thrombocytopenia occurs. 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 
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and symptoms. Thrombotic thrombocytopenic purpura should be managed 
symptomatically according to standard medical practice.
…
Fluid Deficit
Dehydration should be avoided because ixazomib may cause vomiting, diarrhea, and 
dehydration. Acute renal failure has been reported in patients treated with ixazomib, 
commonly in the setting of the previously noted gastrointestinal toxicities and 
dehydration.
Fluid deficit should be corrected before administration of study drug and as needed 
during treatment to avoid dehydration.
…
Posterior Reversible Encephalopathy Syndrome
Posterior reversible encephalopathy syndrome, which ultimately resolved, has been 
reported with ixazomib. This condition is characterized by headache, seizures, and
visual loss, and abrupt increase in blood pressure. Diagnosis may be confirmed by 
magnetic resonance imaging or computed tomography. 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.
Transverse Myelitis
One case of transverse myelitis has been reported with ixazomib. It is not known 
whether ixazomib causes transverse myelitis; however, because transverse myelitis 
happened to a patient receiving ixazomib, the possibility that ixazomib may have 
contributed to the transverse myelitis cannot be excluded. Transverse myelitis should 
be managed according to standard medical practice.
Overdose
An overdose is defined as a known deliberate or accidental administration of 
investigational drug, to or by a study subject, at a dose above that which is assigned to 
that individual subject according to the study protocol. If overdose occurs, consider 
close observation including hospitalization for hemodynamic support. Gastric lavage 
may be considered if instituted within 1 hour of ingestion of ixazomib overdose.
…
Amended 
or new 
wording:
Prophylaxis Against Risk of Reactivation of Herpes Infection
Patients may be at an increased risk of infection, including reactivation of herpes 
zoster and herpes simplex viruses. All patients continuing to receive ixazomib in 
this rollover study should receive prophylactic Aantiviral therapy, such as 
acyclovir, valacyclovir, or other antivirals, may be initiated as. Patients receiving a 
non-ixazomib-containing regimen should be guided by the physician's clinically
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indicatedpractice.
Nausea or Vomiting
Prophylaxis with Sstandard anti emetics, including serotonin 5-hydroxytryptamine 3 
receptor antagonists, areis recommended for emesis if it occurs; prophylactic 
anti emetics may also be considered at the physician’s discretion.. Any Ffluid deficit 
should be correctedoccurring during treatment should be promptly corrected. 
Diarrhea
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. Any Ffluid deficit should be 
correctedoccurring during treatment should be promptly corrected.
Erythematous Rash With or Without Pruritus
Rash may range from limited erythematous areas, macular 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 predominantly 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 and self-limiting and is typically Grade 1 or 2 in severity. If rash occurs, 
consideration should be given to alternate causes of the rash such as concomitant 
medications, infections, etc; these other causative agents should be discontinued 
and alterative agents considered if medically necessary.
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 (eg, prednisone ≤ 10 mg per 
day or equivalent) is permitted. 
Management of a Grade 3 rash may require IV antihistamines or corticosteroids. 
Administration of ixazomib (and other causative agent if given in combination) should 
be modified and re-initiated at a reduced level from where rash was noted (per parent 
study). 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). 
The rare risks of Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN), drug 
reaction with eosinophilia and systemic symptoms (DRESS syndrome), and 
pemphigus vulgaris have been reported in oncology studies when ixazomib (or 
placebo) was given with concomitant medications that are known to cause rash (eg, 
Bactrim, lenalidomide, aspirin), and/or in the setting of confounding 
treatment-emergent AEs. These severe, potentially life-threatening or deadly 
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conditions may involve rash with skin peeling and mouth sores and should be 
clinically managed according to standard medical practice. Punch biopsies for 
histopathological analysis are encouraged at the discretion of the investigator. Study 
medications should be discontinued in the event of severe, potentially 
life-threatening rash. Additional information regarding these reactions can be found 
in the IB.
Thrombocytopenia
Blood counts should be monitored regularly according to standard clinical practice. 
Thrombocytopenia may be severe but has been manageable with platelet transfusions 
according to standard clinical practice. Ixazomib administration should be modified 
according to dose modification recommendations in the parent study when 
thrombocytopenia occurs. Therapy can be reinitiated at a reduced level upon recovery 
of platelet counts. A rare risk isThrombotic microangiopathy (TMA), including
thrombotic thrombocytopenica purpura, a and hemolytic uremic syndrome, are
rare, serious blood disorders wherethat cause low levels of platelets and red blood 
cells and result in 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. Symptoms may include fatigue, fever, bruising, nose bleeds, and 
decreased urination. These disorders, including fatal cases, have been reported 
in patients receiving ixazomib. If TMA is suspected, consider withdrawal of the 
suspected causative agent and manage according to standard medical practice.
…
Fluid Deficit
Dehydration should be avoided because ixazomib may cause vomiting, diarrhea, and 
dehydration. Acute renal failure has been reported in patients treated with ixazomib, 
commonly in the setting of the previously noted gastrointestinal toxicities and 
dehydration.
Fluid deficit should be promptly corrected before administration of study drug and as 
needed during treatment to avoid dehydration.
…
Posterior Reversible Encephalopathy Syndrome
Posterior reversible encephalopathy syndrome, which ultimately resolved, has been 
reported with ixazomib. This condition is usually transient and reversible. It is 
characterized by headache, seizures, and visual loss, and abrupt increase in blood 
pressure. Diagnosis may be confirmed by magnetic resonance imaging or computed 
tomography. 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.
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Transverse Myelitis
One case of tTransverse myelitis has been reported with ixazomib. It is not known 
whether ixazomib causes transverse myelitis; however, because transverse myelitis 
happened to a patient receiving ixazomib, the possibility that ixazomib may have 
contributed to the transverse myelitis cannot be excluded. Transverse myelitis should 
be managed according to standard medical practice.
Overdose
An overdose is defined as a known deliberate or accidental administration of 
investigational drug, to or by a study subject, at a dose above that which is assigned to 
that individual subject according to the study protocol. Overdose has been reported 
in patients taking ixazomib. Symptoms of overdose are generally consistent with 
the known risks of ixazomib. Reports of accidental overdose have been
associated with serious adverse events, such as nausea, lung infections including 
aspiration pneumonia, multiple organ failure, and death. If overdose occurs, 
consider close observation including hospitalization for hemodynamic support. 
Gastric lavage may be considered if instituted within 1 hour of ingestion of ixazomib 
overdose.
…
Rationale for Change:
To add information currently available around clinical events.
Change 13: Clarified the instructions for management of combination therapy clinical events.
The primary change occurs in Section 8.7.2 Management of Combination Therapy Clinical 
Events: 
Initial 
wording:
For each medication(s) used as combination therapy with ixazomib please refer to the 
prescribing information for the applicable medication used in combination with 
ixazomib for the management of the clinical events.
Amended 
or new 
wording:
For each medication(s) used as combination therapy with or without ixazomib, please 
refer to the prescribing information and details in the parent protocol for the 
applicable medication used in combination with ixazomib for the management of the 
clinical events. 
Rationale for Change:
To add clarification to this protocol. 
Change 14: Updated the storage, handling, and accountability text to clarify procedures and 
account for the COVID-19 pandemic.
The primary change occurs in Section 8.12 Storage, Handling, and Accountability: 
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Initial 
wording:
On receipt at the investigative site, ixazomib should remain in the blister and carton 
provided until use or dispensation. The container should be stored as directed by the 
label on the packaging. All excursions should be brought to the sponsor’s attention for 
assessment and authorization for continued use. 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.
Ixazomib dispensed to the patient for take-home dosing should remain in the blister 
packaging and carton and stored as directed by the label on the packaging as noted 
previously until the point of use. Patients who are receiving take-home medication 
should be given a supply of study drug as per the parent study schedule or for up to 
3 cycles at the discretion of the investigator. Comprehensive instructions should be 
provided to the patient to ensure compliance with dosing procedures and to avoid the 
potential for incorrect self-administration or overdose of medication. Patients should 
be instructed to store the medication as directed by the label on the packaging. Patients 
should be instructed to return their empty or partially used cartons to the investigative 
site at their next visit, rather than discarding them, as permitted by site policy. 
Reconciliation will occur accordingly when the patient returns at their next visit for 
take-home medication. Any excursions in temperature should be reported and dealt 
with on a case-by-case basis. 
Amended 
or new 
wording:
On receipt at the investigative site, ixazomib should remain in the blister pack and 
carton provided until use or dispensation. The container should be stored as directed 
by the label on the packaging. All excursions should immediately be brought to the 
sponsor’s attention for assessment and authorization for continued use. Ensure that the 
drug is used before the retest expiry date provided by MillenniumTakeda. Expiry 
extensions will be communicated accordingly with updated documentation to support 
the extended shelf life.
Ixazomib dispensed to the patient for take-home dosing should remain in the blister 
packaging and carton and stored as directed by the label on the packaging as noted 
previously until the point of use. Patients who are receiving take-home medication 
should be given a supply of study drug as per the parent study schedule or for up to 
3 cycles at the discretion of the investigator. (Note: Patients in France are only 
permitted to receive 1 cycle of medication at a time). In case of the COVID-19 
pandemic preventing a patient from attending the study site, sites may use 
alternative strategies to deliver study drug to patients (eg, via courier or site 
staff), per local standard practice and regulations and with prior approval from 
the investigator and the sponsor’s project clinician/designee. Comprehensive 
instructions should be provided to the patient to ensure compliance with, and 
understanding of, dosing procedures and to avoid the potential for incorrect 
self-administration or overdose of medication. 
Patients should be instructed to store the medication as directed by the label on the 
packaging. Patients should be instructed to return their empty or partially used cartons 
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to the investigative site at their next visit, rather than discarding them, as permitted by 
site policy. Reconciliation will occur accordingly when the patient returns at their next 
visit for take-home medication. In case of the COVID-19 pandemic preventing a 
patient from attending the study site, drug packs and dosing diaries should be 
returned at the next available on-site clinic visit. Any excursions in temperature 
should be reported and dealt with on a case-by-case basis. 
Rationale for Change:
To add clarification to this protocol.
Change 15: Added language regarding alternative methods for administering study 
procedures/assessments when it is not possible for the patient to come to the study site due to the 
COVID-19 pandemic.
The primary change occurs in Section 9.4 Study Procedures: 
Added text:In acknowledgement of hospital, local, state or national government restrictions, 
or other site-related factors caused by the COVID-19 pandemic that may 
prevent investigators from conducting the study according to the Schedule of 
Events at the clinical study site, investigators may continue patients in the study 
despite departure from the Schedule of Events. Investigators are expected to 
evaluate the impact to the safety of the study participants and site personnel for 
patients to continue. In evaluating such requests, the investigator/study site staff 
will give the highest priority to the safety and welfare of the patients. Patients 
must be willing and able to continue taking study medication and remain 
compliant with the protocol. For patients that are impacted by the COVID-19 
pandemic, any procedures not conducted per the study protocol will be 
documented in the eCRF. 
Alternative methods should be considered for performing the assessments by 
other means than the patient presenting to the clinic (eg, remote assessment, 
having lab assessment performed at a facility closer to the patient’s home, etc.) If 
a patient misses an in-person study visit, the investigator/study team staff will 
speak directly with the patient by telephone or other medium (eg, a 
computer-based video communication) during each visit window to assess 
subject safety and overall clinical status. During this contact with the patient, the 
study site physician or other qualified site staff should at minimum conduct AE 
collection and an assessment of clinical symptoms. Other study assessments may 
be collected remotely as is feasible and may involve audio or video recording. 
Assessments/procedures that cannot be completed during the protocol-specified 
window because a site visit is done remotely (eg, hematology, clinical chemistry, 
concomitant medications/procedures) are waived. 
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Rationale for Change:
To account for the COVID-19 pandemic affecting study conduct.
Change 16: Clarified that patients previously enrolled in this study who remain on study treatment 
upon implementation of Amendment 3 may need to be reconsented, according to IRB/IEC 
standards.
The primary change occurs in Section 9.4.1 Informed Consent: 
Added text:Patients previously enrolled in this study who remain on study treatment upon 
implementation of Amendment 3 may need to be reconsented, according to 
IRB/IEC standards. Reconsenting should be done in person, where possible. 
Remote reconsenting is permitted as long as the process adheres to site, 
IRB/IEC, and GCP standards and local regulations.
Rationale for Change:
To clarify that patients previously enrolled and still on treatment in this rollover study may need to 
reconsent.
The following sections also contain this change:

Section 15.2 Subject Information, Informed Consent, and Subject Authorization. 

Appendix A Schedule of Events, footnote “d”.
Change 17: Clarified regional exceptions for assessment of carbon dioxide, depending on 
standard of care.
The primary change occurs in Section 9.4.8.1 Clinical Chemistry, Hematology, and Urinalysis: 
Description 
of change:
Footnote added to “Carbon Dioxide” in Table 9.a
Clinical Chemistry and 
Hematology Tests.
Added text: a If CO2 is not done as a part of standard care in the participant’s region, then 
this test does not need to be performed.
Rationale for Change:
To clarify assessments in this protocol.
Change 18: Updated the criteria for withdrawing patients from study.
The primary change occurs in Section 9.6 Withdrawal of Patients From Study: 
Initial 
wording:
A patient will be withdrawn from the study for any of the following reasons:

Study terminated by sponsor.

Withdrawal by subject.
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
Lost to follow-up. 

Death.
A patient may also be withdrawn from the study for any of the following reasons:

Adverse event.

Protocol deviation. 

Progressive disease (as defined in the patient’s parent study). 

Clinical deterioration, in the investigator’s opinion. 

Pregnancy.

Other.
Amended 
or new 
wording:
A patient will be withdrawn from the study for any of the following reasons:

Progressive disease (as defined in the patient’s parent study). 

Pregnancy.

Transition to commercial supply of study drug(s).

Study terminated by sponsor.

Withdrawal by subject.

Lost to follow-up.

Death.
A patient may also be withdrawn from the study for any of the following reasons:

Adverse event.

Protocol deviation. 

Progressive disease (as defined in the patient’s parent study). 

Clinical deterioration, in the investigator’s opinion.

PregnancyInvestigator’s decision.

Other.
Rationale for Change:
To clarify the withdrawal criteria in this protocol. 
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Change 19: Added language to Procedures for Recording and Reporting Adverse Events and 
Serious Adverse Events.
The primary change occurs in Section 10.2 Procedures for Recording and Reporting Adverse 
Events and Serious Adverse Events: 
Added text:The paper SAE forms must be submitted via fax (see fax numbers below) within 
24 hours of awareness. In case of fax, site personnel must confirm successful 
transmission of all pages and include an e-mail address on the fax cover sheet so 
that an acknowledgment of receipt can be returned via e-mail within 1 business 
day. E-mail submission of paper SAE forms with a PDF attachment should only 
be used in the case where fax is not possible within 24 hours of receiving the 
event. In case of e-mail, site personnel must confirm successful transmission by 
awaiting an acknowledgment of the receipt via e-mail within 1 business day. If 
SAEs are reported via fax or by e-mail, the EDC application must be updated as 
soon as possible with the appropriate information.
Rationale for Change:
To assist in timely submission of SAE reports.
Change 20: Revised language regarding the statistical analyses.
The primary change occurs in Section 13.1.3 Safety Analysis: 
Initial 
wording:
The following AEs will be summarized using the FAS: 

All SAEs.

All ≥Grade 3 AEs. 

≥Grade 2 peripheral neuropathy.

New primary malignancies. 

Any AE resulting in dose modification or discontinuation of any study drug.

Any other AE that in the opinion of the investigator is a clinically significant 
event. 
No statistical testing or inferential statistics will be generated.
All AEs will be coded using MedDRA. Data will be summarized using preferred term 
and primary system organ class. Local laboratory assessment changes and vital sign 
changes from study entry to end of study will also be summarized.
Exposure to study drug and study regimen will be tabulated. In addition, reasons for 
drug discontinuation will be summarized. 
Concomitant medications and procedures related to treatment of AEs from screening 
through the end of study will be classified by generic terms according to the WHO 
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drug dictionary. 
Data will be presented by the entire safety population, by population of monotherapy 
of ixazomib and by population of ixazomib in combination with other anticancer 
agents(s) as specified in the SAP. Additional safety analyses by subgroups such as 
drug indication and baseline characteristics may be performed as specified in the SAP. 
Amended 
or new 
wording:
The following AEs will be summarized with descriptive statistics for all patients 
who receive at least 1 dose of ixazomib using the FAS: 

All SAEs.

All ≥Grade 3 AEs. 

≥Grade 2 peripheral neuropathy.

New primary malignancies. 

Any AE resulting in dose modification or discontinuation of any study drug.

Any other AE that in the opinion of the investigator is a clinically significant 
event. 
No formal statistical testing or inferential statistics will be generated.
All AEs will be coded using the current MedDRA version at the time of the 
analysis. Data will be summarized using preferred term and primary system organ 
class. Local laboratory assessment changes and vital sign changes from study entry to 
end of study will also be summarized.
Exposure to study drug and study regimen will be tabulated. In addition, reasons for 
drug discontinuation will be summarized. 
Concomitant medications and procedures related to treatment of AEs from screening 
through the end of study will be classified by generic terms according to the WHO 
drug dictionary. 
Data will be presented by the entire ixazomib safety population, by population of 
monotherapy of ixazomib, and by population of ixazomib in combination with other 
anticancer agents(s) as specified in the SAP. Safety listings will be prepared for 
patients receiving other study drugs and not ixazomib. Additional safety analyses 
by subgroups such as drug indication and baseline characteristics may be performed as 
specified in the SAP.
Rationale for Change:
To clarify the statistical analyses for this study. 
Section 2.0 STUDY SUMMARY also contains this change.
Change 21: Clarified language regarding procedures for reporting product complaints or 
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medication errors.
The change occurs in Section 10.5 Procedures for Reporting Product Complaints or Medication 
Errors (Including Overdose): 
Initial 
wording:
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 report this via the phone numbers or e-mail addresses provided below.
A medication error is a preventable event that involves an identifiable patient and that 
leads to inappropriate medication use, which may result in patient harm. Whereas 
overdoses and underdoses constitute medication errors, doses missed inadvertently by 
a patient do not. Individuals who identify a potential medication error (including 
overdose) situation should immediately report this via the phone numbers or e-mail 
address provided below.
[Table of contact information]
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 Cognizant (refer to Section 
10.2).
Amended 
or new 
wording:
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 report this via the phone numbers or e mail addresses provided belowto: 
ctmcomplaint@takeda.com.
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 Cognizant 
(refer to Section 10.2).
A medication error is a preventable event that involves an identifiable patient and that 
leads to inappropriate medication use, which may result in patient harm. Whereas 
overdoses and underdoses constitute medication errors, doses missed inadvertently by 
a patient do not. Individuals who identify a potential medication error (including 
overdose) situation should immediately report this via the phone numbers or e mail 
address provided belowto Cognizant (refer to Section 10.2). 
[Deleted table of contact information]
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 Cognizant (refer to Section 
10.2).
Rationale for Change:
To clarify procedures in this protocol. 
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Change 22: Clarified language regarding quality assurance audits and Regulatory Agency 
inspections.
The change occurs in Section 14.3 Quality Assurance Audits and Regulatory Agency Inspections: 
Initial 
wording:
The study site also may be subject to quality assurance audits by the sponsor or 
designees. In this circumstance, the sponsor-designated auditor will contact the site in 
advance to arrange an auditing visit. 
Amended 
or new 
wording:
The study site also may be subject to quality assurance audits by the sponsor or 
designees. In this circumstanceThe investigator agrees to provide access to 
records, facilities, and personnel for conduct of any inspection or audit. If a 
quality assurance audit is requested, the sponsor-designated auditor will contact the 
site in advance to arrange an auditing visit.
Rationale for Change:
To clarify procedures in this protocol. 
Change 23: Add information about alternative monitoring approaches, such as remote source data 
verification, in the event a monitor cannot visit the site in a timely manner due to the COVID-19 
pandemic.
The change occurs in Section 14.1 Study-Site Monitoring Visits: 
Added text:In the event a monitor cannot visit the site in a timely manner due to the 
COVID-19 pandemic, alternative monitoring approaches such as remote source 
data verification (SDV) or telephone contact may be used to ensure data quality 
and integrity and maintain patient safety. Alternative monitoring approaches 
should be used only where allowed by the local Health Authority and permitted 
by the IRB/IEC.
Rationale for Change:
To clarify remote source data verification procedures to account for the COVID-19 pandemic.
Change 24: Clarify the ixazomib capsule strengths that are available.
The primary change occurs in Section 8.9 Description of Investigational Agents: 
Initial 
wording:
The ixazomib capsule formulation consists of the drug substance (ixazomib citrate), 
microcrystalline cellulose, talc, and magnesium stearate. There are 6 capsule 
strengths: 0.2, 0.5, 2.0, 2.3, 3.0, and 4.0 mg. Each strength is differentiated by a unique 
capsule size and color. Dosage strength is stated as ixazomib. Ixazomib capsules are 
individually packaged in blisters.
For additional details, please see the ixazomib IB and Pharmacy Manual.
Amended 
or new 
The ixazomib capsule formulation consists of the drug substance (ixazomib citrate), 
microcrystalline cellulose, talc, and magnesium stearate. There are 6 7 capsule 
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wording:
strengths: 0.2, 0.5, 2.0, 2.3, 3.0, and 4.0, and 5.5 mg. Each strength is differentiated by 
a unique capsule size and color. Dosage strength is stated as ixazomib. Ixazomib 
capsules are individually packaged in blisters.
For additional details, please see the ixazomib IB and Pharmacy Manual.
Section 8.10 Preparation, Reconstitution, and Dispensation also contains this change.
Rationale for Change:
To clarify that capsule strength 5.5 mg is available.
For non-commercial use only


For non-commercial use only

SAP_001.pdf: 
For non-commercial use only


STATISTICAL ANALYSIS PLAN 
STUDY NUMBER: C16027 
An Open-Label, Rollover Protocol for Patients Previously Enrolled in Takeda-Sponsored 
Ixazomib Studies 
Ixazomib Rollover Study 
Version: Draft Version 4 
Date: 15 September 2023 
Prepared by: 
, MS 
, Oncology Statistics 
Based on: 
Protocol Version: Amendment 03 
Protocol Date: 03 June 2021 
CONFIDENTIAL PROPERTY OF TAKEDA 
This document is a confidential communication of Takeda. Acceptance of this document 
constitutes the agreement by the recipient that no information contained herein will be published 
or disclosed without written authorization from Takeda. 
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Page 2 of 20
Statistical Analysis Plan v4.0 
15SEP2023
 
CONFIDENTIAL 
Amendment History: 
Date 
Amendment Number 
Amendment type 
Reason 
23 March 2017 
Initial SAP 
Not applicable 
 
04 February 2021 
2.0 
 
Initial SAP not 
signed off 
01 February 2023 
3.0 
Substantial 
amendment 
Updated to align 
with protocol 
v3.0. 
Protocol 
deviation 
categories added. 
 
15 September 2023 
4.0 
 
Previous SAP not 
signed off 
 
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Statistical Analysis Plan v4.0 
15SEP2023
 
CONFIDENTIAL 
1.0 
APPROVAL SIGNATURES 
Electronic signatures can be found on the last page of this document. 
 
 
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Study C16027 
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Statistical Analysis Plan v4.0 
15SEP2023
 
CONFIDENTIAL 
2.0 
TABLE OF CONTENTS 
1.0 
APPROVAL SIGNATURES...............................................................................................3 
2.0 
TABLE OF CONTENTS .....................................................................................................4 
3.0 
LIST OF ABBREVIATIONS ..............................................................................................6 
4.0 
OBJECTIVES ......................................................................................................................7 
4.1 
Primary Objectives.........................................................................................................7 
4.2 
Study Design ..................................................................................................................7 
5.0 
ANALYSIS ENDPOINTS ..................................................................................................8 
5.1 
Primary Endpoints .........................................................................................................8 
6.0 
DETERMINATION OF SAMPLE SIZE ............................................................................8 
7.0 
METHODS OF ANALYSIS AND PRESENTATION .......................................................8 
7.1 
General Principles ..........................................................................................................8 
7.1.1 
Study Definitions ...................................................................................................9 
7.1.2 
Definition of Study Days .......................................................................................9 
7.1.3 
Definition of Study Visit Windows .......................................................................9 
7.1.4 
Conventions for Missing Adverse Event Dates ...................................................10 
7.1.5 
Conventions for Missing Concomitant Medication/Procedure Dates .................11 
7.2 
Analysis Sets ................................................................................................................12 
7.3 
Disposition of Patients .................................................................................................12 
7.4 
Demographic and Other Baseline Characteristics .......................................................13 
7.5 
Concomitant Medications and Procedures...................................................................13 
7.6 
Study Drug Exposure and Compliance ........................................................................14 
7.7 
Efficacy Analysis .........................................................................................................15 
7.8 
Pharmacokinetic/Pharmacodynamic Analysis .............................................................15 
7.9 
Other Outcomes ...........................................................................................................15 
7.10 
Safety Analysis ............................................................................................................15 
7.10.1 
Adverse Events ....................................................................................................15 
7.10.2 
Serious Adverse Events .......................................................................................16 
7.10.3 
All Grade 3 or Higher Adverse Events ................................................................17 
7.10.4 
All Grade 2 or Higher Peripheral Neuropathy Events .........................................17 
7.10.5 
New Primary Malignancies .................................................................................17 
7.10.6 
Adverse Events Resulting in Dose Modification or Discontinuation of Study 
Drug .....................................................................................................................18 
7.10.7 
Deaths ..................................................................................................................18 
7.10.8 
Clinical Laboratory Evaluations ..........................................................................18 
7.10.9 
Vital Signs ...........................................................................................................18 
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Statistical Analysis Plan v4.0 
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CONFIDENTIAL 
7.10.10 12-Lead ECGs .....................................................................................................19 
7.10.11 Other Observations Related to Safety .................................................................19 
7.11 
Interim Analysis ...........................................................................................................19 
7.12 
Changes in the Statistical Analysis Plan ......................................................................19 
8.0 
REFERENCES ..................................................................................................................20 
 
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Statistical Analysis Plan v4.0 
15SEP2023
 
CONFIDENTIAL 
3.0 
LIST OF ABBREVIATIONS 
Abbreviation 
Term 
AE 
adverse event 
AL amyloidosis 
systemic light-chain amyloidosis 
ASCT 
autologous stem cell transplant 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
AST 
aspartate aminotransferase 
BUN 
blood urea nitrogen 
CO2 
carbon dioxide 
eCRF 
case report form (electronic or paper) 
CRO 
contract research organization 
CSR 
clinical study report 
ECG 
electrocardiogram 
EOS 
end of study 
EOT 
end of treatment 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GGT 
g-glutamyl transferase 
ICH 
International Conference on Harmonisation 
IEC 
independent ethics committee 
IP 
investigational product 
IRB 
institutional review board 
IV 
Intravenous 
IVRS 
interactive voice response system 
IWRS 
interactive web response system 
LDH 
lactate dehydrogenase 
LenDex 
lenalidomide plus dexamethasone 
MedDRA 
Medical Dictionary for Regulatory Activities 
MLN2238 
research name for ixazomib, the biologically active boronic acid form of the drug substance 
MLN9708 
research name for ixazomib citrate, the stable citrate ester of ixazomib 
MM 
multiple myeloma 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NOS/NEC 
MedDRA terms for “Not otherwise specified” and “Not elsewhere classified” 
NDMM 
newly diagnosed multiple myeloma 
PN 
peripheral neuropathy 
RRAL amyloidosis 
relapsed and/or refractory systemic light-chain amyloidosis 
RRMM 
relapsed and/or refractory multiple myeloma 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SmPC 
Summary of Product Characteristics 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment-emergent adverse event 
US 
United States 
USPI 
United States Prescribing Information 
WHO 
World Health Organization 
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4.0 
OBJECTIVES 
4.1 
Primary Objectives 
The primary objective is to provide continued access to ixazomib and/or other study drugs from 
an ixazomib parent study and to evaluate the long-term safety profile of ixazomib. 
4.2 
Study Design 
This is an open-label, multicenter, rollover study to provide continued access to ixazomib and/or 
other study drugs from a designated ixazomib parent study (ie, Studies C16003, C16005, 
C16006, C16007, C16008, C16010 Global, C16011, C16013, C16014 Global and Korean 
Continuation, C16017, C16020, C16029, and C16047) when the patient has no other means to 
access study treatment. The study will also evaluate the long-term safety profile of ixazomib in 
those patients who continue to receive ixazomib. The patient population will consist of patients 
who have previously received and tolerated treatment in a Takeda-sponsored clinical study of 
ixazomib, and in the investigator’s opinion and approved by the Takeda medical monitor, may 
benefit from continued therapy with 1 or more of the drugs from a parent protocol (eg, response 
to therapy or stable disease without evidence of disease progression). 
Patients participating in a designated ixazomib parent study will enter the rollover study at the 
time-point when they have completed the end of treatment (EOT) visit in the parent study and 
when the rollover study is active at the investigative site. Patients should enter the study within a 
maximum of 8 weeks of their last dose of ixazomib in the parent study or as agreed upon with 
the Takeda clinician/designee. Following enrollment, patients may receive study drug(s) until 
they experience disease progression, clinical deterioration in the investigator’s judgment, 
experience an unacceptable toxicity, withdraw consent, pursue an alternative therapy, meet other 
study-specified reasons for discontinuation of study drug, or until the patient is transitioned to 
ixazomib/other therapy through commercial channels.  
The disease assessments are recommended to be performed per standard of care.  At the end of 
study (EOS) visit, an overall investigator assessment of best response during this rollover study 
and the investigator assessment of date of progression will be captured in the electronic case 
report forms (eCRFs). 
Local safety-related laboratory evaluations and vital sign measurements will be performed 
according to the parent study schedule; however, they will only be recorded in the eCRFs prior 
to the first dose of ixazomib in the rollover study, at the EOT, and as spontaneously reported by 
the investigator. Electrocardiogram assessments will only be performed as clinically indicated. 
During treatment, dosing modification decisions will be made per the parent study. Systemic 
treatment with strong cytochrome P-450 (CYP) 3A inducers is prohibited during the study. The 
procedures and medication prohibited in the patient’s parent study are prohibited during this 
study.  
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5.0 
ANALYSIS ENDPOINTS 
5.1 
Primary Endpoints 
The primary endpoint is safety which will be assessed by the incidence of the following 
treatment-emergent adverse events (TEAEs): 
• All serious adverse events (SAEs). 
• All ≥Grade 3 AEs. 
• ≥Grade 2 peripheral neuropathy. 
• New primary malignancies. 
• Any AE resulting in dose modification or discontinuation of any study drug. 
• Any other AE that in the opinion of the investigator is a clinically significant event. 
6.0 
DETERMINATION OF SAMPLE SIZE 
There is no statistical hypothesis and no power consideration in this study. The estimated number 
of patients to be enrolled is approximately 250. Enrollment is defined as when the patient 
receives the first dose of study drug in this rollover study.  
7.0 
METHODS OF ANALYSIS AND PRESENTATION 
7.1 
General Principles  
In general, analyses will be primarily descriptive in nature. No formal statistical tests will be 
performed.  
Summary tabulations will be presented to display the number of observations, mean, standard 
deviation, median, minimum, and maximum for continuous variables. Means and medians will 
be presented to 1 more decimal place than the recorded data. The standard deviations (SDs) will 
be presented to 2 more decimal places than the recorded data. 
For categorical variables, the number and percentage per category for categorical data will be 
presented, unless specified otherwise. The denominator for the proportion will be based on the 
number of patients who provided non-missing responses to the categorical variable.  
Patients will be analyzed by whether they received monotherapy of ixazomib or ixazomib in 
combination with other anticancer agent(s) according to the regimen the patient was receiving at 
the time of rollover from the parent study, or according to the required modification from a 
parent study. A windowing convention will be used to determine the analysis value for a given 
study visit for observed data analyses.  
At the time of clinical study report (CSR) lock, all relevant data will be queried and cleaned; a 
database snapshot will be taken and used for the CSR.  
All statistical analyses will be conducted using SAS® Version 9.4, or higher. 
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7.1.1 
Study Definitions 
Ixazomib in combination with lenalidomide and dexamethasone was approved by the US FDA in 
November 2015 for the treatment of patients with multiple myeloma who have received at least 1 
prior therapy. The exploration of the drug is ongoing in other indications. This study will enable 
continued access to ixazomib for qualified patients who have participated in previous designated 
ixazomib clinical studies and have derived clinical benefit until ixazomib is available to the 
patient through commercial channels, or until patient treatment discontinuation, whichever is 
sooner up to approximately 5 years post study entry. Upon the review and agreement with the 
Takeda medical monitor, done every 24 months, continued access to ixazomib will be allowed 
for patients who in the investigator’s opinion are deriving clinical benefit from ixazomib. 
7.1.2 
Definition of Study Days 
Study Day 1 is defined as the date on which a patient is administered their first dose of 
medication in the rollover study. The Study Entry/Day 1 visit for this rollover study should be 
coincident with or as soon as possible after the EOT/EOS visit in the parent study. Other study 
days are defined relative to the Study Day 1 with Day 1 being Study Day 1 and Day -1 being the 
day prior to Study Day 1. 
Baseline values are defined as the last observed value before the first dose of study drug in the 
roll-over study.  
Unless otherwise specified, the reference for assessment during this study will be based on the 
value collected at the time closest to, but before, the start of study drug administration in the 
rollover study. The end of parent study assessment could serve as the baseline evaluation if 
occurring within 8 weeks from the start of rollover study.  
These imputation rules will be applicable where baseline/screening dates are incomplete; 
• If only the day-component is missing, the first day of the month will be used if the year 
and the month are the same as those for the first dose of study drug. Otherwise, the 
fifteenth will be used. 
• If only the year is present, and it is the same as the year of the first dose of study drug, the 
fifteenth of January will be used unless it is later than the first dose, in which case the 
date of the first of January will be used. 
• If only the year is present, and it is not the same as the year of the first dose of study 
drug, the fifteenth of June will be used.  
7.1.3 
Definition of Study Visit Windows 
All data will be categorized based on the scheduled visit at which it was collected.  These visit 
designators are predefined values that appear as part of the visit tab in the eCRF. 
Notwithstanding visit windows used in the course of treatments. During the treatment period, 
there will be a +/- 2-day window for study visits unless otherwise noted. Therefore, a scheduled 
visit will account appropriately for the windows applied without any effect on the visit schedule 
designation. 
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Where a patient is provided a 3-month supply of study medication and an on-site visit is not 
completed for the 2nd and 3rd dose cycles, the date of visit should be entered as at the date of the 
first dose of study drug. 
7.1.4 
Conventions for Missing Adverse Event Dates 
All data will be categorized based on the scheduled visit at which it was collected.  These visit 
designators are predefined values that appear as part of the visit tab in the eCRF.  
If an AE start date is missing, the derived start date will be calculated as the first non-missing 
valid date from the following list (in order of precedence): 
a. First study medication date in the C16027 study 
b. Informed consent date (for SAEs only)  
AEs or SAEs, with start date that are completely or partially missing will be imputed as follows: 
1. If the start date has month and year but day is missing 
a. If the start month and year are same as that of first dose date, the first dose date will 
be used instead. If the onset month and year are different from that of the first dose 
date, then the first day of the month will be used. 
b. After imputation, the imputed dates will be compared against the stop date. If this 
imputed date is later than the stop date (possibly imputed), then the stop date will be 
used instead. 
2. If the start date has year, but day and month are missing 
a. If the start year is same as that of first dose date, then the first dose date will be used 
instead. 
b. If start year is different than that of the first dose date, the 1st of January of the year 
will be imputed. 
c. After the imputation, the imputed dates will be compared against the dose stop date. 
If this imputed date is later than the stop date (possibly imputed), then the stop date 
will be used instead. 
3. If the start date of an adverse event is completely missing, then it is imputed with the first 
dose date. 
4. When imputing a start date ensure that the new imputed date is sensible, that is, the 
imputed date is prior to the end date of the AE. 
For AEs or SAEs, a missing or incomplete end date will be imputed according to the following 
conventions: 
1. If an end date is missing, the derived end date will be imputed as the last assessment date, 
assuming that the last assessment occurs after the AE start. If the last assessment occurs 
prior to the AE start date, the derived end date will be imputed as the AE start date. 
2. If an end date is incomplete, the derived end date will be calculated following: 
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a. Missing day, but month and year present: the day will be imputed as the last date (for 
example February 2021 will be imputed as 28 February2021) of the month.  
b. Missing day and month, but year present: the day and month will be imputed as the 
31st December of the year.  
c. If the imputed AE end date occurs after the database lock date, the imputed AE end 
date will be imputed as the database lock date 
d. After the imputation, the imputed dates will be compared against the date of death, if 
available.  If the imputed date is later than the date of death, the date of death will be 
used as the imputed date instead.  
3 If the stop date of an adverse event is completely missing, then this event will be 
regarded as ongoing and will be included in the summary table. 
7.1.5 
Conventions for Missing Concomitant Medication/Procedure Dates 
Concomitant therapies with start date that are completely or partially missing will be analyzed as 
follows: 
If the start date has month and year but day is missing, the therapy will be included in the 
summary table if the month and year are:  
a) On or after the month and year of the date of the first dose of study drug and  
b) On or before the month and year of the date of the last dose of study drug plus 30 
days. 
If the start date has year, but day and month are missing, the therapy will be included in the 
summary table if the year is: 
a. On or after the year of the date of the first dose of study drug and  
b. On or before the year of the date of the last dose of study drug plus 30 days. 
If the start date of concomitant therapies is completely missing and the stop date of concomitant 
therapies is prior to the date of the first dose of study drug, then this therapy will not be included.  
If the start date of concomitant therapies is completely missing and the stop date of concomitant 
therapies is on or after the date of the first dose of study drug, then the therapy will be included 
in the summary table. 
When imputing a start date ensure that the new imputed date is sensible, that is, the imputed date 
is prior to the end date of the concomitant medication. 
If the stop date is missing, partial or “continuing:”: 
a. If the day is missing, the stop day will be the last day of the month reported  
b. If the month is missing, the stop month will be the month during which the last 
assessment occurred  
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c. If the month and day are missing, the stop date will be imputed in this order; the 
month according to (b), and the day according to (a). 
d. If the year or the entire date is missing or if the medication is “continuing”, the date 
will be the date of the last assessment. 
If the start date and stop date of concomitant therapies are completely missing, then the therapy 
will be included in the summary table. 
7.2 
Analysis Sets 
Data will be presented by the entire Safety population. This will include all enrolled patients who 
receive at least 1 dose of ixazomib medication.  
7.3 
Disposition of Patients 
Summary of patient disposition will be presented by monotherapy of ixazomib or ixazomib in 
combination, and will include the number and percentage of patients for the following:  
• Number of Patients Enrolled by Site and Treatment dosage group 
• Disposition of patients - this should include; 
o patients on-going on study,  
o patients discontinued from the study, and  
o primary reason to discontinue from the study.  All percentages will be based on 
the number of patients in the Safety population. 
Important  Protocol Deviations –  Identification of significant protocol deviations will be 
according to the Clinical Study Protocol Deviations Management Plan (version 3.0) for the 
study.  
Summary of significant protocol deviations will be presented by monotherapy of ixazomib or 
ixazomib in combination, and will include the number and percentage of patients with a 
significant deviation in at least one of the following categories:  
• Entered study but did not satisfy entry criteria  (inclusion/exclusion) 
• Informed consent 
o Failure to obtain initial written consent prior to study-related procedures being 
performed 
o Patient was not re-consented in a timely manner, or at all 
o Use of Incorrect Informed Consent Form 
• No safety lab results collected  prior to dosing 
• Endpoint not assessed correctly/Safety reporting 
• Used prohibited concomitant medication 
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• Treatment of patient before receipt of IRB/EC approval 
• Study treatment compliance 
o Non adherence to scheduled IP dose administration times 
o Patient IP compliance- major overdose 
• Other protocol deviations 
o Pregnancy event 
o Pt met criteria for discontinuation but remained on treatment 
 
By-patient listings will present data on; 
• Patient disposition including. 
o Study Information, including date first patient signed ICF, date of last patient’s 
last visit/contact, date of last patient’s last procedure for collection of data for 
primary endpoint, dose level, and cycle duration. 
o MedDRA Version,  
o WHODrug Version and  
o Any other information of clinical importance 
• Protocol deviations 
7.4 
Demographic and Other Baseline Characteristics 
Demographic and baseline characteristics will be summarized and presented by monotherapy of 
ixazomib or ixazomib in combination. For continuous variables, summary statistics (mean, 
median, standard deviation, minimum and maximum of non- missing values) will be generated. 
For categorical variables, counts and percentages of each possible value will be generated.  
Demographic and baseline characteristics such as age, age group (<65, >=65 - <75, >=75), sex 
and weight, will be summarized by monotherapy of ixazomib or ixazomib in combination. Age 
will be calculated from date of birth to date of enrollment.  
Listing of by patient demographic and baseline characteristics will also be provided. 
7.5 
Concomitant Medications and Procedures 
Only concomitant medications and therapeutic procedures related to the treatment of AEs, that 
are to be reported in this study, will be recorded in the eCRF. Concomitant medications and will 
be summarized and reported separately by monotherapy of ixazomib or ixazomib in 
combination. This includes all medications and procedures meeting this criterion initiated 
on/after the date of first dose of ixazomib and within 30 days after the last dose date. 
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Concomitant medication will be assessed through the study period will be classified by generic 
terms according to the World Health Organization (WHO) drug dictionary. 
The number and percentage of patients receiving concomitant medications or procedures will be 
tabulated separately by Anatomical Therapeutic Chemical (ATC) classification pharmacological 
subgroup and WHO drug generic term for monotherapy of ixazomib or ixazomib in combination 
for the safety population.  
By-patient listing will also be presented for concomitant medications and/or procedures. 
7.6 
Study Drug Exposure and Compliance 
A summary of drug exposure to ixazomib will be characterized by number of treated cycles, 
numbers and percentages of patients who had ≥1,  ≥2 , …, and ≥ 18 treated cycles, total amount 
of dose taken, total number of dose taken, relative dose intensity (%) and drug compliance  in the 
safety population. Aggregate summary of numbers and percentages of patients who had 1 to 6, 7 
to 12, 13 to 18, and ≥ 19 treated cycles will also be presented in the same table. All summaries 
will be presented by monotherapy of ixazomib or ixazomib in combination.  
Extent of exposure (days), which is calculated as (last dose date of study drug – first dose date of 
study drug + 1), will also be presented. The number of patients, and summary of duration of 
exposure (days) will be provided as mean, SD, median, minimum and maximum duration of 
exposure.  
A treated cycle is defined as a cycle in which the patient received any amount of any study drug. 
A length of treatment cycle (days) is determined per the patient’s parent study (e.g., 21- or 28-
day cycles). 
Drug exposure is presented by relative dose intensity (RDI) and calculated as follows:  
Relative dose intensity (%) = 100 * (Total amount of dose taken) / (Total prescribed dose of 
treated cycles). 
The number of patients with 100% relative dose intensity, 80% to < 100%, 50% to < 80%, and 
< 50% will be summarized by monotherapy of ixazomib or ixazomib in combination, and for all 
patients.  
Percent compliance is calculated as 100% * (study drug taken in mg) / (study drug expected to 
be taken in mg). Only reduced prescribed or increased prescribed or dose hold or discontinued 
permanently will change the expected prescribed dose.  
The actions on the study drug, ixazomib, such as dose reduction, held, missed, increased, 
delayed, or discontinued permanently will be summarized separately for monotherapy of 
ixazomib or ixazomib in combination, and for all patients. and by cycle aggregates such as for 
Cycles 1-6, 7-12, 13-20 and >20 if there is sufficient data for analysis. 
 
Dosing data will also be presented in a by-patient listing. 
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7.7 
Efficacy Analysis 
No efficacy analyses are planned for this study as there is no statistical hypothesis testing. The 
overall investigator assessment of best response obtained during this rollover study and 
investigator assessment of date of progression will be listed.  
7.8 
Pharmacokinetic/Pharmacodynamic Analysis 
Not applicable 
7.9 
Other Outcomes 
Not applicable 
7.10 
Safety Analysis 
Safety analysis will include assessments of: 
• Adverse events 
• All clinically relevant deterioration in clinical laboratory assessments 
• Vital signs 
• Other clinically relevant assessments 
7.10.1 
Adverse Events 
All reported adverse events, including all clinically relevant deterioration in laboratory 
assessments or other clinical findings, will be coded using the current Medical Dictionary for 
Regulatory Activities (MedDRA) version at time of database lock. Severity of AEs will be 
determined according to NCI CTCAE, Version 5.0 or appropriate version. Treatment-emergent 
AE is defined as any AE that occurs after administration of the first dose of the study treatment 
through 30 days after the last dose of the study treatment. TEAEs will be tabulated according to 
the MedDRA by system organ class and preferred terms separately for monotherapy of ixazomib 
or ixazomib in combination. Adverse events of interest that are ongoing at the time of study 
entry will be recorded in the eCRF as baseline AEs. 
The following TEAEs will be summarized using the safety analysis set: 
• All SAEs. 
• All ≥Grade 3 AEs. 
• ≥Grade 2 peripheral neuropathy. 
• New primary malignancies. 
• Any AE resulting in dose modification or discontinuation of any study drug. 
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• Any other AE that in the opinion of the investigator is a clinically significant event. This 
includes any clinically relevant deterioration in laboratory assessments or other clinical 
finding. These events will be included as part of the overall AE table and not reported 
separately. 
Patients with the same AE more than once will have that event counted only once within each 
body system and once within each preferred term. 
An overall summary TEAE table will include numbers and percentages of patients who had at 
least one TEAE of the above-mentioned categories, respectively. 
Most commonly reported (at least 10% of all patients) treatment-emergent AEs will be presented 
by preferred term only. 
In this study, intensity for each AE, including any lab abnormality, will be determined using the 
NCI CTCAE, Version 5.0 or appropriate version. 
 
A by-patient listing of all deaths regardless of whether on study or not will also be presented. In 
this listing, on-study deaths will be flagged. On-study death is defined as the death that occurs 
between the first dose of any study drug and 30 days of the last dose of any study drug. 
7.10.2 
Serious Adverse Events 
Serious adverse events, including all TEAEs of the following characteristics; 
• Results in death. 
• Is life-threatening: Refers to an AE in which the patient was at risk of death at the time 
of the event. It does not refer to an event which hypothetically might have caused death if 
it were more severe. 
• Requires inpatient hospitalization or prolongation of an existing hospitalization (see 
Section 10.2 of Protocol). 
• Results in persistent or significant disability or incapacity: Defined as a substantial 
disruption of a person’s ability to conduct normal life functions. 
• Is a congenital anomaly/birth defect. 
• Is a medically important event. This refers to an AE that may not result in death, be 
immediately life threatening, or require hospitalization, but may be considered serious 
when, based on appropriate medical judgment, may jeopardize the patient, require 
medical or surgical intervention to prevent 1 of the outcomes listed above, or involves 
suspected transmission via a medicinal product of an infectious agent. Examples of such 
medical events include: 
o allergic bronchospasm requiring intensive treatment in an emergency room or at 
home, 
o blood dyscrasias or convulsions that do not result in inpatient hospitalization, 
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o development of drug dependency or drug abuse;  
o any organism, virus, or infectious particle (eg, prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or nonpathogenic, is 
considered an infectious agent. 
The number and percentage of patients experiencing at least one SAE will be summarized by 
MedDRA primary system organ class, and preferred term by monotherapy of ixazomib or 
ixazomib in combination. 
In addition, a by-patient listing of all SAEs will be presented regardless of status or causality. 
7.10.3 
All Grade 3 or Higher Adverse Events 
The number and percentage of patients experiencing at least one grade 3 or higher treatment-
emergent adverse event will be summarized by MedDRA primary system organ class, and 
preferred term for monotherapy of ixazomib or ixazomib in combination.  
In addition, a by-patient listing of all grade 3 or higher adverse events will be presented (the 
listing will contain all grade 3 or higher AEs regardless of treatment-emergent AE status). 
7.10.4 
All Grade 2 or Higher Peripheral Neuropathy Events 
A peripheral neuropathy (PN) event is defined as the treatment-emergent adverse event in the 
high-level term of peripheral neuropathies NEC according to MedDRA.  
A PN event is considered resolved if its final outcome is resolved with no subsequent PN event 
of the same preferred term occurring on the resolution date or the day before and after.  A PN 
event is considered as improved if the event improves from the maximum grade.   
The number of patients with grade 2 or higher PN events, resolution of any grade 2 or higher  PN 
event, improvement of any grade 2 or higher PN event during the treatment period and entire 
study period may be summarized for monotherapy of ixazomib or ixazomib in combination if 
data permits. 
7.10.5 
New Primary Malignancies  
The incidence proportions for new primary malignancies will be calculated for the safety 
population based on the new primary malignancy assessment. The incidence proportion is 
defined as the percentage of the patients reporting any new primary malignancy in the safety 
population with available information. A by-patient listing of new primary malignancies will be 
presented for monotherapy of ixazomib or ixazomib in combination. 
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7.10.6 
Adverse Events Resulting in Dose Modification or Discontinuation of Study Drug 
The number and percentage of patients experiencing at least one treatment-emergent adverse 
event resulting in dose modification or discontinuation of any study drug will be summarized by 
MedDRA system organ class and preferred term for monotherapy of ixazomib or ixazomib in 
combination. 
A by-patient listing of AEs resulting in dose modification or discontinuation of any study drug 
will be presented. 
7.10.7 
Deaths 
A by-patient listing of the deaths together with the cause of death, will be presented. All deaths 
occurring on-study and during follow-up will be displayed regardless of AE status for 
monotherapy of ixazomib or ixazomib in combination. 
7.10.8 
Clinical Laboratory Evaluations 
Laboratory test results from local laboratory will be used. Laboratory test results will be 
summarized according to scheduled sample collection visit; at baseline and EOS, for 
monotherapy of ixazomib or ixazomib in combination.  
Lab parameters to be analyzed are as follows: 
• Hematology: Leukocytes, Erythrocytes, Hemoglobin, Hematocrit, Platelet count (and 
character descriptors), Lymphocyte count, Monocyte count, Eosinophil count, Basophil 
count, Neutrophil count, and Blasts. 
• Serum Chemistry: Glucose, Blood urea nitrogen, Creatinine, Sodium, Potassium, Chloride, 
Carbon Dioxide, Urate or Uric acid, Calcium, Magnesium, Phosphate, Albumin, Bilirubin, 
Aspartate aminotransferase (AST), Alanine aminotransferase (ALT), Alkaline phosphatase, 
Lactate Dehydrogenase (LDH), Gamma Glutamyl Transferase. 
• Serum β-hCG pregnancy test for women of childbearing potential 
By-patient listings of scheduled laboratory along with unscheduled test results including 
hematology, serum chemistry and β-hCG pregnancy test for women of childbearing potential 
will provided. Unscheduled hematology and chemistry laboratory assessments are performed if 
clinically indicated. 
For the purposes of listings, all laboratory values will be converted to standardized units where 
appropriate. If a lab value is reported using a non-numeric qualifier (e.g., less than (<) a certain 
value, or greater than (>) a certain value), the given numeric value will be used in the summary 
statistics, ignoring the non-numeric qualifier. 
7.10.9 
Vital Signs 
A by-patient listing for the actual values at baseline and changes at end of study from baseline 
for vital sign parameters including systolic blood pressure, diastolic blood pressure, heart rate, 
and body weight, will be presented. 
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7.10.10 
12-Lead ECGs 
Not applicable 
7.10.11 
Other Observations Related to Safety 
Not applicable 
7.11 
Interim Analysis 
Not applicable 
7.12 
Changes in the Statistical Analysis Plan  
None 
 
 
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8.0 
REFERENCES 
1. Durie BG, Harousseau JL, Miguel JS, Blade J, Barlogie B, Anderson K, et al. International 
uniform response criteria for multiple myeloma. Leukemia 2006; 20(9): 1467-73. 
2. U.S. Department of Health and Human Services, National Institutes of Health National 
Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE). Version 4.03. 
14 June 2010. 
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Signature Page for Statistical_Analysis_Plan_V4
Title: 
Document Number: TDN-000203551 v1.0
Approval
Statistics
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