Conditions: Waldenstrom's Macroglobulinemia
Keywords: Waldenstrom's Macroglobulinemia
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 26
Healthy volunteers: no

Brief summary:
This research study is evaluating a drug called ixazomib (also known as MLN9708) in combination with dexamethasone and rituximab (the regimen is called IDR) as a possible treatment for Waldenstrom's Macroglobulinemia (WM).

Detailed description:
This research study is a Phase II clinical trial. Phase II clinical trials test the safety and effectiveness of an investigational regimen, IDR, to learn whether IDR works in treating a specific cancer. "Investigational" means that IDR is still being studied and that research doctors are trying to find out more about it-such as the safest dose to use, the side effects it may cause, and if IDR is effective for treating different types of cancer. It also means that the FDA (the U.S. Food and Drug Administration) has not yet approved IDR for use in participants with your type of cancer.

Ixazomib is a drug that may kill or stop cancer cells from growing by blocking the proteasome within the cell, which is responsible for degrading or breaking down a variety of proteins. This type of drug is called a proteasome inhibitor.

Rituximab is a type of protein called an antibody that attacks the cluster of differentiation 20 (CD20), a protein found on B-cells like WM. Rituximab is approved by the FDA for treating non-Hodgkin lymphoma (NHL). Dexamethasone is a steroid and is similar to the hormones naturally produced by the adrenal glands; it prevents the release of substances that cause inflammation. Rituximab and dexamethasone are often used to treat WM, alone or in combination with other drugs. Combinations with rituximab, dexamethasone and other proteasome inhibitors have shown good response rates in WM participants. Ixazomib is a proteasome inhibitor; thus the investigator swill investigate if the combination of Ixazomib, Rituximab, and Dexamethasone is also active in WM.

In this research study, the investigators are combining a new treatment ixazomib with a standard regimen, rituximab and dexamethasone, to determine whether this combination (IDR) is effective and safe for participants with previously untreated WM.

Arms:
arm 1: \- IDR The study treatment will consist on an induction and a maintenance phase. Dose modification will be permitted for toxicity

* Induction cycles will be 4 weeks long, Maintenance cycles 8 weeks long.
* Ixazomib- administered orally on predetermined days and dosage during Induction and Maintenance Phase
* Dexamethasone- administered via IV or orally on predetermined days and dosage during Induction and Maintenance Phase
* Rituximab- administered via IV on predetermined days and dosage during Induction and Maintenance Phase

Interventions: intervention 1: Ixazomib intervention 2: Dexamethasone intervention 3: Rituximab
Intervention descriptions: intervention 1: Doses given on Days 1, 8, and 15 in induction and maintenance cycles. intervention 2: Doses given on Days 1, 8, and 15 in induction and maintenance cycles. intervention 3: Doses given on Day 1 of induction and maintenance cycles.

Protocol document:
Prot_SAP_000.pdf: 
Version 9 9/13/2017 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
Protocol Version  9 Date: September 13, 2017 
 
NCI Protocol #: N/A 
 
Local Protocol #: 
 
(Millennium #X16057) 
 
Title:  
 
Phase II Trial of ixazomib, dexamethasone and rituximab in patients with untreated 
Waldenstrom’s Macroglobulinemia. 
 
Principal Investigator:  
 
Jorge J. Castillo, MD 
Email: jorgej_castillo@dfci.harvard.edu  
 
Coordinating Center:  
 
Bing Center for Waldenstrom’s Macroglobulinemia  
Dana-Farber Cancer Institute 
450 Brookline Ave. 
Boston, MA 02215 
 
Co-Investigators:  
 
Steven P. Treon, MD, PhD 
Dana-Farber Cancer Institute 
450 Brookline Ave. 
Boston, MA 02215 
 
Statistician:  
 
Katherine Kacena, Ph.D. 
66 Speen Street 
Natick, MA 01760 
Tel: 508-808-4383 
Email: kk@kkstats.com  
 
Responsible Nurse Practitioner:  
 
Toni Dubeau, NP 
Bing Center for Waldenstrom’s Macroglobulinemia  
Dana-Farber Cancer Institute 
450 Brookline Ave. 
Boston, MA 02215 
Tel: 617-632-3685 


[Type text] 
 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
Fax: 617-582-9982 
Email: toni_dubeau@dfci.harvard.edu  
 
Study Coordinator:  
 
Kirsten Meid 
Bing Center for Waldenstrom’s Macroglobulinemia  
Dana-Farber Cancer Institute 
450 Brookline Ave. 
Boston, MA 02215 
Tel: 617-632-5598 
Fax: 617-582-9982 
E-mail: Kirsten_meid@dfci.harvard.edu 
 
 
Responsible Data Manager:  
 
Kirsten Meid 
Bing Center for Waldenstrom’s Macroglobulinemia  
Dana-Farber Cancer Institute 
450 Brookline Ave. 
Boston, MA 02215 
Tel: 617-632-5598 
Fax: 617-582-9982 
E-mail: Kirsten_meid@dfci.harvard.edu 
 
 
Agents: Ixazomib, Rituximab, Dexamethasone 
 
 
This is an investigator-initiated study.  The principal investigator Jorge J. Castillo, MD  (who 
may also be referred to as the sponsor-investigator), is conducting the study and acting as the 
sponsor.  Therefore, the legal/ethical obligations of the principal investigator include both those 
of a sponsor and those of an investigator. 
 
  


IDR in WM Version 9 9/13/2017 
Millennium #X16057 
 
 
 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Induction  
 
Cycles 1 and 2 q4weeks 
Days 1, 8, 15  
Dexamethasone, Ixazomib 
 
Cycles 3-6 q4 weeks 
Days 1, 8, 15  
Dexamethasone, Ixazomib 
Day 1 
 
 
     Rituximab 
Maintenance 
 
Cycles 1-6 q8 weeks ± 2 weeks 
Day 1, 8, 15 
  Dexamethasone, Ixazomib 
Day 1 
 
 
, Rituximab 
8 weeks ± 2 weeks 
Screening 
Registration 
Remove from Trial 
Disease Progression, 
No Response, 
Unacceptable 
Toxicity 
Disease 
Progression, 
Unacceptable 
Toxicity 
Follow up 


IDR in WM Version 9 9/13/2017 
Millennium #X16057  
 
 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS ............................................................................... 5 
1. 
OBJECTIVES .................................................................................................................................................... 8 
1.1 Study Design ....................................................................................................................................................... 8 
1.2 Primary Objectives ............................................................................................................................................. 9 
1.3 Secondary Objectives .......................................................................................................................................... 9 
2. BACKGROUND ...................................................................................................................................................... 9 
2.1 Study Agents ........................................................................................................................................................ 9 
2.1 Pharmacokinetics and Drug Metabolism.......................................................................................................... 12 
Preclinical Experience ............................................................................................................................................ 13 
2.2 Study Disease .................................................................................................................................................... 29 
2.3 Rationale ........................................................................................................................................................... 30 
2.4 Correlative Studies Background ....................................................................................................................... 31 
3. PARTICIPANT SELECTION ............................................................................................................................. 32 
3.1 Eligibility Criteria ............................................................................................................................................. 32 
3.2 Exclusion Criteria .......................................................................................................................................... 33 
4. REGISTRATION PROCEDURES ...................................................................................................................... 33 
4.1 General Guidelines for DF/HCC and DF/PCC Institutions ......................................................................... 3334 
4.2 Registration Process for DF/HCC and DF/PCC Institutions ......................................................................... 34 
5. TREATMENT PLAN ............................................................................................................................................ 34 
5.1 Pre-Medication ................................................................................................................................................ 35 
5.2 Agent Administration ....................................................................................................................................... 35 
5.3 General Concomitant Medication and Supportive Care Guidelines ................................................................ 39 
5.4 Duration of Therapy .......................................................................................................................................... 40 
5.5 Duration of Follow Up...................................................................................................................................... 40 
5.6 Criteria for Removal from Study ....................................................................................................................... 41 
6. EXPECTED TOXICITIES AND DOSING DELAYS/DOSE MODIFICATIONS ......................................... 41 
6.1 Anticipated toxicities ......................................................................................................................................... 41 
6.2 Toxicity Management and Dose Modifications/Delays .................................................................................... 53 
7. DRUG FORMULATION AND ADMINISTRATION ....................................................................................... 58 
7.1 Ixazomib ............................................................................................................................................................ 58 
7.2 Rituximab ......................................................................................................................................................... 61 
7.3 Dexamethasone ................................................................................................................................................. 62 
7.4 Study compliance .............................................................................................................................................. 64 


IDR in WM Version 9 9/13/2017 
Millennium #X16057  
 
 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
7.5 Termination of Treatment and/or Study Participation ...................................................................................... 64 
8. CORRELATIVE/SPECIAL STUDIES ............................................................................................................... 64 
8.1 Determination of MYD88 and CXCR4 mutational status ................................................................................. 64 
9. STUDY CALENDAR ............................................................................................................................................ 65 
10. MEASUREMENT OF EFFECT ........................................................................................................................ 66 
10.1 Response Criteria ........................................................................................................................................... 66 
10.2 Evaluation of Best Overall Response .............................................................................................................. 66 
10.3 Duration of Response ...................................................................................................................................... 67 
10.4 Time to Progression ........................................................................................................................................ 67 
11. ADVERSE EVENT REPORTING REQUIREMENTS ................................................................................... 67 
11.1 Definitions ....................................................................................................................................................... 67 
11.2 Procedures for AE and SAE Recording and Reporting .................................................................................. 69 
11.3 Reporting to the Institutional Review Board (IRB) ......................................................................................... 71 
11.4 Reporting to the Food and Drug Administration (FDA) ................................................................................. 71 
11.5 Reporting to Hospital Risk Management ........................................................................................................ 72 
11.6 Pregnancy Reporting ...................................................................................................................................... 72 
11.7 Monitoring of Adverse Events and Period of Observation ............................................................................. 72 
11.8 Product Complaints ........................................................................................................................................ 73 
12. DATA AND SAFETY MONITORING ............................................................................................................. 73 
12.1 Data Reporting ............................................................................................................................................... 73 
12.2 Safety Meetings ............................................................................................................................................... 74 
12.3 Monitoring ...................................................................................................................................................... 74 
13. REGULATORY CONSIDERATIONS ............................................................................................................. 74 
13.1 Protocol Review and Amendments .................................................................................................................. 74 
13.2 Informed Consent ............................................................................................................................................ 75 
13.3 Ethics and Good Clinical Practice (GCP) ...................................................................................................... 75 
13.4 Study Documentation ...................................................................................................................................... 75 
13.5 Records Retention ........................................................................................................................................... 76 
13.6 IND Annual Reports ........................................................................................................................................ 76 
14. STATISTICAL CONSIDERATIONS ............................................................................................................... 76 
14.1 Study Design/Endpoints .................................................................................................................................. 76 
14.2 Populations for analysis ................................................................................................................................. 76 
14.3 Participant Disposition ................................................................................................................................... 77 
14.4 Participants Baseline Characteristics ............................................................................................................ 77 


IDR in WM Version 9 9/13/2017 
Millennium #X16057  
 
 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
14.5 Exposure to Investigational Material.............................................................................................................. 77 
14.6 Safety Analysis ................................................................................................................................................ 77 
14.7 Efficacy Analyses ............................................................................................................................................ 77 
14.8 Sample Size/Accrual Rate ............................................................................................................................... 77 
14.9 Stratification Factors ...................................................................................................................................... 78 
14.10 Analysis of Secondary Endpoints .................................................................................................................. 78 
14.11 Evaluation of toxicity .................................................................................................................................... 78 
14.12 Evaluation of response .................................................................................................................................. 78 
15. PUBLICATION PLAN ....................................................................................................................................... 78 
16. REFERENCES .................................................................................................................................................... 79 
17. APPENDICES ..................................................................................................................................................... 81 
Appendix A: Performance Status Criteria ............................................................................................................ 81 
 
 
 
 
 


IDR in WM Version 9 9/13/2017 
Millennium #X16057  
 
 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS 
 
Abbreviation 
Term 
5-HT3 
5-hydroxytryptamine 3 serotonin receptor 
AE 
adverse event 
ALL 
acute lymphoblastic leukemia 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AML 
acute myelogenous leukemia 
ANC 
absolute neutrophil count 
API 
active pharmaceutical ingredient 
aPTT 
activated partial thromboplastin time 
Ara-C 
Cytarabine 
ASCO 
American Society of Clinical Oncology 
AST 
aspartate aminotransferase 
AUC 
area under the plasma concentration versus time curve 
AUC24 hr 
area under the plasma concentration versus time curve from zero to 
24 hours 
AUCinf 
area under the plasma concentration versus time curve from zero to 
infinity 
AUCτ 
area under the plasma concentration versus time curve from zero to 
next dose 
BCRP 
breast cancer resistance protein 
hCG 
beta-human chorionic gonadotropin 
BID 
bis in die; twice a day 
BM 
bone marrow 
BSA 
body surface area 
BUN 
blood urea nitrogen 
BZD 
Benzodiazepines 
CBC 
complete blood count 
CFR 
Code of Federal Regulations 
CL 
clearance, IV dosing 
CLP 
plasma clearance 
CLTotal 
total clearance 
Cmax 
single-dose maximum (peak) concentration   
CNS 
central nervous system 
CO2 
carbon dioxide 
CR 
complete response  
CRM 
continual reassessment method 
CRP 
C-reactive protein 
CSF-1R 
colony-stimulating factor 1 receptor 
CT 
computed tomography 
Ctrough 
single-dose end of dosing interval (trough) concentration 
CV 
cardiovascular 
CYP 
cytochrome P450 


IDR in WM Version 9 9/13/2017 
Millennium #X16057  
 
 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
Abbreviation 
Term 
DDI 
drug-drug interaction 
DLT 
dose-limiting toxicity 
DME 
drug metabolizing enzymes 
DNA 
deoxyribonucleic acid 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EDC 
electronic data capture 
ELISA 
enzyme-linked immunosorbent assay 
EOS 
End of Study (visit) 
EOT 
End of Treatment (visit) 
EU 
European Union 
FDA 
United States Food and Drug Administration 
GCP 
Good Clinical Practice 
G-CSF 
granulocyte colony stimulating factor 
GGT 
gamma glutamyl transferase 
GI 
Gastrointestinal 
GLP 
Good Laboratory Practices 
GM-CSF 
granulocyte macrophage-colony stimulating factor 
GMP 
Good Manufacturing Practice 
Hb 
Hemoglobin 
Hct 
Hematocrit 
HDPE 
high-density polyethylene 
hERG 
human ether-à-go-go related gene 
HIV 
human immunodeficiency virus 
HNSTD 
highest nonseverely toxic dose 
IB 
Investigator’s Brochure 
IC50 
concentration producing 50% inhibition 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IDR 
Ixazomib, dexamethasone, rituximab 
IEC 
independent ethics committee 
IRB 
institutional review board 
ITT 
intent-to-treat 
IV 
intravenous; intravenously 
IVRS 
interactive voice response system 
Ki 
inhibition constant 
KPS 
Karnofsky Performance Status 
LDH 
lactate dehydrogenase 
LFT 
liver function test(s) 
MedDRA 
Medical Dictionary for Regulatory Activities 
Millennium 
Millennium Pharmaceuticals, Inc., and its affiliates 
MRI 
magnetic resonance imaging 


IDR in WM Version 9 9/13/2017 
Millennium #X16057  
 
 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
Abbreviation 
Term 
MRU 
medical resource utilization 
MTD 
maximum tolerated dose 
MUGA 
multiple gated acquisition (scan) 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for 
Adverse Events 
NPO 
nothing by mouth 
NYHA 
New York Heart Association 
PBMC 
peripheral blood mononuclear cell 
PCR 
polymerase chain reaction 
PD 
progressive disease (disease progression) 
Pgp 
P-glycoprotein 
PK 
pharmacokinetic(s) 
PO 
per os; by mouth (orally) 
PR 
partial response 
PRO 
patient-reported outcome 
PSA 
prostate-specific antigen 
QD 
quaque die; each day; once daily 
QID 
quater in die; 4 times a day 
QOD 
quaque altera die; every other day 
QOL 
quality of life 
QTc 
rate-corrected QT interval (millisec) of electrocardiograph 
RBC 
red blood cell 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
serious adverse event 
SC 
Subcutaneous 
SD 
stable disease 
SmPC 
Summary of Product Characteristics 
t1/2 
terminal disposition half-life 
TGI 
tumor growth inhibition 
Tmax 
single-dose time to reach maximum (peak) concentration 
UK 
United Kingdom 
ULN 
upper limit of the normal range 
US 
United States 
Vz 
volume of distribution in the terminal phase 
WBC 
white blood cell 
WHO 
World Health Organization 
WM 
Waldenström Macroglobulinemia 


IDR in WM 
Millennium #X16057  
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
8 
1. OBJECTIVES 
 
1.1Study Design 
 
This is a single-arm, open-label, prospective phase II study to evaluate the safety and efficacy of 
IDR in symptomatic untreated WM patients. The study treatment will consist on an induction 
and a maintenance phase. Dose modification will be permitted for toxicity. 
 
IDR Induction: 
Cycles 1 and 2 will consist on ixazomib 4 mg and dexamethasone 20 mg  IV or PO administered 
on days 1, 8 and 15. 
Cycles 3-6 will consist on ixazomib 4 mg PO and dexamethasone 20 mg  IV or PO on days 1, 8 
and 15, and rituximab 375 mg/m2 IV on day 1 every 28 days. 
Total duration of induction: 24 weeks. 
 
IDR Maintenance: 
Maintenance therapy will start 2 months ± 2 weeks after day 1 of cycle 6 and will consist on 
ixazomib 4 mg PO and dexamethasone 20 mg IV or PO administered on days 1, 8 and 15, and 
and rituximab 375 mg/m2 IV administered on day 1 every 2 months for 1 year (6 cycles). 
Total duration of maintenance: 52 weeks. 
 
Supportive therapy: 
Acyclovir 400 mg PO BID or Valacyclovir 1000mg PO QD will start on day 1 of study and will 
continue for 6 months after the last dose of ixazomib. 
Famotidine 20 mg PO (or other gastritis prophylactic medication) will start on day 1 of study and 
will continue until the last dose of dexamethasone. 
Acetaminophen 650 mg PO, diphenhydramine 50 mg PO and famotidine 20mg IV will be 
administered at least 30 minutes prior to each rituximab infusion. 
 
A Screening visit will be conducted within 30 days before baseline (baseline being Day 1, Cycle 
1, before study drug administration). At this visit, a medical history will be obtained with 
complete physical examination, vital signs, and an ECOG performance status. A bone marrow 
aspirate and biopsy, beta-2-microglobulin, serum and protein electrophoresis with quantification 
of immunoglobulins (IgM, IgG, IgA) and immunofixation studies, and computed tomography 
(CT) scans of the chest, abdomen and pelvis will also be conducted at the Screening visit. Bone 
marrow biopsy and CT scans will not be required if collected up to 90 days prior to screening 
visit. MYD88 L265P mutational status will be determined by BWH Molecular Diagnostics Lab. 
CXCR4 mutational status and FcγRIIIA-158 polymorphisms will be determined by the Bing 
Center for Waldenström Macroglobulinemia Laboratory. Clinical laboratory tests including a 
complete blood count plus differential, electrolytes, BUN, creatinine, comprehensive chemistry 
panel, magnesium, total bilirubin, liver function tests, and serum pregnancy tests for women of 
child-bearing potential will also be performed at the Screening visit. 
 
Patients who meet the eligibility requirements at the Screening visit, and provide written consent, 
will be enrolled in the study and initiated on study treatment. Patients will be evaluated for 


 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
 
9 
tolerance and response on Day 1 of each cycle for the duration of the trial. Patients will be 
eligible to continue therapy as long as they do not demonstrate progressive disease or 
unacceptable toxicity. Modified response criteria updated at the Sixth International Workshop on 
WM (Owen 2013) will be used to assess response, stable disease, and progressive disease. 
Response outcomes to be determined will include: ORR and major response rates (including 
VGPR and CR rates); landmark analysis for 2 and 4-year PFS; median TTP; median TTNT. The 
final analysis will be undertaken when all participants would have completed the maintenance 
phase of the study.  
 
1.2Primary Objectives 
 
• To evaluate the rate of very good partial response (VGPR) or better to IDR in patients 
with untreated WM 
• To evaluate the toxicity profile of IDR in patients with untreated WM 
 
1.3Secondary Objectives 
 
• To evaluate the rate of CR, partial response (PR), minimal response (MR), stable disease 
(SD) and progressive disease (PD)  
• To evaluate the PFS, disease-free survival (DFS), time to progression (TTP), duration of 
response (DOR) and time to next therapy (TTNT) 
• To evaluate the attainment of response, and depth of response (VGPR or better) and 
expression of MYD88 L265P and CXCR4-WHIM mutations in WM. 
• To determine changes in MYD88 L265P burden in response to IDR in patients with WM 
using real-time quantitative PCR. 
• To evaluate the FcγRIIIA-158 polymorphisms as surrogate markers for response to IDR 
in WM. 
 
2.BACKGROUND 
 
2.1Study Agents 
 
2.1.1Ixazomib 
 
2.1.1.1Ixazomib Background 
 
Ixazomib is a next generation, small molecule inhibitor of the 20S proteasome that is under 
development for the treatment of non-hematologic malignancies, lymphoma, multiple myeloma 
(MM), and other plasma cell dyscrasias. Inhibition of the 20S proteasome has been validated as a 
therapeutic target for the treatment of malignancies using VELCADE® (bortezomib) for 
Injection, Millennium Pharmaceuticals’ first-in-class proteasome inhibitor. 
 
In an effort to broaden activity against a wider range of tumor types and increase activity in 
tumor types where VELCADE has shown activity, Millennium has developed the proteasome 
inhibitor, Ixazomib, formulated for both intravenous (IV) and oral (PO) administration. Ixazomib 
is structurally different from VELCADE. MLN2238 refers to the biologically active, boronic 


 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
 
10 
acid form of the drug substance, Ixazomib. Ixazomib refers to the citrate ester of MLN2238. In 
water or aqueous systems, the equilibrium shifts from Ixazomib to form MLN2238. All doses 
and concentrations are expressed as the boronic acid, MLN2238. 
 
2.1.1.2Ixazomib Toxicology Studies 
 
After PO administration of MLN2238, the exposures that were tolerated in rats were similar to 
those tolerated in dogs, indicating similar species sensitivity. Additionally, PO administration for 
5 cycles to rats and dogs resulted in higher plasma exposures of MLN2238 on Day 94 than on 
Day 0, indicating accumulation of MLN2238. Dose-limiting toxicity (DLT) in the GLP-
compliant PO toxicology studies up to 5 cycles in duration in rat and dogs was primarily due to 
effects in the gastrointestinal (GI) and lymphoid systems. Additionally, at doses below those 
associated with DLT, alterations in leukocyte and coagulation parameters consistent with an 
inflammatory response were seen in both rats and dogs, and neuronal degeneration of the 
sympathetic, dorsal root, and end organ ganglia was seen mainly in dogs (possibly due to higher 
exposures). All of the effects seen in the GLP-compliant PO toxicology studies in both rats and 
dogs at tolerated doses were reversible/reversing and can be monitored in the clinic with routine 
clinical observations (GI disturbances and opportunistic infections secondary to lymphoid 
depletion), clinical pathology assessments (inhibition of erythropoiesis, thrombocytopenia, and 
inflammatory leukogram), and neurologic assessment, as are commonly done for patients treated 
with bortezomib. Ixazomib did not cause significant toxicities that have not been previously 
observed after dosing with bortezomib, and the neurologic lesions in these studies are similar to 
what has been described after treatment with bortezomib and are believed to be the cause of the 
peripheral neuropathy observed in patients treated with bortezomib. 
 
MLN2238 caused embryo-fetal toxicity to pregnant rabbits at a dose of 1 mg/kg (mean Gestation 
Day 19 AUC0-72hr  1280 hr*ng/mL). Embryo-fetal toxicity has been observed in rats and rabbits 
with other proteasome inhibitors, and thus there is the potential for similar effects in humans. A 
dose of 0.5 mg/kg (mean Gestation Day 19 AUC0-72hr  910 hr*ng/mL) was considered the no-
observed-effect level (NOEL) for embryo-fetal effects in this study. 
 
MLN2238 was not mutagenic in a GLP-compliant bacterial reverse mutation assay (Ames assay) 
nor was it clastogenic in a GLP-compliant bone marrow micronucleus assay in mice. Therefore, 
MLN2238 is not a genotoxicant. 
 
Ixazomib demonstrates minimal to no absorbance between 290 to 700 nm, and there is no 
absorption maximum in that range. In a quantitative whole body autoradiography (QWBA) 
study, [14C] Ixazomib -derived radioactivity was present in melanin-containing tissues (eg, 
pigmented skin and eye uveal tract), but the concentrations decreased in a manner similar to most 
other tissues throughout the study and so a specific association of radioactivity to melanin was 
not obvious. The data indicate that Ixazomib does not represent a photosafety risk. 
 
2.1.1.3Ixazomib Preclinical Antitumor Activity 
 
Ixazomib is a next generation proteasome inhibitor. Its active form, MLN2238, is a potent, 
reversible, and selective inhibitor of the 5 site of the 20S proteasome. MLN2238 inhibits the 


 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
 
11 
5 site 20S proteasome activity in vitro, with a concentration producing IC50 of 3.4 nM. Potency 
is reduced roughly 10-fold versus 1 (IC50  31 nM) and 1000-fold versus 2 (IC50  3500 
nM). MLN2238 was also tested for inhibition against a panel of 103 kinases, 18 receptors 
(neurotransmitter, ion channel, brain and gut receptors), and 9 serine proteases. In all cases, the 
IC50 was  10 M. Proteasome inhibition results in the accumulation of poly-ubiquitinated 
substrates within the cell and leads to cell cycle disruption, with concomitant activation of 
apoptotic pathways and cell death. Consistent with inhibition of 5 20S proteasome activity, 
MLN2238 demonstrated potent activity against cultured MDA-MB-231 human breast cancer 
cells in the WST cell viability assay. 
 
The iMycC/Bcl-XL GEM model of PCM recapitulates key features of human MM, including 
elevation of serum paraprotein, manifestation of malignant plasma cells in bone marrow, and 
involvement of osteolytic lesions. iMycC/Bcl-XL mice of C57BL6/FVB background develop de 
novo PCM accompanied by splenomegaly. This model was used to assess the anti-tumor activity 
of bortezomib and MLN2238. In addition, the anti-tumor activity of bortezomib and MLN2238 
was evaluated in a disseminated model of PCM in immunocompromised mice and in an 
intratibial model of PCM in nude mice. These 2 models utilized the DP54-Luc cell line, a 
luciferase-tagged cell line derived from a tumor originating in an iMycC/Bcl-XL transgenic 
mouse. 
 
Study CPPI-09-EF29 
 
Male and female iMycC/Bcl-XL mice of the hybrid (B6  FVB/N) F1 background were 
administered bortezomib at 1.2 mg/kg IV BIW or MLN2238 at 18 mg/kg IV BIW for 6 
consecutive weeks (treatment phase) (n  30), with an untreated group as a control. The doses 
used represent the MTD for each drug in (B6  FVB/N) F1 hybrid mice. After the treatment 
phase, mice were clinically monitored for an additional 25 weeks to assess the effect of drug 
treatment on overall survival, spleen weight, and plasma immunoglobulin G2a (IgG2a) levels (a 
marker for myeloma disease). The results of this study showed that IV BIW administration of 
MLN2238 at 18 mg/kg and bortezomib at 1.2 mg/kg prolonged overall survival, reduced 
splenomegaly, and attenuated IgG2a levels in the iMycC/Bcl-XL GEM model of de novo PCM. 
 
Study CPPI-09-EF26 
 
Female NOD-SCID mice bearing disseminated DP54-Luc iMycC/Bcl-XL PCM were dosed with 
vehicle (5% hydroxypropyl-beta-cyclodextrin [HP--CD]) IV BIW, bortezomib at 0.7 mg/kg IV 
BIW, MLN2238 at 11 mg/kg IV BIW, or MLN2238 at 3 mg/kg SC QD. The doses used 
represent the MTD for each drug and route of administration in NOD-SCID mice. A total of 5 
doses were administered in the IV dose groups and a total of 15 doses were administered in the 
SC dose group. Anti-tumor activity was determined by calculating the T/C ratio of the mean total 
photon flux measurement of tumor burden on Day 20 after inoculation. In addition, cranial suture 
widening was assessed on Day 23 after inoculation in the IV dose groups by measuring sagittal 
suture separation areas (SSSA) using computed tomography (CT) imaging. 
 
The results of this study demonstrated that bortezomib and MLN2238 show anti-tumor activity 
against DP54-Luc iMycC/Bcl-XL PCM. Importantly, IV MLN2238, but not bortezomib, 


 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
 
12 
significantly reduced osteolytic lesions (widening of cranial sutures) in this model. 
 
Study CPPI-09-EF27 
 
Female nude mice bearing intratibial DP54-Luc iMycC/Bcl-XL PCM were dosed IV BIW with 
vehicle (5% HP--CD), bortezomib at 0.8 mg/kg, or MLN2238 at 13 mg/kg for 3 consecutive 
weeks. Anti-tumor activity was determined by calculating the T/C ratio of the mean photon flux 
measurement of tumor burden on Day 29 after inoculation.  
 
The results of this study demonstrated that bortezomib and MLN2238 show anti-tumor activity 
against intratibial DP54-Luc iMycC/Bcl-XL plasma cell malignancy. 
 
2.1 Pharmacokinetics and Drug Metabolism 
Clinical IV and PO PK data show that ixazomib citrate (measured as the biologically active 
boronic acid form of ixazomib [MLN2238]) has multi-exponential disposition with a rapid initial 
phase that is largely over by 4 hours. Oral ixazomib citrate is rapidly absorbed with a median 
single-dose first time of occurrence of maximum (peak) concentration (Tmax) of approximately 
0.5 to 2.0 hours and a terminal disposition half-life (t1/2) after multiple dosing of approximately 5 
to 7 days [1]. Results of a population PK analysis (n = 137) show that there is no relationship 
between body surface area (BSA) or body weight and clearance (CL). Also, based on stochastic 
simulations for fixed dose, exposures are independent of the individual patient’s BSA [2]. Based 
on these data, a recommendation was made for fixed dosing in clinical trials. An absolute 
bioavailability of 67% was determined for ixazomib using the population PK analysis. Please 
refer to the current ixazomib IB and Safety Management Attachment (SMA) for information on 
the PK for IV doses of ixazomib. 
 
Metabolism appears to be the major route of elimination for ixazomib, and urinary excretion of 
the parent drug is negligible (< 5% of dose). In vitro studies indicate that ixazomib is 
metabolized by multiple cytochrome P450s (CYPs) and non-CYP enzymes/proteins. The rank 
order of relative biotransformation activity of the 5 major human CYP isozymes was 3A4 
(34.2%) > 1A2 (30.7%) > 2D6 (14.7%) > 2C9 (12.1%) > 2C19 (< 1%). Ixazomib is not an 
inhibitor of CYPs 1A2, 2C9, 2C19, 2D6, or 3A4 nor a time-dependent inhibitor of CYP3A4/5. 
The potential for ixazomib treatment to produce drug-drug interactions (DDIs) via CYP 
inhibition is inferred to be low. However, there may be a potential for DDIs with a concomitant 
strong CYP3A4 or CYP1A2 inhibitor or inducer because of the potential for first-pass 
metabolism when ixazomib is administered via the PO route and because of the moderate 
contribution of CYP3A4- and CYP1A2-mediated metabolism of ixazomib in human liver 


 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
 
13 
microsomes. Ixazomib may be a weak substrate of P-glycoprotein (Pgp), breast cancer resistance 
protein (BCRP), and multidrug resistance associated protein (MRP2) efflux pump transporters. 
Ixazomib is not an inhibitor of Pgp, BCRP, and MRP2. The potential for DDIs with substrates or 
inhibitors of Pgp, BCRP, and MRP2 is, therefore, inferred to be low. Clinical Study C16009 
(Arm 1) with ketoconazole, a strong CYP3A4 inhibitor, showed a 2-fold increase in area under 
the plasma concentration versus time curve (AUC) in the presence of ketoconazole. This resulted 
in the continued exclusion of strong CYP3A4 inhibitors in ongoing/planned clinical studies. 
 
Further details on these studies are provided in the IB. 
 
Preclinical Experience 
Please refer to the current ixazomib Investigator’s Brochure (IB) and Safety Management 
Attachment (SMA). 
 
2.1.1.1 Clinical Experience with Ixazomib 
 
Ixazomib has been evaluated as an oral single agent in phase 1 studies that have included patients 
with advanced solid tumors, lymphoma, relapse/refractory MM (RRMM), and relapsed or 
refractory light-chain (AL) amyloidosis and demonstrated early signs of activity. Ongoing 
studies continue to investigate both single-agent ixazomib and ixazomib in combination with 
standard treatments. Based on encouraging preliminary data observed in patients with MM 
requiring systemic treatment, 2 phase 3 trials in newly diagnosed MM (NDMM) (C16014) and 
RRMM (C16010) patient populations are currently evaluating ixazomib in combination with 
Revlimid and Dexamethasone (RevDex) versus placebo/RevDex. Both trials are combining 
ixazomib at a weekly dose of 4.0 mg on Days 1, 8, and 15 in a 28-day cycle to a standard dose of 
lenalidomide with a weekly dexamethasone dose of 40 mg. In addition, ongoing clinical 
pharmacology studies include evaluation of drug-drug interactions with ketoconazole and 
rifampin, effect of food, and oral bioavailability. Studies evaluating the safety and 
pharmacokinetic (PK) of ixazomib alone (in Japanese patients) and in combination with 
lenalidomide and dexamethasone in Asian adult patients (including Japanese patients) with a 
diagnosis of NDMM are ongoing. 
 
As of 27 March 2013, preliminary clinical data is available for a total of 653 patients across 13 
studies. The emerging safety profile indicates that ixazomib is generally well tolerated. The 
adverse events (AEs) are consistent with the class-based effects of proteasome inhibition and are 


 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
 
14 
similar to what has been previously reported with VELCADE though the severity of some, for 
example peripheral neuropathy, is less. While some of these potential toxicities may be severe, 
they can be managed by clinical monitoring and standard medical intervention, or, as needed, 
dose modification or discontinuation. 
 
Fatigue was the most common AE reported among 384 patients treated in the oral (PO) studies 
(47%). Other common AEs reported in the pooled intravenous (IV) and PO safety populations 
include nausea, thrombocytopenia, diarrhea, and vomiting. Rash is also a commonly reported 
treatment-emergent event; however, there is some variety in its characterization and causality 
resulting in different preferred terms to describe it. A high-level term outline of rash events 
includes rashes, eruptions and exanthems NEC; pruritus NEC; erythemas; papulosquamous 
conditions; and exfoliative conditions. The dose escalation phases of most trials reported in the 
IB have now completed enrollment, and gastrointestinal (GI) symptoms were the common dose-
limiting toxicities (DLTs) when the use of prophylactic anti-emetics was not permitted per 
protocol. In the expansion cohorts or phase 2 cohorts (as per each study), the incidence and 
severity of GI symptoms was mitigated by the use of the lower maximum tolerated dose 
(MTD)/recommended phase 2 dose (RP2D) (as per each study) and standard clinical usage of 
anti-emetics and/or antidiarrheal medications as deemed appropriate. Prophylactic use of anti-
emetics has not been required as with other agents but (as outlined in Section 6.7) has been used 
according to standard practice and are effective. 
 
The most frequent (at least 20%) treatment-emergent adverse events (TEAEs) reported with the 
PO formulation pooled from single-agent studies (n = 201) irrespective of causality to ixazomib, 
include nausea (53%), fatigue (51%), diarrhea (44%), thrombocytopenia (34%), vomiting (38%), 
decreased appetite (32%), fever (21%), and anemia (21%). The most frequent (at least 20%) 
TEAEs reported with the PO formulation pooled from combination trials (irrespective of the 
combination) (n = 173), irrespective of causality to ixazomib, include diarrhea (47%), fatigue 
(44%), nausea (38%), peripheral edema (35%), constipation (33%), insomnia (29%), 
thrombocytopenia (28%), anemia (26%), vomiting (26%), neutropenia (25%), back pain (24%), 
pyrexia (23%), peripheral edema (21%, each), fever (20%), cough (20%), hypokalemia (20%), 
neutropenia (20%), and upper respiratory tract infection (20%). Overall rash of all grades is 
reported in approximately 50% of patients and is more common when ixazomib is given in 
combination with lenalidomide where rash is an overlapping toxicity. 
 


 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
 
15 
Additional detailed information regarding the clinical experience of ixazomib may be found in 
the IB, including information on the IV formulation.   
 
As of 27 March 2013, a total of 507 patients with differing malignancies (multiple myeloma, AL 
amyloidosis, non-hematologic cancers, and lymphoma) have been treated in studies evaluating 
the oral ixazomib formulation.  These patients have been treated with different doses of ixazomib 
either as a single-agent treatment (in 201 patients) or in combination with currently clinically 
available treatments (in 306 patients).  Information regarding the ongoing studies, patient 
populations, and doses investigated is included in Table 1-1. 


 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
 
16 
Table 1-1 Clinical studies of Oral Ixazomib 
Trial/ 
Population 
Description 
Doses Investigated 
C16003 
RRMM 
N = 60 
PO, TW, single agent 
0.24-2.23 mg/m2 TW 
MTD:  2.0 mg/m2 
DLT:  rash, thrombocytopenia 
Closed to enrollment 
C16004 
RRMM 
N = 60 
PO, W, single agent 
0.24-3.95 mg/m2 W 
MTD:  2.97 mg/m2 
DLT:  rash, nausea, vomiting, diarrhea 
Closed to enrollment 
C16005 
NDMM 
N = 65 
PO, W, combination with LenDex 
28-day cycle 
1.68-3.95 mg/m2 W 
MTD:  2.97 mg/m2 
DLT:  nausea, vomiting, diarrhea, syncope 
RP2Da:  4.0 mg fixed (switched to fixed dosing in 
phase 2, equivalent  to 2.23mg/m2) 
Closed to enrollment 
C16006 
NDMM 
N = 20 
PO, TW (Arm A- 42 day cycle) and 
W (Arm B- 28 day cycle), 
combination with Melphalan and 
Prednisone 
Arm Aa:  3-3.7-mg fixed dose TW 
DLT:  rash, thrombocytopenia, subileus 
Arm Ba:  3-5.5-mg fixed dose, W 
DLT:  Esophageal ulcer nausea, vomiting, 
hematemesis, thrombocytopenia, ileus, 
neurogenic bladder 
MTD = 3.0 mg 
C16007 
RRAL 
N = 27 
PO, W, single agent 
4-5.5-mg fixed dosea W 
DLT:  thrombocytopenia, diarrhea, dyspnea, acute 
rise in creatinine, cardiac arrest  
MTD:  4.0  mg W 
 
C16008 
NDMM 
N = 64 
PO, TW, combination with LenDex 
21-day cycle 
3.0-3.7-mg fixed dosea W 
MTD:  3.0 mg 
Closed to enrollment 
C16009 
Solid tumors, 
Lymphomas 
N = 54 
PO, W, single agent 
5.5-mg fixed dosea W 
C16010 
RRMM 
N = 200 
PO, W, with LenDex versus placebo-
LenDex 
4.0 mg W 
C16011 
RRAL 
N = 4 
PO, W, with Dex versus physician’s 
choice of a Dex-based regimen 
4.0 mg W 
C16013 
RRMM 
N = 9 
PO, W, with LenDex 
4.0 mg W 


 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
 
17 
Table 1-1 Clinical studies of Oral Ixazomib 
Trial/ 
Population 
Description 
Doses Investigated 
C16014 
Symptomatic 
MM 
N=701 
PO, combination with LenDex 
ixazomib 4.0 mg or matching placebo on Days 1, 
8, and 15, plus Len 25 mg on Days 1-21 (10 mg if 
low creatinine clearance, with escalation to 15 mg 
if tolerated) and Dex 40 mg (or 20 mg if >75 
years old) on Days 1, 8, 15, and 22 
C16015 
Symptomatic 
MM with 
normal renal 
function or 
severe renal 
impairment 
N=28 
PO, combination with Dex 
Part A: ixazomib  3.0 mg on Day 1 
Part B: ixazomib  4.0 mg on Days 1, 8, and 15, 
plus Dex 40 mg (or 20 mg if >75 years old) on 
Days 1, 8, 15 and 22 of a 28-day cycle 
 
C16017 
RR follicular 
lymphoma 
N=58 
PO, W 
4.0, 5.3, and 7.0 mg, W 
Treatment at RP2D once determined. 
 
C16018 
Advanced 
solid tumors 
or 
hematologic 
malignancies 
with varying 
degrees of 
liver 
dysfunction 
N=45 
Part A: PO, Day 1 of 15-day cycle 
Part B: PO, W 
1.5 mg (severe hepatic impairment), 2.3 mg 
(moderate hepatic impairment), or 4.0 mg (normal 
hepatic function) 
 
TB-
MC010034 
RRMM 
N = 10 
PO, W 
4.0 mg, W 
Single agent: 4.0 mg 
Combination with Rd 
Abbreviations:  RRAL = Relapsed and/or refractory Primary systemic light chain (AL) amyloidosis; BSA = 
body surface area; Dex=dexamethasone; DLT = dose-limiting toxicity; IV = intravenously; LenDex = 
lenalidomide plus dexamethasone; MTD = maximum tolerated dose; NDMM = newly diagnosed multiple 
myeloma; PO = orally; RR= relapsed and/or refractory; RRAL= relapsed and/or refractory systemic light 
chain amyloidosis RRMM = relapsed and/or refractory multiple myeloma; TBD = to be determined; TW 
= twice weekly; W = weekly; RP2D= recommended phase 2 dose. 
Note that blinded data from pivotal Studies C16010 and C16011 are not included.   
a Approximate BSA and fixed dosing equivalence:  3 mg~ equivalent to 1.68 mg/m2 BSA dosing; 4.0 mg ~ 
equivalent to 2.23 mg/m2 BSA dosing; and 5.5 mg~ equivalent to 2.97 mg/m2 BSA dosing. 
 
2.1.1.2 Clinical Experience with Ixazomib as Monotherapy 
  
The C16003 study was a phase 1 study in adult patients with relapsed and/or refractory MM who 
had received at least 2 lines of prior therapy that must include Velcade, thalidomide or 


 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
 
18 
lenalidomide) and steroids. This study enrolled 60 out of 63 planned participants and is closed to 
accrual. Ixazomib was administered twice weekly on days 1, 4, 8 and 11 of a 21-day cycle and 
underwent dose escalation from 0.24 mg/m2 to 2.23 mg/m2. The MTD for twice weekly 
ixazomib was determined at 2.0 mg/m2. 
 
The C16004 study was a phase 1 study in adult patients with relapsed and/or refractory MM who 
had received at least 2 lines of prior therapy that must include Velcade, thalidomide or 
lenalidomide) and steroids. This study enrolled 60 out of 70 planned participants and is closed to 
accrual. Ixazomib was administered once weekly on days 1, 8 and 15 of a 28-day cycle with dose 
escalation from 0.24 mg/m2 to 3.95 mg/m2. The MTD for weekly ixazomib was determined at 
2.97 mg/m2. 
 
The C16009 study is an ongoing phase 1 study in adult patients with non-hematologic 
malignancy or lymphoma. The primary objectives are to evaluate safety, bioavailability, DDI 
and food effect. There are four arms evaluating ixazomib at different dosages and in combination 
with ketoconazole and rifampin. The study has enrolled 57 out of 90 planned participants.  
 
2.1.1.3 Experience with Ixazomib in Combination with Lenalidomide and Dexamethasone  
 
The C16005 study is a phase 1/2 study in adult patients with newly diagnosed MM. The 
objectives of the phase 1 component are safety, MTD and inform RP2D. The objective of the 
phase 2 component is efficacy. Ixazomib is administered once weekly on days 1, 8 and 15 with 
dose escalation from 1.68 mg/m2 to 3.95 mg/m2. Ixazomib was administered in combination 
with dexamethasone 40 mg PO on days 1, 8, 15 and 22, and lenalidomide 25 mg PO on days 1-
21 of 28-day cycles for 12 cycles. This is followed by maintenance therapy with ixazomib on 
days 1, 8 and 15 every 28 days until disease progression or unacceptable toxicity. The MTD of 
ixazomib was 2.97 mg/m2 and the RP2D is a fixed dose of 4.0 mg (approximate equivalent to 
2.23 mg/m2) with full-dose lenalidomide and dexamethasone. This study enrolled 65 participants 
and is currently closed to accrual. 
 
2.1.1.4 Dose Rationale 
 
After oral dosing, MLN2238 is rapidly absorbed with a median Tmax of 1 hour. The observed 
range for the terminal half-life after multiple doses is 2.1 to 11.3 days. Dose proportionality has 
been observed for doses between 0.48 and 3.95 mg/m2 (0.8-8.9 actual administered dose range) 
of Ixazomib. The 2-fold increase in AUC observed in the presence of ketoconazole, a strong 
inhibitor of CYP3A (Study C16009), resulted in the continued exclusion of strong CYP3A4 
inhibitors in ongoing/planned studies.  
 
Pharmacokinetic parameters for MLN2238 co-administered with lenalidomide and 
dexamethasone (Studies C16005 and C16008), or melphalan and prednisone (Study C16006), 
appear to be similar to those observed when Ixazomib is administered as a single agent. This 
suggests that there is no readily apparent effect of co-administration of lenalidomide and 
dexamethasone, or melphalan and prednisone, on the clinical PK of MLN2238. Likewise, no 
significant alterations in the disposition of MLN2238 have been noted between patients with 
different malignancies. 


 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
 
19 
 
Following either oral administration of ixazomib, maximal 20S proteasome inhibition in blood is 
observed shortly after dosing, mirroring the obtainment of maximum plasma concentrations of 
MLN2238. Maximum inhibition of 20S proteasome activity is dose dependent with mean values 
approaching 70% to 80% in some of the higher dosing cohorts examined. With the exception of 
some of the higher dosing cohorts studied, prolonged 20S proteasome inhibition (> 96 hours) by 
Ixazomib is not observed. These findings are consistent with MLN2238 being a reversible 
proteasome inhibitor. 
 
A population PK analysis has been performed using preliminary PK data from 137 patients 
treated with IV and PO Ixazomib as a single agent across 4 ongoing, phase 1 studies intensive 
PK sampling). Patients with solid tumors, lymphoma, or MM were administered Ixazomib via IV 
or PO routes using BSA-based dosing on a twice weekly (Days 1, 4, 8, and 11; 21-day cycle) or 
weekly (Days 1, 8, and 15; 28-day cycle) schedule. Effects of age, body weight, BSA, sex, 
creatinine clearance, ALT, AST, and bilirubin were not significant on the CL of Ixazomib on the 
basis of a univariate analysis (p < 0.05). Because MLN2238 was dosed on the basis of BSA in 
the early phase 1 clinical studies, it was of interest to see if any of the body size covariates 
(weight or BSA) were significant on CL or V2. On the basis of the univariate testing, neither 
weight nor BSA was significant on CL or V2 suggesting that interpatient variability in BSA does 
not contribute to MLN2238 PK variability.  
 
The lack of a discernible relationship between BSA and Ixazomib clearance over a relatively 
wide BSA range (1.4-2.6 m2) indicates that total systemic exposure (AUC) following fixed 
dosing should be independent of the individual patient’s BSA. Therefore, BSA is not expected to 
affect Cmax or AUC after IV or oral dosing, and thus fixed dosing is appropriate for both oral and 
IV routes of administration. The clinical development of Ixazomib has therefore transitioned 
from the use of BSA-based dosing to fixed dosing in all recently initiated phase 1/2 studies 
(Studies C16005 phase 2, C16007, C16008, and C16009). Accordingly, the starting dose of 
Ixazomib in the proposed phase 3 study in relapsed/refractory multiple myeloma is a fixed dose 
of 4.0 mg, on the basis of the recommended dose of 2.23 mg/m2 (using mean patient BSA of 1.86 
m2 from the 2208 patients with MM in VELCADE clinical studies for conversion to a fixed 
dose). Also, no relationship between creatinine clearance and CL was observed in patients with a 
wide range of renal function (creatinine clearance range: 21.9-236.1 mL/min) as shown in So, 
starting dose adjustment is not required in patients with mild (60-90 mL/min) and moderate (30-
60 mL/min) renal impairment in clinical studies. 
 
2.1.1.5 Overview of the Oral Formulation of ixazomib 
 
The emerging safety profile indicates that ixazomib is generally well tolerated.  The adverse 
events (AEs) are consistent with the class-based effects of proteasome inhibition and are similar 
to what has been previously reported with VELCADE though the severity of some, for example 
peripheral neuropathy, is less.  While some of these potential toxicities may be severe, they can 
be managed by clinical monitoring and standard medical intervention, or, as needed, dose 
modification or discontinuation.   


 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
 
20 
In the 4 ongoing studies (C16003, C16004, C16007, and C16009) investigating single-agent oral 
ixazomib in patients with differing malignancies (multiple myeloma, AL amyloidosis, 
nonhematologic cancers, and lymphoma), a total of 201 patients have been treated as of 27 
March 2013. These patients have been treated with different doses of ixazomib as they are all 
phase 1 trials. An overview of the most frequent (at least 10%) AEs occurring in the pooled 
safety population from single-agent oral ixazomib Studies (C16003, C16004, C16007, and 
C16009) is shown in Table 1-2. 
 
 
Table 1-2    Most Common (At Least 10% of Total) Treatment-Emergent Adverse 
Events in Oral Single-Agent Studies 
Primary System Organ Class 
     Preferred Term 
Primary System Organ Class 
      Preferred Term 
Subjects with at Least One Adverse Event 
Subjects with at Least One Adverse Event 
Gastrointestinal disorders 
Gastrointestinal disorders 
 Nausea 
 Nausea 
Diarrhoea 
 Diarrhoea 
 Vomiting 
 Vomiting 
 Constipation 
 Constipation 
 Abdominal pain 
 Abdominal pain 
General disorders and 
administration site 
conditions 
General disorders and administration site conditions 
Fatigue 
 Fatigue 
Pyrexia 
 Pyrexia 
 Oedema peripheral 
 Oedema peripheral 
Asthenia 
 Asthenia 
Nervous system disorders 
Nervous system disorders 
 Headache 
 Headache 
Dizziness 
 Dizziness 
 Neuropathy peripheral 
 Neuropathy peripheral 
Metabolism and nutrition disorders 
Metabolism and nutrition disorders 
 Decreased appetite 
 Decreased appetite 
 Dehydration 
 Dehydration 
Blood and lymphatic system disorders 
Blood and lymphatic system disorders 


 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
 
21 
Table 1-2    Most Common (At Least 10% of Total) Treatment-Emergent Adverse 
Events in Oral Single-Agent Studies 
Primary System Organ Class 
     Preferred Term 
Primary System Organ Class 
      Preferred Term 
 Thrombocytopenia 
 Thrombocytopenia 
Anaemia 
 Anaemia 
Neutropenia 
 Neutropenia 
 Lymphopenia 
 Lymphopenia 
Skin and subcutaneous tissue disorders 
Skin and subcutaneous tissue disorders 
 Rash maculara 
 Rash maculara 
Musculoskeletal and connective 
tissue disorders 
Musculoskeletal and connective tissue disorders 
 Back pain 
 Back pain 
 Arthralgia 
 Arthralgia 
Respiratory, thoracic and mediastinal 
disorders 
Respiratory, thoracic and mediastinal disorders 
 Cough 
 Cough 
 Dyspnoea 
 Dyspnoea 
Infections and infestations 
Infections and infestations 
Upper respiratory tract infection 
 Upper respiratory tract infection 
Source:  Ixazomib Investigator’s 
Brochure Edition 7 
Abbreviations:  MedDRA = 
Medical Dictionary for Regulatory 
Activities, version 15.0. 
Subject Incidence:  A subject counts 
once for each preferred term.  
Percentages use the number of 
treated subjects as the denominator. 
a Note that rash maculopapular and rash 
macular represent the 2 most common terms 
used to describe rash. 
Source:  Ixazomib Investigator’s Brochure Edition 7 
Abbreviations:  MedDRA = Medical Dictionary for Regulatory 
Activities, version 15.0. 
Subject Incidence:  A subject counts once for each preferred term.  
Percentages use the number of treated subjects as the 
denominator. 
a Note that rash maculopapular and rash macular represent the 2 
most common terms used to describe rash. 
Table 1-2    
Most Common (At Least 
10% of Total) Treatment-Emergent 
Adverse Events in Oral Single-Agent 
Studies 
Table 1-2    
Most Common (At Least 10% of Total) Treatment-
Emergent Adverse Events in Oral Single-Agent Studies 
Primary System Organ Class 
     Preferred Term 
Primary System Organ Class 
 Preferred Term 
Subjects with at Least One Adverse Event 
 


 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
 
22 
As of 27 March 2013, there are 5 studies actively enrolling patients with multiple myeloma to 
investigate oral ixazomib in combination with standard combination regimens.   
 
The most frequent (at least 10%) AEs occurring in the pooled safety population from Studies 
C16005, C16006, C16008, and C16013 are shown for all grades (Table 1-3).  Note that in 
combination trials, related is defined as related to any study drug in the combination regimen. 
 
 
Table 1-3    Most Common (At Least 10% of Total) Treatment-Emergent Adverse 
Events in Oral Combination Studies 
Primary System Organ Class 
     Preferred Term 
Total Oral Combo Agent 
(5/6/8/13) 
n = 173 
n (%) 
Subjects with at Least One Adverse Event 
163 (94) 
Gastrointestinal disorders 
139 (80) 
Nausea 
65 (38) 
Diarrhoea 
81 (47) 
Vomiting 
51 (29) 
Constipation 
57 (33) 
General disorders and administration site 
conditions 
132 (76) 
Fatigue 
76 (44) 
Pyrexia 
39 (23) 
Oedema peripheral 
61 (35) 
Asthenia 
20 (12) 
Nervous system disorders 
115 (66) 
Headache 
28 (16) 
Dizziness 
34 (20) 
Neuropathy peripheral 
45 (26) 
Metabolism and nutrition disorders 
91 (53) 
Decreased appetite 
25 (14) 
Hypokalaemia 
34 (20) 
Blood and lymphatic system disorders 
88 (51) 
Thrombocytopenia 
49 (28) 
Anaemia 
45 (26) 
Neutropenia 
43 (25) 
Lymphopenia 
20 (12) 
Skin and subcutaneous tissue disorders 
102 (59) 
Rash maculopapulara 
29 (17) 


 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
 
23 
Table 1-3    Most Common (At Least 10% of Total) Treatment-Emergent Adverse 
Events in Oral Combination Studies 
Primary System Organ Class 
     Preferred Term 
Total Oral Combo Agent 
(5/6/8/13) 
n = 173 
n (%) 
Rash maculara 
22 (13) 
Musculoskeletal and connective tissue 
disorders 
99 (57) 
Back pain 
42 (24) 
Pain in extremity 
31 (18) 
Arthralgia 
22 (13) 
Respiratory, thoracic and mediastinal 
disorders 
80 (46) 
Cough 
36 (21) 
Dyspnoea 
26 (15) 
Infections and infestations 
92 (53) 
Upper respiratory tract infection 
35 (20) 
Psychiatric disorders 
73 (42) 
Insomnia 
50 (29) 
Source:  Ixazomib Investigator’s Brochure Edition 7 
Abbreviations:  MedDRA = Medical Dictionary for Regulatory Activities, version 15.0. 
Subject Incidence:  A subject counts once for each preferred term.  Percentages use the number of treated 
subjects as the denominator.  
Data from ongoing blinded pivotal trials (C16010) are not included. 
a Note that rash maculopapular and rash macular represent the 2 most common terms used to describe rash.   
 
 
The clinical experience with ixazomib also shows early signs of antitumor activity as evidenced 
by at least a 50% reduction in disease burden in some patients and prolonged disease stabilization 
in others across all ongoing trials. The antitumor activity has been seen with single-agent ixazomib, 
when combined with established therapies, and across the malignancies studied (advanced solid 
tumors [6], non-Hodgkin’s disease, Hodgkin’s disease [7], relapsed and/or refractory multiple 
myeloma [RRMM; 8, 9], relapsed or refractory systemic light chain amyloidosis [RRAL; 10], and 
newly diagnosed multiple myeloma [NDMM; 11-13]) to date. 
 
Though additional data are needed to characterize the clinical benefit of this drug, the emerging 
data supports the ongoing development of ixazomib. 
 
 
2.1.1.6 Relapsed and/or Refractory Multiple Myeloma 
 
The early development of ixazomib in patients with RRMM involves 2 studies (C16003 and 


 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
 
24 
C16004) with similar objectives, but each investigated 1 of the 2 dosing schedules commonly 
used with the first-in-class proteasome inhibitor, VELCADE. 
Study C16003 is an open-label, dose escalation, phase 1 study of ixazomib dosing on a twice-
weekly schedule on Days 1, 4, 8, and 11 of a 21-day cycle in adult patients with RRMM.(11, 12)  
Study C16004 is an open-label, dose escalation, phase 1 study of ixazomib dosing on a weekly 
schedule on Days 1, 8, and 15 of a 28-day cycle in adults patients with RRMM.(13, 14, 15)  Both 
studies have now completed enrollment.  The DLTs in Study C16003 were rash macular and 
thrombocytopenia and the DLTs in C16004 were nausea, diarrhea, vomiting, and erythema 
multiforme. 
In the dose escalation component of both studies, patients had multiple myeloma that had 
relapsed following at least 2 lines of therapy that must have included bortezomib, thalidomide 
(or lenalidomide), and corticosteroids.  In both studies, when the MTD was established, cohorts 
of patients representing the heterogeneous patient population currently seen in clinical practice 
were to be enrolled into 1 of 4 expansion cohorts, including a relapsed and refractory cohort, a 
carfilzomib cohort, a proteasome inhibitor-naïve cohort, and a VELCADE-relapsed cohort. 
Final study results are currently being analyzed, but preliminary data suggest that ixazomib has 
anti-tumor activity in heavily pretreated MM patients, with durable responses/disease control, 
and is generally well tolerated. Please refer to the ixazomib IB and SMA for further information.  
 
2.1.1.7 Newly Diagnosed Multiple Myeloma (NDMM) 
 
Multiple research paths are being explored in patients with NDMM with a focus on evaluating 
ixazomib in combination with agents commonly used across treatment settings.  The 
development of ixazomib in combination with lenalidomide with dexamethasone (LenDex) in 
patients with NDMM who are transplant eligible or ineligible involves 2 studies (C16005 and 
C16008) with similar study designs except for a few key differences, namely the schedules of 
ixazomib and dexamethasone.  Ixazomib is also being evaluated in combination with melphalan 
and prednisone (MP) for patients who are not transplant eligible due to age or coexisting 
morbidity (in Study C16006).  
 
All 3 studies are phase 1/2, with phase 1 focusing on safety and phase 2 on efficacy (and further 
characterization of safety).  Please refer to the ixazomib IB and SMA for further information. 
 
2.1.1.8 Clinical Trial Experience Using the Intravenous Formulation of ixazomib 
 
See the IB for descriptions of the 2 studies that investigated IV ixazomib in advanced solid 
tumors and advanced lymphoma (Studies C16001 and C16002, respectively). 
 


 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
 
25 
2.1.1.9 Potential Risks and Benefits 
 
Please refer to the current ixazomib IB and SMA. 
The clinical benefit of ixazomib continues to be studied in a comprehensive and global 
development plan that involves studies sponsored by Millennium.  Ixazomib appears to show 
early signs of anti-tumor activity as evidenced by at least 50% reduction in disease burden in 
some patients, including patients that have been heavily pretreated as well as those with newly 
diagnosed MM, and prolongs stabilization of the underlying disease in other patients across all 
ongoing trials.  The preliminary findings are favorable when considering historical and currently 
available therapies for the patient populations evaluated.  Though additional data are needed to 
characterize the clinical benefit of this drug, the emerging data supports expanded development 
of ixazomib for the treatment of patients with advanced malignancy. 
This study will be conducted in compliance with the protocol, good clinical practice (GCP), 
applicable regulatory requirements, and International Conference on Harmonisation 
(ICH) guidelines. 
 
2.1.2 Rituximab 
 
2.1.2.1 Description of Rituximab 
 
Rituximab is a genetically engineered chimeric murine/human monoclonal antibody directed 
against the CD20 cell surface antigen. The antibody is an IgG kappa immunoglobulin 
containing murine light- and heavy-chain variable region sequences and human constant region 
sequences. Rituximab is a composed of two heavy chains of 451 amino acids and two light 
chains of 213 amino acids (based on cDNA analysis) and has an approximate molecular weight 
of 145 kD. Rituximab has a binding affinity for the CD20 antigen of approximately 8.0 nM. The 
chimeric anti-CD20 antibody is produced by mammalian cell (Chinese Hamster ovary) 
suspension culture in a nutrient medium containing the antibiotic gentamicin. Gentamicin is not 
detectable in the final product. Rituximab is purified by affinity and ion exchange 
chromatography. The purification process includes specific viral inactivation and removal 
procedures. 
 
Hepatitis B virus (HBV) reactivation with fulminant hepatitis, hepatic failure, and death has 
been reported in some patients with hematologic malignancies treated with rituximab.  The 
majority of patients received rituximab in combination with chemotherapy.  The median time to 
the diagnosis of hepatitis was approximately 4 months after the initiation of rituximab and 
approximately one month after the last dose. 
 
2.1.2.2 Immunologic Events  
 


 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
 
26 
Rituximab induced B-cell depletion occurred in 70 to 80% of patients, and was associated with 
decreased serum immunoglobulins in a minority of patients. The incidence of infection does not 
appear to be increased. During the treatment period, 50 patients in the pivotal trial developed 68 
infectious events; 6 (9%) were grade 3 in severity, and none were Grade 4 events. Of the 6 
serious infectious events, none were associated with neutropenia. The serious bacterial events 
included sepsis due to Listeria (n=1), staphylococcal bacteremia (n=1), and polymicrobial sepsis 
(n=1). In the post-treatment period (30 days to 11 months following the last dose), bacterial 
infections included sepsis (n=1); significant viral infections included herpes simplex infections 
(n=2) and herpes zoster (n=3). The following immune serious adverse events have been 
reported to occur rarely (<0.1%) in patients following completion of rituximab infusions: 
arthritis, disorders of blood vessels (vasculitis, serum sickness and lupus-like syndrome), lung 
disorders including pleuritis and scarring of the lung (bronchiolitis obliterans), eye disorders 
(uveitis and optic neuritis), and severe bullous skin reactions (including toxic epidermal 
necrolysis and pemphigus) that may result in fatal outcomes. Patients may have these symptoms 
alone or in combination with rash and polyarthritis.  
 
Hepatitis B virus (HBV) reactivation with fulminant hepatitis, hepatic failure, and death has 
been reported in some patients with hematologic malignancies treated with rituximab.  The 
majority of patients received rituximab in combination with chemotherapy.  The median time to 
the diagnosis of hepatitis was approximately 4 months after the initiation of rituximab and 
approximately one month after the last dose. 
 
2.1.2.3 Retreatment Events  
 
Twenty-one patients have received more than one course of Rituximab. The percentage of 
patients reporting any adverse event upon retreatment was similar to the percentage of patients 
reporting adverse events upon initial exposure. The following events were reported more 
frequently in retreated participants: asthenia, throat irritation, flushing, tachycardia, anorexia, 
leukopenia, thrombocytopenia, anemia, peripheral edema, dizziness, depression, respiratory 
symptoms, night sweats and pruritus. 
 
2.1.2.4 Hematologic Events  
 
In clinical trials, Grade 3 and 4 cytopenias were reported in 48% of patients treated with 
rituximab; these include: lymphopenia (40%), neutropenia (6%), leukopenia (4%), anemia (3%), 
and thrombocytopenia (2%).  The median duration of lymphopenia was 14 days (range, 1 to 588 
days) and of neutropenia was 13 days (range, 2 to 116 days).  A single occurrence of transient 
aplastic anemia (pure red cell aplasia) and two occurrences of hemolytic anemia following 
rituximab therapy were reported.  
 
In addition, there have been a limited number of post marketing reports of prolonged 
pancytopenia, marrow hypoplasia, and late onset neutropenia (defined as occurring 40 days after 
the last dose of rituximab) in patients with hematologic malignancies.  In reported cases of late 
onset neutropenia (NCI-CTC Grade 3 and 4), the median duration of neutropenia was 10 days 
(range 3 to 148 days). Documented resolution of the neutropenia was described in approximately 
one-half of the reported cases; of those with documented recovery, approximately half received 


 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
 
27 
growth factor support. In the remaining cases, information on resolution was not provided.  More 
than half of the reported cases of delayed onset neutropenia occurred in patients who had 
undergone prior autologous bone marrow transplantation.  In an adequately designed, controlled, 
clinical trial, the reported incidence of NCI-CTC Grade 3 and 4 neutropenia was higher in 
patients receiving rituximab in combination with fludarabine as compared to those receiving 
fludarabine alone (76% [39/51] vs. 39% [21/53]).  
 
2.1.2.5 Cardiopulmonary Events  
 
Patients with pre-existing cardiac conditions, including arrhythmia and angina have had 
recurrences of these cardiac events during rituximab infusions. Four patients developed 
arrhythmias during rituximab infusion. One of the four discontinued treatment related incidence 
was because of ventricular tachycardia and supraventricular tachycardia. The other three 
patients experienced trigeminy (1) and irregular pulse (2) and did not require discontinuation of 
therapy. Angina was reported during infusion and myocardial infarction occurred 4 days post-
infusion in one participant with a history of myocardial infarction. In rare cases, severe and fatal 
cardiopulmonary events, including hypoxia, pulmonary infiltrates, acute respiratory distress 
syndrome, myocardial infarction, and cardiogenic shock have occurred. Nearly all-fatal 
infusion-related events occurred in association with the first infusion. 
 
2.1.2.6 Potential for fatal infusion reactions  
 
In post marketing studies, rare events of tumor lysis syndrome have been reported in patients 
who had a high number of circulating malignant cells (>25,000/ul), with a rapid reduction in 
tumor volume, renal insufficiency, hyperkalemia, hypocalcemia, hyperuricemia, and 
hyperphosphatemia noted in these patients. For additional details, and updates see current 
rituximab package insert. In rare cases, severe and fatal cardiopulmonary events, including 
hypoxia, pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, and 
cardiogenic shock, have occurred. Nearly all-fatal infusion-related events occurred in 
association with the first infusion.  
 
2.1.2.7 Prevention and management of abrupt increases in serum IgM and viscosity following 
Rituximab use in patents with WM. 
 
Abrupt and paradoxical increases in IgM levels have been reported with the use of rituximab in 
patients with WM, which may aggravate hyperviscosity and contribute to hyperviscosity related 
symptoms. Plasmapheresis is strongly encouraged for those patients at increased risk for 
hyperviscosity. Rituximab will also be omitted for Cycles 1and/or 2 as necessary and at the 
discretion of the Principal Investigator for at risk patients. 
 
2.1.3 Dexamethasone 
 
2.1.3.1 Intravenous Dexamethasone 
 
Each mL of clear, colorless sterile solution contains: dexamethasone sodium phosphate 
equivalent to dexamethasone phosphate 4 mg (equal to 3.33 mg of dexamethasone or roughly 


 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
 
28 
about 100 mg of hydrocortisone). Non-medicinal ingredients: creatinine, sodium citrate, sodium 
hydroxide (to adjust pH) and water for injection with sodium bisulfite, methylparaben, and 
propylparaben are added as preservatives. 
 
2.1.3.2 Oral Dexamethasone 
 
Dexamethasone is commercially available as tablets for oral administration in following 
potencies: 0.25 mg, 0.5 mg, 0.75 mg, 1 mg, 1.5 mg, 2 mg, 4 mg, and 6 mg. Inactive ingredients 
are calcium phosphate, lactose, magnesium stearate, and starch. 
 
In the unlikely event of a drug supply interruption, oral dexamethasone will be substituted 
for IV dexamethasone at same dose used for intravenous administration. 
 
2.1.3.3 Contraindications for Dexamethasone therapy 
 
Dexamethasone will be omitted from therapy while on study in the following 
circumstances: 
• History of tuberculosis or other granulomatous disease; 
• Systemic fungal infection; 
• History of or development of uncontrollable steroid related glucose intolerance; 
• History of or development of steroid related hypersensitivity; 
• Intolerance due to gastric and duodenal ulcers despite adequate upper 
gastrointestinal prophylactic therapy. 
• Recipient of a live virus vaccine within 30 days. 
• Pregnancy and lactation. 
• Development of moderate to severe acute infections. 
 
In the event dexamethasone is omitted, patients will not be removed from study treatment, and 
will continue to receive all other intended therapy on study. 
 
2.1.3.4 Drug-Interactions for Dexamethasone 
 
The following drug interactions with dexamethasone have been reported: 
• Concurrent administration of dexamethasone with thiazides or furosemide may cause 
excessive potassium loss. 
• Dexamethasone may decrease the effect of anti-muscarinic drugs. 
• Dexamethasone may increase the incidence of gastro-intestinal ulceration when 
administered concurrently with non-steroidal anti-inflammatory drugs. 
• Barbiturates, phenytoin, rifampicin, ephedrine, may enhance the metabolism clearance of 
corticosteroids and reduce the effects of dexamethasone. 
• Dexamethasone decreases the serum concentration of salicylates. 
• Response to anticoagulants may be altered by dexamethasone. 
 
2.1.3.5Adverse Events with Dexamethasone 
 


 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
 
29 
Fluid and electrolyte disturbances: sodium retention; fluid retention; congestive heart failure in 
susceptible patients; potassium loss; hypokalemic alkalosis; hypertension; hypotension or shock-
like reaction. 
 
Musculoskeletal: muscle weakness; steroid myopathy; loss of muscle mass; osteoporosis; 
vertebral compression fractures; aseptic necrosis of femoral and humeral heads; pathologic 
fracture of long bones; tendon rupture.  
 
Gastrointestinal: peptic ulcer with possible subsequent perforation and hemorrhage; perforation 
of the small and large bowel, particularly in patients with inflammatory bowel disease; 
pancreatitis; abdominal distention; ulcerative esophagitis.  
 
Dermatologic: impaired wound healing; thin fragile skin; petechiae and ecchymoses; erythema; 
increased sweating; may suppress reactions to skin tests, burning or tingling, especially in the 
perineal area (after i.v. injection), other cutaneous reactions such as allergic dermatitis, urticaria, 
angioneurotic edema.  
 
Neurological: convulsions; increased intracranial pressure with papilledema (pseudotumor 
cerebri) usually after treatment; vertigo; headache; psychic disturbances.  
 
Endocrine: menstrual irregularities; development of cushingoid state; suppression of growth in 
children; secondary adrenocortical and pituitary unresponsiveness, particularly in times of stress, 
as in trauma, surgery or illness; decreased carbohydrate tolerance; manifestations of latent 
diabetes mellitus; increased requirements for insulin or oral hypoglycemic agents in diabetes; 
hirsutism.  
 
Ophthalmic: posterior subcapsular cataracts; increased intraocular pressure; glaucoma; 
exophthalmos; retinopathy of prematurity. 
 
Cardiovascular: myocardial rupture following recent myocardial infarction; hypertrophic 
cardiomyopathy in low birth weight infants. 
 
Metabolic: negative nitrogen balance due to protein catabolism. 
 
Other: anaphylactoid or hypersensitivity reactions, thromboembolism, weight gain, increased 
appetite, nausea, malaise, hiccups.  
 
The following additional adverse reactions are related to parenteral corticosteroid therapy: rare 
instances of blindness associated with intralesional therapy around the face and head; 
hyperpigmentation or hypopigmentation; s.c. and cutaneous atrophy; sterile abscess; post 
injection flare (following intra-articular use); Charcot-like arthropathy. 
 
2.2Study Disease 
 
WM is a rare B-cell lymphoproliferative disorder characterized by the uncontrolled accumulation 
of IgM-producing lymphoplasmacytic cells. The disease was first reported by Jan Waldenström, 


 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
 
30 
who described two patients with a high level of macroglobulin, i.e. pentameric immunoglobulin 
M (IgM), marked hyperviscosity, typical funduscopic picture and lymphocytoid bone marrow 
infiltration (Waldenström 1944). Such malignant cells accumulate in the bone marrow, liver, 
spleen and lymph nodes. WM is diagnosed by the presence of lymphoplasmacytic cells in the 
bone marrow and an IgM monoclonal spike (M-spike) identified in a serum protein 
electrophoresis (SPEP) (Owen 2003). The incidence of WM in the United States (US) is 
approximately 3 per million persons per year accounting for 1000-1500 new cases per year. The 
clinical course of WM is variable and although patients might experience an overall survival 
(OS) measured in decades, WM remains incurable with current therapeutic regimens. Hence, the 
disease course is characterized by continual relapses, each harder to treat than the previous one. 
Additionally, many of the disabling symptoms associated with the disease, such as 
hyperviscosity, fatigue, anemia and/or neuropathy, can be exacerbated by our therapy. Hence, 
the careful evaluation of agents with novel mechanisms of action is needed to improve the 
quality of life (QOL), and response and survival rates in patients with WM. 
 
2.3Rationale 
 
Despite advances in the treatment, WM remains incurable and as such; novel therapeutics are 
needed. Among the first line treatment options for WM are oral alkylators such as chlorambucil, 
nucleoside analogues, rituximab, alone and in combination treatment, thalidomide, and 
bortezomib (Treon 2006; Dimopoulos 2008). The use of oral alkylators and nucleoside 
analogues is associated with risk of myelodysplasia/acute leukemia, disease transformation and 
stem cell damage thereby limiting their usefulness, particularly in younger stem cell eligible 
transplant patients (Treon 2009a; Leleu 2009). Rituximab is an important therapeutic, generating 
overall response rates in 30-40% of patients. Among WM patients receiving rituximab as 
monotherapy, lower response rates have been observed in those patients with high serum IgM 
(>6,000 mg/dL) and beta-2 microglobulin (B2M) (>3.0 mg/L) levels, as well as homozygous 
expression of phenylalanine at amino acid position 158 on CD16 (FcγRIIIA-158) (Treon 2005a; 
Dimopoulos 2005; Treon 2005b). Limiting the application of rituximab is an idiopathic IgM flare 
phenomenon, which can provoke symptomatic hyperviscosity, as well as symptomatic IgM 
related morbidity. Moreover, patients with WM appear to develop earlier intolerance to 
rituximab versus patients with other indolent lymphomas, which may be related to the frequent 
presence of auto-IgG antibodies in WM patients.  
 
Bortezomib (Velcade®) is active in WM. As a single agent in relapsed/refractory WM, overall 
response rates of 40-60% have been reported. In combination with rituximab, higher response 
rates have been observed in relapsed/refractory or untreated patients (70-80%). The combination 
of bortezomib with dexamethasone and rituximab (BDR) is particularly active as primary 
therapy in WM with 96% overall response rate, and VGPR or better categorical responses in 
35% of patients. In a recent update at the 6th International Workshop on WM, the projected 
progression free survival for BDR was estimated at >56 months. An important limitation 
however to the use of bortezomib is the development of >grade 3 peripheral neuropathy in 20-
30% of patients using twice a week schedule of administration, and 5-10% with once a week. 
However, CR rates are potentially lower (5% vs. 20%), and risk of rituximab related IgM flare 
higher (20% vs. 10%) with attenuation of bortezomib dose to once a week, versus twice a week. 


 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
 
31 
(Treon 2009b; Ghobrial 2010). As such, the identification of novel, neuropathy and stem cell 
sparing agents is an important goal for therapy of WM.  
 
We recently reported our experience with the combination of carfilzomib (Kyprolis®), 
dexamethasone and rituximab (CaRD) in 31 proteasome-inhibitor- and rituximab-naïve patients 
with WM (Treon 2013). Carfilzomib was administered IV on days 1, 2, 8 and 9 every 3 weeks. 
The median IgM levels declined from 3,510 mg/dL to 1,876 mg/dL, and the median M-protein 
from 2.09 g/dL to 0.99 g/dL. Median hemoglobin levels improved from 10.6 g/dL to 12 g/dL. 
Bone marrow tumor burden decreased from a median of 60% to 10%. The ORR was 74% (1 CR, 
6 VGPR, 9 PR and 1 MR). The treatment was well tolerated with the only grade 3 or 4 AE of 
neutropenia (7%). Grade 1 peripheral neuropathy developed in 19% of the patients. There was no 
grade 2 or higher peripheral neuropathy. 
 
2.4Correlative Studies Background 
 
2.4.1MYD88 L265P and CXCR4-WHIM-like mutations, and FcRIIIA-158 (CD16) 
polymorphisms 
 
One of the major advances in the field of WM has been the recent discovery of a recurrent 
genetic abnormality, the MYD88 L265P mutation (Treon 2012). Sanger sequencing detected 
such mutation in tumor samples from 49 out of 54 patients (91%) with WM. Interestingly, the 
mutation was not detected in normal cells from WM patients and B-cells from healthy donors, 
and was absent or rarely expressed in cells from patients with multiple myeloma or marginal 
zone lymphoma. Such finding has been independently validated in subsequent studies from Italy, 
France the United States with prevalence rates ranging between 90-100% (Varettoni 2013; 
Poulain 2013; Ondrejka 2013). More recently, allele-specific PCR assays have been developed to 
improve the sensitivity of detection of the mutation and the quantification of the MYD88 L265P 
mutation burden (Xu 2013).  
 
More recently, mutations in the CXC chemokine receptor 4 (CXCR4) gene were identified in 16 
out of 55 (29%) WM patients investigated (Cao 2012). CXCR4 mutations are the second most 
common mutations found in WM patients. Such mutations are similar to the ones seen in patients 
with WHIM syndrome, an autosomal dominant genetic disorder characterized by warts, 
hypogammaglobulinemia, infections and myelokathexis (Hunter 2013) conferring gain of 
function and decreased CXCR4 internalization. In preclinical and clinical studies, CXCR4-
WHIM mutations have been associated with lower responses to Bruton tyrosine kinase inhibitors 
(Cao 2013), but their significance in proteasome inhibitor-treated patients is not yet known. 
 
As part of these efforts, the impact of FcRIIIA-158 (CD16) polymorphisms as a predictor of 
categorical response in WM will be assessed. In previous studies by Treon et al, the presence of 
at least one valine at amino acid position 158 at FcRIIIA (CD16) predicted for response to 
rituximab (Treon 2005b). Patients displaying either valine/valine (V/V) or valine/phenylalanine 
(V/F) had a four-fold higher rate of response to single agent rituximab compared to patients 
displaying phenylalanine/phenylalanine (F/F) alone at FcRIIIA-158. The impact of 
polymorphisms at FcRIIIA-158 on response outcome has also been validated in other indolent 


 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
 
32 
lymphomas (Cartron 2002; Weng 2003), and has lead to U.S. FDA clearance for such testing. 
The impact of FcRIIIA-158 polymorphisms in predicting categorical response attainment in 
WM patients has recently been reported. Hunter et al demonstrated that better categorical 
responses (i.e. VGPR or better) were associated with V/V or V/F at FcRIIIA-158 in patients 
who received combination therapy with rituximab (Treon 2011). As such, as part of these studies 
we will seek to determine the impact of FcRIIIA-158 polymorphisms on categorical response 
attainment in WM patients in this study. 
 
 
3.PARTICIPANT SELECTION 
 
3.1Eligibility Criteria 
 
Participants must meet the following criteria on screening examination to be eligible to 
participate in the study: 
 
Each patient must meet all of the following inclusion criteria to be enrolled in the study: 
1. Male or female patients 18 years or older. 
2. Voluntary written consent must be given before performance of any study related 
procedure not part of standard medical care, with the understanding that the patient may 
withdraw consent at any time without prejudice to future medical care. 
3. Female patients who:  
• Are postmenopausal for at least 1 year before the screening visit, OR 
• Are surgically sterile, OR 
• Are of childbearing potential,  
o agree to practice 2 effective methods of contraception, at the same time, from 
the time of signing the informed consent form through 90 days after the last 
dose of study drug, OR 
o Agree to practice true abstinence when this is in line with the preferred and 
usual lifestyle of the subject.  (Periodic abstinence [eg, calendar, ovulation, 
symptothermal, post-ovulation methods] and withdrawal are not acceptable 
methods of contraception.) 
Male patients, even if surgically sterilized (ie, status post-vasectomy), must agree to one of 
the following: 
• Agree to practice effective barrier contraception during the entire study treatment 
period and through 90 days after the last dose of study drug, OR 
• Agree to practice true abstinence when this is in line with the preferred and usual 
lifestyle of the subject.  (Periodic abstinence (eg, calendar, ovulation, symptothermal, 
post-ovulation methods] and withdrawal are not acceptable methods of contraception.) 
4. Patients must have a clinicopathological diagnosis of WM (Owen 2003), with symptomatic 
disease meeting criteria for treatment using consensus panel criteria from the Second 
International Workshop on WM (Kyle 2003) or serum IgM >6000 mg/dL, and measurable 
disease, defined as presence of immunoglobulin M (IgM) paraprotein with a minimum IgM 
level of >2 times the upper limit of normal. 
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2. 


 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
 
33 
6. Patients must meet the following clinical laboratory criteria 
7. Absolute neutrophil count (ANC) 1,000/mm3 and platelet count 75,000/mm3.  Platelet 
transfusions to help patients meet eligibility criteria are not allowed within 3 days before 
study enrollment. 
8. Total bilirubin 1.5  the upper limit of the normal range (ULN). 
9. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) 3  ULN. 
10. Calculated creatinine clearance  30 mL/min. 
 
3.2Exclusion Criteria 
 
Patients meeting any of the following exclusion criteria are not to be enrolled in the study: 
1. Female patients who are lactating or have a positive serum pregnancy test during the 
screening period.  
2. Major surgery within 14 days before enrollment. 
3. Central nervous system involvement. 
4. Infection requiring systemic antibiotic therapy or other serious infection within 14 days 
before study enrollment. 
5. Evidence of current uncontrolled cardiovascular conditions, including uncontrolled 
hypertension, uncontrolled cardiac arrhythmias, symptomatic congestive heart failure, 
unstable angina, or myocardial infarction within the past 6 months. 
6. Systemic treatment, within 14 days before the first dose of MLN9708, with strong 
inhibitors of CYP1A2 (fluvoxamine, enoxacin, ciprofloxacin), strong inhibitors of CYP3A 
(clarithromycin, telithromycin, itraconazole, voriconazole, ketoconazole, nefazodone, 
posaconazole) or strong CYP3A inducers (rifampin, rifapentine, rifabutin, carbamazepine, 
phenytoin, phenobarbital), or use of Ginkgo biloba or St. John’s wort. 
7. Known hepatitis B or C virus, or human immunodeficiency virus (HIV) infection. 
8. Any serious medical or psychiatric illness that could, in the investigator’s opinion, 
potentially interfere with the completion of treatment according to this protocol. 
9. Known allergy to any of the study medications, their analogues, or excipients in the various 
formulations of any agent. 
10. Known GI disease or GI procedure that could interfere with the oral absorption or tolerance 
of ixazomib including difficulty swallowing. 
11. Diagnosed or treated for another malignancy within 2 years before study enrollment or 
previously diagnosed with another malignancy and have any evidence of residual disease.  
Patients with non-melanoma skin cancer or carcinoma in situ of any type are not excluded 
if they have undergone complete resection.  Male patients with incidental histological 
findings of prostate cancer (T1a or T1b using the TNM (tumor nodes, metastasis) clinical 
staging system are not excluded. 
12. Participation in other clinical trials, including those with other investigational agents not 
included in this trial, within 30 days of the start of this trial and throughout the duration of 
this trial.  
 
 
4.REGISTRATION PROCEDURES 
 
4.1General Guidelines for DF/HCC and DF/PCC Institutions 


 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
 
34 
 
Institutions will register eligible participants in the Clinical Trials Management System (CTMS) 
OnCore. Registration must occur prior to the initiation of therapy. Any participant not 
registered to the protocol before treatment begins will be considered ineligible and 
registration will be denied.  
 
An investigator will confirm eligibility criteria and complete the protocol-specific eligibility 
checklist. 
  
Following registration, participants may begin protocol treatment. Issues that would cause 
treatment delays should be discussed with the Principal Investigator. If a participant does not 
receive protocol therapy following registration, the participant’s registration on the study must be 
canceled. Registration cancellations must be made in OnCore as soon as possible. 
 
4.2Registration Process for DF/HCC and DF/PCC Institutions 
 
 
5.TREATMENT PLAN   
 
Treatment will be administered on an outpatient or inpatient basis. Expected toxicities and 
potential risks as well as dose modifications for ixazomib, rituximab, and dexamethasone are 
described in Section 6 (Expected Toxicities and Dosing Delays/Dose Modification). No 
investigational or commercial agents or therapies other than those described below may be 
administered with the intent to treat the participant’s malignancy. 
 
IDR Induction Phase 
Agent 
 Premedications 
Dose 
Route 
Schedule 
Cycle 
Length 
Dexamethasone 
None 
20 mg 
IV or PO 
Days 1, 8, 15 
Before 
ixazomib and 
rituximab 
Every 4 
weeks for 
Cycles 1-6  
 
Rituximab 
omitted 
from 
cycles 1 
and 2 
Ixazomib 
None 
4 mg 
PO 
Days 1, 8 15 
After 
dexamethasone 
Rituximab 
Diphenhydramine 
25-50 mg PO/IV 
Acetaminophen 
650-1000 mg PO 
Famotidine 20mg IV 
375 mg/m2 
IV infusion 
Day 1 
After Ixazomib 
 
IDR Maintenance Phase 
Agent 
Premedications 
Dose 
Route 
Schedule 
Cycle 
Length 


 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
 
35 
Dexamethasone 
None 
20 mg 
 
IV or PO 
Day 1, 8, and 15 
Before Ixazomib 
and Rituximab 
Every 8 
weeks +/- 2 
weeks for 
Cycles 1-6 
Ixazomib 
None 
4 mg 
PO 
Day 1, 8, and 15 
After 
Dexamethasone 
Rituximab 
Diphenhydramine 
25-50 mg PO/IV 
Acetaminophen 
650-1000 mg PO 
Famotidine 20mg IV 
375 mg/m2 
IV infusion 
 Day 1 
 After Ixazomib 
 
5.1Pre-Medication 
   
5.1.1Rituximab 
 
To prevent infusion related or hypersensitivity reactions from occurring during infusion of 
rituximab, premedication consisting of diphenhydramine 25-50 mg PO/IV, and Acetaminophen 
650-1000 mg PO should be given to patients prior to administration of all infusions of 
rituximab, unless the patient has an allergy to either medication. Since transient hypotension 
may occur during rituximab administration, consideration should be given to withholding anti-
hypertensive medications 12 hours prior to rituximab infusion. Prophylactic anti-emetic therapy 
for rituximab is generally not necessary, but may used at the discretion of the treating physician.  
 
5.2Agent Administration  
 
5.2.1Ixazomib 
 
5.2.1.1Form of Ixazomib 
 
All later phase studies are conducted with the Capsule formulation.  
Ixazomib Capsules 
The ixazomib drug product is provided in strengths of 4.0-, 3.0-, and 2.3-mg and 2.0-, 0.5-, 
and 0.2 mg capsules as the active boronic acid. The different dose strengths are differentiated 
by both capsule size and color as described below: 
 
 
 
Dose Strength 
Capsule Size 
Capsule Color 
4.0 mg 
Size 4 
Ivory 
3.0 mg 
Size 3 
Light gray 
2.3 mg 
Size 2 
Light pink 
2.0 mg 
Size 2 
Swedish orange 
0.5 mg 
Size 3 
Dark green 
0.2 mg 
Size 4 
White opaque 


 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
 
36 
 Ixazomib Capsules are individually packaged in foil-foil blisters with a paper backing for child 
resistance. 
 
For additional details, please see the ixazomib IB. 
 
5.2.1.2Hydration   
 
IV hydration is recommended prior to ixazomib for Cycle 1 of induction therapy ONLY.  
This will consist of 500 mL normal saline or other appropriate IV fluid over 1 hour.  IV 
hydration in subsequent cycles will be at the discretion of the Principal Investigator. 
 
5.2.1.3Ixazomib Administration 
 
Ixazomib should be administered after dexamethasone each and every cycle, unless 
dexamethasone is omitted. Please refer to section 2.1.3.3. The order of administration 
should be dexamethasone followed by ixazomib followed by rituximab. 
 
All protocol-specific criteria for administration of study drug must be met and documented before 
drug administration.  Study drug will be administered or dispensed only to eligible patients under 
the supervision of the investigator or identified sub-investigator(s).  Patients should be monitored 
for toxicity, as necessary, and doses of ixazomib should be modified as needed to accommodate 
patient tolerance to treatment; this may include symptomatic treatment, dose interruptions, and 
adjustments of ixazomib dose (see Section 6.2). 
 
Capsules of ixazomib will also be referred to as study drug.  Study drug will be supplied by 
Millennium as capsules of 2.3, 3.0 and 4.0 mg ixazomib. The prescribed administration of 
ixazomib doses in this study is 4 mg ixazomib PO once weekly (+/-3 days) on days 1, 8 and 15 
in a 28-day cycle during induction therapy, and once on days 1, 8, and 15 in each maintenance 
cycle. 
 
Patients should be instructed to swallow ixazomib capsules whole, with water, and not to break, 
chew, or open the capsules.  Study drug should be taken on an empty stomach (no food or drink) 
at least 1 hour before or 2 hours after a meal.  Each capsule should be swallowed separately with 
a sip of water.  A total of approximately 8 ounces (240 mL) of water should be taken with the 
capsules.   
 
Missed doses can be taken as soon as the patient remembers if the next scheduled dose is 72 hours 
or more away.  A double dose should not be taken to make up for a missed dose.  If the patient 
vomits after taking a dose, the patient should not repeat the dose but should resume dosing at the 
time of the next scheduled dose. 
 
Ixazomib drug product is an anti-cancer drug. Refer to the published institutional guidelines 
regarding the proper handling and disposal of anti-cancer agents. 
 
Investigational ixazomib (expired or end of study) should be destroyed on site according to the 
institution’s standard operating procedure.  Be sure to document removal and destruction on drug 


 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
 
37 
accountability logs. 
 
5.2.2Rituximab 
 
5.2.2.1Form of Rituximab  
 
Rituximab is supplied as a sterile, colorless, preservative free liquid concentrate for intravenous 
(IV) administration. Rituximab is supplied at a concentration of 10 mg/ml in either 100 mg (10 
mL) or 500 mg (50 mL) single-use vials. The product is formulated for IV administration in 9 
mg/ml sodium chloride, 7.35-mg/mL sodium citrate dehydrate, 0.7 mg/mL polysorbate 80, and 
sterile water for injection. The pH is adjusted to 6.5. 
 
5.2.2.2Method of Procurement for Rituximab    
 
Rituximab is a commercially available drug, which is approved by the U.S. Food and Drug 
Administration for use in patients with low grade and follicular Non-Hodgkin Lymphoma 
(NHL). Use of this drug to treat patients with lymphoplasmacytic lymphoma (Waldenstrom's 
macroglobulinemia) is considered to be a labeled indication since it is included under the 
indolent NHL indication. Drug used in this study will be billed to patient and/or their third party 
payer (insurance).  
 
5.2.2.3Drug Stability and Compatibility of Rituximab 
 
Rituximab vials are stable at 2-8 C. Vials of rituximab beyond expiration date on the carton 
should not be used. Rituximab vials should be protected from direct sunlight. 
 
5.2.2.4Preparation of Rituximab 
 
Rituximab is diluted to a final concentration of 1 to 4 mg/ml into an infusion bag containing 
either 0.9% sodium chloride USP or 5% dextrose in water USP. Rituximab solutions for 
infusion are stable at 2 to 8 C for 24 hours and at room temperature for an additional 12 hours. 
No incompatibilities between rituximab and polyvinylchloride or polyethylene bags have been 
reported.  
 
5.2.2.5Rituximab Pre-Treatment Medications 
 
To prevent infusion related or hypersensitivity reactions from occurring during infusion of 
rituximab, premedication consisting of diphenhydramine 25-50 mg IV, and acetaminophen 650-
1000 mg PO should be given to patients prior to administration of all infusions of rituximab, 
unless the patient has an allergy to either medication. Lower doses may be used if the patient 
demonstrates tolerance. Since transient hypotension may occur during rituximab administration, 
consideration should be given to withholding anti-hypertensive medications 12 hours prior to 
rituximab infusion. Prophylactic anti-emetic therapy for rituximab is generally not necessary, 
but may used at the discretion of the treating physician. 
 
5.2.2.6Rituximab Treatment Schedule and Administration 


 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
 
38 
 
Rituximab should be administered after ixazomib on day 1 of induction cycles 3-6 and 
maintenance cycles 1-6. The order of administration should be dexamethasone followed by 
ixazomib followed by rituximab. Please see section 5.2.1.3. 
 
During the induction phase Cycles 3-6 on Day 1 and the maintenance phase Cycles 1-6 on Day 
1, Rituximab 375 mg/m2 IV is to be administered at an initial rate of 50 mg/hour for the first 
hour then escalate the rate in 50 mg/ hours increments approximately every 30 minutes, to a 
maximum of 400 mg/hour. If hypersensitivity or an infusion-related event develops such as 
T>101.3, mucosal edema, or a >30mm Hg decrease in SBP, interrupt the infusion, administer 
hypersensitivity rescue medications. When symptoms have resolved, the infusion can continue at 
one-half the previous rate and escalate in 50 mg/hr increments approximately each half hour, as 
tolerated. The infusion may be discontinued early at the discretion of the treating investigator.   
For patients who have tolerated previous infusions without hypersensitivity, subsequent 
infusions can be administered at an initial rate of 100 mg/hr, and increased by 100 mg/hr 
increments at approximately 30-minute intervals, to a maximum of 400 mg/hr as tolerated. 
Alternatively, subsequent infusions can be administered at an initial rate of 20 percent of the total 
dose over 30 minutes, followed by the remaining 80 percent of the total dose over 60 minutes.  
 
Vital signs:  At the first infusion, vital signs should be checked and recorded at baseline, at the 
first rate change (usually at the approximately 1 hour point), as needed for signs and symptoms 
of hypersensitivity reaction, and at the end of the infusion. For subsequent infusions, vitals 
should be taken at baseline, and as needed for signs or symptoms of a reaction.  
 
5.2.2.7First Infusion of Rituximab 
 
The rituximab solution for infusion should be administered intravenously at an initial rate of 50 
mg/hr. Rituximab should not be mixed or diluted with other drugs. If hypersensitivity or infusion 
related events do not occur, the infusion can be escalated in 50 mg/hr increments approximately 
every 30 minutes, to a maximum of 400 mg/hr. If hypersensitivity or an infusion-related event 
develops, such as, T>101.3, mucosal edema, or a >30mm Hg decrease in SBP interrupt the 
infusion, administer hypersensitivity rescue medications. When symptoms have resolved, the 
infusion can continue at one-half the previous rate and escalate in 50 mg/hr increments each half 
hour, as tolerated. 
 
5.2.2.8Subsequent Rituximab infusions 
 
Subsequent rituximab infusions can be administered at an initial rate of 100 mg/hr, and 
increased by 100 mg/hr increments at approximately 30-minute intervals, to a maximum of 400 
mg/hr as tolerated. Rituximab is administered intravenously. Alternatively, subsequent 
infusions can be administered at an initial rate of 20 percent of the total dose over 30 minutes, 
followed by the remaining 80 percent of the total dose over 60 minutes. To prevent infusion 
related or hypersensitivity events, Rituximab is not to be administered as an intravenous 
push or bolus.  
 
5.2.2.9Modification of Rate for Infusion of Rituximab  


 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
 
39 
 
In the event that patients develop an infusion related or hypersensitivity reaction to rituximab 
then the rate of drug administration is altered as described above. The total dose administered 
remains the same in such cases. In the event of serious or life threatening reactions, the infusion 
should be terminated and such adverse events reported.  In the event of serious or life threatening 
events attributed to rituximab, patients may permanently discontinue rituximab and remain on 
the study after consultation with the overall PI. 
 
5.2.3Dexamethasone 
 
5.2.3.1Intravenous Dexamethasone  
 
Each mL of clear, colorless sterile solution contains: dexamethasone sodium phosphate 
equivalent to dexamethasone phosphate 4 mg (equal to 3.33 mg of dexamethasone or roughly 
about 100 mg of hydrocortisone). Non-medicinal ingredients: creatinine, sodium citrate, sodium 
hydroxide (to adjust pH) and water for injection with sodium bisulfite, methylparaben, and 
propylparaben are added as preservatives. Store below 25°C. Do not freeze. Protect from light. 
 
5.2.3.2Contraindications and Drug interactions for Dexamethasone therapy  
 
Refer to sections 2.1.3.3 and 2.1.3.4 for contra-indications and drug interactions with 
dexamethasone. 
 
5.2.3.3Dexamethasone Administration 
 
Dexamethasone should be administered before ixazomib unless dexamethasone is omitted. 
Please refer to section 2.3.3.3.  The order of administration should be dexamethasone 
followed by ixazomib followed by rituximab. Please see section 5.2.1.3. 
 
During the induction phase, Cycles 1-6, Days 1, 8 and 15, a total of 20 mg IV or PO 
dexamethasone will be administered before ixazomib. During the maintenance phase, Cycles 1-
8, Day 1, a total of 20 mg IV or PO dexamethasone will be administered.   
 
20 mg oral dexamethasone may be substituted in the event of a drug supply shortage of IV 
dexamethasone and on days 8 and 15 of induction and maintenance for dosing outside of clinic. 
Administration method will be documented. 
 
5.3General Concomitant Medication and Supportive Care Guidelines 
 
Concomitant medication is defined as any prescription or over-the-counter preparation including 
vitamins and supplements.  All required and optional/allowed concomitant medications must be 
recorded from screening through the end of the participant’s study participation.  Any change in 
concomitant medications must be recorded. 
 
5.3.1Required Concomitant Medications 
 


 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
 
40 
Female participants of childbearing potential must agree to use methods of contraception for the 
duration of the study.  Male participants must agree to use a barrier method of contraception for 
the duration of the study if sexually active with a female of childbearing potential. Surgically 
sterilized patients are except from contraception requirements. 
 
All participants will receive 400 mg orally twice daily of acyclovir or valcyclovir 1000 mg orally 
daily, unless contraindicated, for Herpes zoster prophylaxis for the duration of the trial and for at 
least 6 months following completion of ixazomib treatment.   
 
5.3.2Optional and Allowed Concomitant Medications  
 
Supportive care is permitted as medically needed. Participants may receive supportive care with 
erythropoietin, darbepoetin, filgrastim or pegfilgrastim, in accordance with institutional 
guidelines. 
 
Participants may receive RBC or platelet transfusions if clinically indicated in accordance with 
institutional guidelines.  Participants who require repeated platelet transfusion support should be 
discussed with the principal investigator. 
 
Participants may receive antiemetic and antidiarrheal medications as necessary, but these should 
not be administered unless indicated.  Colony-stimulating factors may be used if neutropenia 
occurs but should not be given prophylactically.  
 
All vitamins and supplements must be recorded from screening through the end of the 
participant’s participation on trial. 
 
Green tea and/or green tea supplements are prohibited while participating on trial. 
 
5.4Duration of Therapy 
 
Duration of therapy will depend on individual response, evidence of disease progression and 
tolerance. In the absence of treatment delays due to adverse events, treatment may continue 
for 6 cycles of induction therapy with 6 cycles of maintenance or until one of the following 
criteria applies: 
• Disease progression, 
• Intercurrent illness that prevents further administration of treatment, 
• Unacceptable adverse event(s), 
• Participant demonstrates an inability or unwillingness to comply with the 
regimen and/or documentation requirements 
• Participant decides to withdraw from the study, or 
• General or specific changes in the participant's condition render the participant 
unacceptable for further treatment in the opinion of the treating investigator. 
 
5.5Duration of Follow Up  
 


 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
 
41 
Participants will be followed every six months (every 3 months preferred) for two years 
after removal from study until next therapy or until death. Participants removed from study 
for unacceptable adverse events will be followed until resolution or stabilization of the adverse 
event. 
  
5.6Criteria for Removal from Study  
 
Participants will be removed from study when any of the criteria listed in Section 5.4 applies. The 
reason for study removal and the date the participant was removed must be documented in the 
study-specific case report form (CRF). Alternative care options will be discussed with the 
participant. 
 
In the event of unusual or life-threatening complications, participating investigators must 
immediately notify the Principal Investigator, Dr. Jorge J. Castillo, Phone: 401-489-4626. 
 
6.EXPECTED TOXICITIES AND DOSING DELAYS/DOSE MODIFICATIONS  
 
Dose delays and modifications will be made using these recommendations. Toxicity assessments 
will be done using the CTEP Version 4 of the NCI Common Terminology Criteria for Adverse 
Events (CTCAE) Version 4.0, which is identified and located on the CTEP website at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  
 
If possible, symptoms should be managed symptomatically. In the case of toxicity, appropriate 
medical treatment should be used (including antiemetic, antidiarrheal agents, etc.). 
 
All adverse events experienced by participants will be collected from the time of the first dose of 
study treatment, through the study and until the final study visit. Participants continuing to 
experience toxicity at the off study visit may be contacted for additional assessments until the 
toxicity has resolved or is deemed irreversible. 
6.1Anticipated toxicities 
 
 
6.1.1Adverse Event Lists for Ixazomib 
 
 
 


 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
 
42 
Table 6-1 Most frequent treatment-emergent adverse events (in at least 10% of patients), 
overall safety population (part 1) 
 
 
 
 


 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
 
43 
Table 6-1 Most frequent treatment-emergent adverse events (in at least 10% of patients), 
overall safety population (part 2) 
 
 
 
 
 


 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
 
44 
Table 6-2  Treatment-emergent rash events, overall safety population (part 1) 
 
 
 
 
 


 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
 
45 
Table 6-2  Treatment-emergent rash events, overall safety population (part 2) 
 
 
 
6.1.2Excluded Concomitant Medications and Procedures 
 
The following medications and procedures are prohibited during the study: 
• Systemic treatment with any of the following metabolizing enzyme inhibitors is not 
permitted during this study.  A drug-drug interaction [DDI] with a strong inhibitor 
would increase the ixazomib exposure and could lead to a higher probability of an 
AE). Strong inhibitors of CYP1A2:  fluvoxamine, enoxacin, ciprofloxacin. 
• Strong inhibitors of CYP3A:  clarithromycin, telithromycin, itraconazole, voriconazole, 
ketoconazole, nefazodone, and posaconazole. Systemic treatment with any of the following 
metabolizing enzyme inducers should be avoided unless there is no appropriate alternative 
medication for the patient’s use. Unlike with inhibitors, if there were to be a DDI with 
an inducer, ixazomib exposure would be less; therefore, there would be a reduced 
chance of an AE.  However, there may be less chance for an antitumor effect, but that 
is not an absolute reason to be taken off ixazomib. 
• Strong CYP3A inducers:  rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, and 
phenobarbital 
• The dietary supplements St John’s wort and Ginkgo biloba are not permitted. 
The following procedures are prohibited during the study: 
• Any antineoplastic treatment with activity against WM (i.e. high-dose steroids, 
methotrexate, cyclophosphamide, etc.) except for drugs in this treatment regimen. 
• Radiation therapy (note that, in general, the requirement for local radiation therapy 
indicates disease progression) 
• Platelet transfusions to help patients meet eligibility criteria are not allowed within 
3 days prior to the blood draw that will confirm eligibility or any pre-dose CBC blood 
draws to guide dosing decisions (see Section 6.2.1.1) 
6.1.3Permitted Concomitant Medications and Procedures (if applicable) 


 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
 
46 
 
The following medications and procedures are permitted during the study: 
• Antiemetics, including 5-HT3 serotonin receptor antagonists, may be used at the discretion 
of the investigator. 
• Loperamide or other antidiarrheal should be used for symptomatic diarrhea at discretion of 
the investigator. The dose and regimen will be according to institutional guidelines. IVF 
should be given to prevent volume depletion. 
• Growth factors (eg, granulocyte colony stimulating factor [G-CSF], granulocyte 
macrophage-colony stimulating factor [GM-CSF], recombinant erythropoietin) are 
permitted. Their use should follow published guidelines and/or institutional practice;. 
Erythropoietin will be allowed in this study. Their use should follow published guidelines 
and/or institutional practice. 
• Patients should be transfused with red cells and platelets as clinically indicated and 
according to institutional guidelines.  Patients should not have a CBC drawn to confirm 
eligibility or for on-treatment decisions (see section 6.2.1.1: Dose Reductions for 
Hematologic Toxicities) less than 3 days following a platelet transfusion.  Patients MUST 
HAVE a CBC drawn to confirm eligibility or for on-treatment decisions (see section 
6.2.1.1: Dose Reductions for Hematologic Toxicities)  more than 3 days following a 
platelet transfusion. If a patient receives a platelet transfusion, then a 3-day wait is 
recommended for the CBC draw that would either confirm eligibility or guide the decision 
with regards to the next dose (drug hold/dose reduce per Section 6.2.1.1). 
• Antiviral therapy such as acyclovir may be administered if medically appropriate. 
• Concomitant treatment with bisphosphonates will be permitted, as appropriate. 
• Patients who experience worsening neuropathy from baseline may be observed for 
recovery, and have dose reductions/delays as indicated in the protocol, and any supportive 
therapy or intervention may be initiated as appropriate at the discretion of the investigator. 
• Supportive measures consistent with optimal patient care may be given throughout the 
study. 
6.1.4Precautions and Restrictions  
 
• Fluid deficit should be corrected before initiation of treatment and during 
treatment. 
• Nonsteroidal anti-inflammatory drugs (NSAIDs) should be avoided with impaired 
renal function given reported NSAID-induced renal failure in patients with 
decreased renal function. 
 
Pregnancy 
It is not known what effects ixazomib has on human pregnancy or development of the 
embryo or fetus.  Therefore, female patients participating in this study should avoid 
becoming pregnant, and male patients should avoid impregnating a female partner.  


 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
 
47 
Nonsterilized female patients of reproductive age group and male patients should use 
effective methods of contraception through defined periods during and after study 
treatment as specified below. 
Female patients must meet 1 of the following:  
• Postmenopausal for at least 1 year before the screening visit, or 
• Surgically sterile, or 
• If they are of childbearing potential, agree to practice 2 effective methods of 
contraception from the time of signing of the informed consent form through 90 
days after the last dose of study drug, or  
• Agree to practice true abstinence, when this is in line with the preferred and usual 
lifestyle of the subject.  (Periodic abstinence [eg, calendar, ovulation, 
symptothermal, postovulation methods] and withdrawal are not acceptable methods 
of contraception.) 
 
Male patients, even if surgically sterilized (ie, status postvasectomy) must agree to 1 of the 
following: 
• Practice effective barrier contraception during the entire study treatment period 
and through 90 days after the last dose of study drug, or 
• Agree to practice true abstinence, when this is in line with the preferred and usual 
lifestyle of the subject.  (Periodic abstinence [eg, calendar, ovulation, 
symptothermal, postovulation methods for the female partner] and withdrawal are 
not acceptable methods of contraception.) 
6.1.5Management of Clinical Events (if applicable) 
 
Adverse drug reactions such as thrombocytopenia, diarrhea, fatigue, nausea, vomiting, and 
rash have been associated with ixazomib treatment.  Management guidelines regarding 
these events are outlined below.  Further details of management of ixazomib AEs are 
described in Section 6 of the ixazomib IB.   
 
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.  Other antivirals are also acceptable. 
 
Nausea and/or Vomiting 
Standard anti-emetics, including 5-HT3 antagonists, are recommended for emesis occurring upon 
treatment initiation; prophylactic anti-emetics may also be considered.  Dexamethasone should not 
be administered as an anti-emetic.  Fluid deficit should be corrected before initiation of study drug 
and during treatment. 


 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
 
48 
 
Diarrhea 
Prophylactic antidiarrheals will not be used in this protocol. However, diarrhea should be 
managed according to clinical practice, including the administration of antidiarrheals once 
infectious causes are excluded. Fluid intake should be maintained to avoid dehydration. Fluid 
deficit should be corrected before initiation of treatment and during treatment. 
 
Erythematous Rash With or Without Pruritus 
As with bortezomib, rash with or without pruritus has been reported with ixazomib, primarily at 
the higher doses tested and when given with agents where rash is an overlapping toxicity.  The 
rash may range from limited erythematous areas, macular and/or small papular bumps that may 
or may not be pruritic over a few areas of the body, to a more generalized eruption that is 
predominately on the trunk or extremities.  Rash has been most commonly characterized as 
maculopapular or macular.  To date, when it does occur, rash is most commonly reported within 
the first 3 cycles of therapy.  The rash is often transient, self-limiting, and is typically Grade 1 to 
2 in severity.  
Symptomatic measures such as antihistamines or corticosteroids (oral or topical) have been 
successfully used to manage rash and have been used prophylactically in subsequent cycles.  The 
use of a topical, IV, or oral steroid (eg, prednisone ≤ 10 mg per day or equivalent) is permitted.  
Management of a Grade 3 rash may require intravenous antihistamines or corticosteroids.  
Administration of ixazomib (and/or other causative agent if given in combination) should be 
modified per protocol and re-initiated at a reduced level from where rash was noted (also, per 
protocol).   
In line with clinical practice, dermatology consult and biopsy of Grade 3 or higher rash or any 
SAE involving rash is recommended.  Prophylactic measures should also be considered if a 
patient has previously developed a rash (eg, using a thick, alcohol-free emollient cream on dry 
areas of the body or oral or topical antihistamines).  A rare risk is Stevens-Johnson Syndrome, a 
severe and potentially life-threatening rash with skin peeling and mouth sores, which should be 
managed symptomatically according to standard medical practice.  Punch biopsies for 
histopathological analysis are encouraged at the discretion of the investigator. 


 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
 
49 
 
Thrombocytopenia 
Blood counts should be monitored regularly as outlined in the protocol with additional testing 
obtained according to standard clinical practice. Thrombocytopenia may be severe but has been 
manageable with platelet transfusions according to standard clinical practice. Ixazomib 
administration should be modified as noted as per dose modification recommendations in the 
protocol when thrombocytopenia occurs (see Table 6-2). Therapy can be reinitiated at a reduced 
level upon recovery of platelet counts. A rare risk is thrombotic thrombocytopenic purpura 
(TTP), a rare blood disorder where blood clots form in small blood vessels throughout the body 
characterized by thrombocytopenia, petechiae, fever, or possibly more serious signs and 
symptoms. TTP should be managed symptomatically according to standard medical practice. 
 
Neutropenia 
Blood counts should be monitored regularly as outlined in the protocol with additional testing 
obtained according to standard clinical practice.  Neutropenia may be severe but has been 
manageable.  Growth factor support is not required but may be considered according to standard 
clinical practice.  Ixazomib administration should be modified as noted as per dose modification 
recommendations in the protocol when neutropenia occurs (see Table 6-2).  Therapy can be 
reinitiated at a reduced level upon recovery of ANCs. 
 
Fluid Deficit 
Dehydration should be avoided since 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 initiation 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 while the patient is on 
study treatment and fluid deficit should be corrected as needed, especially in the setting of 
concomitant symptoms such as nausea, vomiting, diarrhea, or anorexia.  Patients taking 
medications and/or diuretics to manage their blood pressure (for either hypo- or hypertension) 


 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
 
50 
should be managed according to standard clinical practice, including considerations for dose 
adjustments of their concomitant medications during the course of the trial.  Fluid deficit should 
be corrected before initiation of study drug and as needed during treatment to avoid dehydration. 
Posterior Reversible Encephalopathy Syndrome  
One case of posterior reversible encephalopathy syndrome, which ultimately resolved, has been 
reported with ixazomib.  This condition is characterized by headache, seizures and visual loss, as 
well as abrupt increase in blood pressure.  Diagnosis may be confirmed by magnetic resonance 
imaging (MRI).  If the syndrome is diagnosed or suspected, symptom-directed treatment should 
be maintained until the condition is reversed by control of hypertension or other instigating 
factors. 
Transverse Myelitis 
Transverse myelitis has also been reported with ixazomib. It is not known if ixazomib causes 
transverse myelitis; however, because it happened to a patient receiving ixazomib, the possibility 
that ixazomib may have contributed to transverse myelitis cannot be excluded. 
6.1.6Adverse Event List for Rituximab 
 
Anticipated Drug Toxicities 
 
The following safety data on rituximab related adverse events has been compiled from 315 
patients who were treated in 5 single agent studies. 
 
Infusion Related Events 
 
Rituximab is associated with hypersensitivity reactions, which may respond to adjustments in the 
infusion rate. An infusion related symptom complex consisting of fever and chills/rigors 
occurred in the majority of patients during the first rituximab infusion. Other frequent infusion 
related symptoms include nausea, urticaria, fatigue, headache, pruritus, bronchospasm, dyspnea, 
sensation of tongue or throat swelling (angioedema), rhinitis, vomiting, hypotension, flushing, 
and pain at disease sites. These reactions have generally occurred within 30 minutes to 2 hours of 
beginning the first infusion, and resolved with slowing or interruption of the rituximab infusion 
and with supportive care (IV saline, diphenhydramine, famotidine or cimetidine, acetaminophen, 
glucocorticoids). The incidence of infusion related events decreased from 80% (7% Grade 3/4) 
during the first infusion to approximately 40% (5% to 10% Grade 3/4) with subsequent 
infusions. Mild to moderate hypotension requiring interruption of rituximab infusion with or 
without administration of IV saline occurred in 10% of patients. Isolated occurrences of severe 
reactions requiring epinephrine have been reported in patients receiving rituximab for other 
indications. Angioedema was reported in 13% of patients, and was serious in one patient. 
Bronchospasm occurred in 8% of patients; one quarter of these patients were treated with 
bronchodilators. A single report of bronchiolitis obliterans was noted. 


 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
 
51 
 
Immunologic Events 
 
Rituximab induced B-cell depletion in 70 to 80% of patients, and was associated with decreased 
serum immunoglobulins in a minority of patients. The incidence of infection does not appear to 
be increased. During the treatment period, 50 patients in the pivotal trial developed 68 infectious 
events; 6 (9%) were grade 3 in severity, and none were Grade 4 events. Of the 6 serious 
infectious events, none were associated with neutropenia. The serious bacterial events included 
sepsis due to Listeria (n=1), staphylococcal bacteremia (n=1), and polymicrobial sepsis (n=1). In 
the post-treatment period (30 days to 11 months following the last dose), bacterial infections 
included sepsis (n=1); significant viral infections included herpes simplex infections (n=2) and 
herpes zoster (n=3). The following immune serious adverse events have been reported to occur 
rarely (<0.1%) in patients following completion of rituximab infusions: arthritis, disorders of 
blood vessels (vasculitis, serum sickness and lupus-like syndrome), lung disorders including 
pleuritis and scarring of the lung (bronchiolitis obliterans), eye disorders (uveitis and optic 
neuritis), and severe bullous skin reactions (including toxic epidermal necrolysis and pemphigus) 
that may result in fatal outcomes. Patients may have these symptoms alone or in combination 
with rash and polyarthritis. 
 
Hepatitis B virus (HBV) reactivation with fulminant hepatitis, hepatic failure, and death has been 
reported in some patients with hematologic malignancies treated with rituximab. The majority of 
patients received rituximab in combination with chemotherapy. The median time to the diagnosis 
of hepatitis was approximately 4 months after the initiation of rituximab and approximately one 
month after the last dose. 
 
Retreatment Events 
 
Twenty-one patients have received more than one course of rituximab. The percentage of 
patients reporting any adverse event upon retreatment was similar to the percentage of patients 
reporting adverse events upon initial exposure. The following events were reported more 
frequently in retreated participants: asthenia, throat irritation, flushing, tachycardia, anorexia, 
leukopenia, thrombocytopenia, anemia, peripheral edema, dizziness, depression, respiratory 
symptoms, night sweats and pruritus. 
 
Hematologic Events 
 
In clinical trials, Grade 3 and 4 cytopenias were reported in 48% of patients treated with 
rituximab including: lymphopenia (40%), neutropenia (6%), leukopenia (4%), anemia (3%), and 
thrombocytopenia (2%). The median duration of lymphopenia was 14 days (range, 1 to 588 
days) and of neutropenia was 13 days (range, 2 to 116 days). A single occurrence of transient 
aplastic anemia (pure red cell aplasia) and two occurrences of hemolytic anemia following 
rituximab therapy were reported. 
 
In addition, there have been a limited number of post marketing reports of prolonged 
pancytopenia, marrow hypoplasia, and late onset neutropenia (defined as occurring 40 days after 
the last dose of rituximab) in patients with hematologic malignancies. In reported cases of late 


 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
 
52 
onset neutropenia (NCI-CTC Grade 3 and 4), the median duration of neutropenia was 10 days 
(range 3 to 148 days). Documented resolution of the neutropenia was described in approximately 
one-half of the reported cases; of those with documented recovery, approximately half received 
growth factor support. In the remaining cases, information on resolution was not provided. More 
than half of the reported cases of delayed onset neutropenia occurred in patients who had 
undergone prior autologous bone marrow transplantation. In an adequately designed, controlled, 
clinical trial, the reported incidence of NCI-CTC Grade 3 and 4 neutropenia was higher in 
patients receiving rituximab in combination with fludarabine as compared to those receiving 
fludarabine alone (76% [39/51] vs. 39% [21/53]). 
 
Cardiopulmonary Events 
 
Patients with pre-existing cardiac conditions, including arrhythmia and angina have had 
recurrences of these cardiac events during rituximab infusions. Four patients developed 
arrhythmias during rituximab infusion. One of the four patients discontinued treatment because 
of ventricular tachycardia and supraventricular tachycardias. The other three patients 
experienced trigeminy (1) and irregular pulse (2) and did not require discontinuation of therapy. 
Angina was reported during infusion and myocardial infarction occurred 4 days post-infusion in 
one participant with a history of myocardial infarction. In rare cases, severe and fatal 
cardiopulmonary events, including hypoxia, pulmonary infiltrates, acute respiratory distress 
syndrome, myocardial infarction, and cardiogenic shock have occurred. Nearly all-fatal infusion-
related events occurred in association with the first infusion. 
 
Potential for fatal infusion reactions 
 
In post marketing studies, rare events of tumor lysis syndrome have been reported in patients 
who had a high number of circulating malignant cells (>25,000/ul), with a rapid reduction in 
tumor volume, renal insufficiency, hyperkalemia, hypocalcemia, hyperuricemia, and 
hyperphosphatemia noted in these patients. For additional details, and updates see current 
rituximab package insert. In rare cases, severe and fatal cardiopulmonary events, including 
hypoxia, pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, and 
cardiogenic shock, have occurred. Nearly all-fatal infusion-related events occurred in association 
with the first infusion. 
 
Prevention and management of abrupt increases in serum IgM and viscosity following 
Rituximab use in patients with Waldenström’s macroglobulinemia 
 
Abrupt and paradoxical increases in IgM levels have been reported with the use of rituximab in 
patients with Waldenström’s macroglobulenemia, which may aggravate hyperviscosity and 
contribute to hyperviscosity related symptoms. Plasmapheresis is strongly encouraged for those 
patients at increased risk for hyperviscosity. Rituximab will be omitted for Cycles 1 and 2 in all 
patients. 
 
6.1.7Adverse Event List for Dexamethasone 
 


 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
 
53 
Fluid and electrolyte disturbances: sodium retention; fluid retention; congestive heart failure 
in susceptible patients; potassium loss; hypokalemic alkalosis; hypertension; hypotension or 
shock-like reaction. 
 
Musculoskeletal: muscle weakness; steroid myopathy; loss of muscle mass; osteoporosis; 
vertebral compression fractures; aseptic necrosis of femoral and humeral heads; pathologic 
fracture of long bones; tendon rupture. 
 
Gastrointestinal: peptic ulcer with possible subsequent perforation and hemorrhage; perforation 
of the small and large bowel, particularly in patients with inflammatory bowel disease; 
pancreatitis; abdominal distention; ulcerative esophagitis. 
 
Dermatologic: impaired wound healing; thin fragile skin; petechiae and ecchymoses; erythema; 
increased sweating; may suppress reactions to skin tests, burning or tingling, especially in the 
perineal area (after i.v. injection), other cutaneous reactions such as allergic dermatitis, urticaria, 
angioneurotic edema. 
 
Neurological: convulsions; increased intracranial pressure with papilledema (pseudotumor 
cerebri) usually after treatment; vertigo; headache; psychic disturbances. 
 
Endocrine: menstrual irregularities; development of cushingoid state; suppression of growth in 
children; secondary adrenocortical and pituitary unresponsiveness, particularly in times of stress, 
as in trauma, surgery or illness; decreased carbohydrate tolerance; manifestations of latent 
diabetes mellitus; increased requirements for insulin or oral hypoglycemic agents in diabetes; 
hirsutism. 
 
Ophthalmic: posterior subcapsular cataracts; increased intraocular pressure; glaucoma; 
exophthalmos; retinopathy of prematurity. 
 
Cardiovascular: myocardial rupture following recent myocardial infarction; hypertrophic 
cardiomyopathy in low birth weight infants. 
 
Metabolic: negative nitrogen balance due to protein catabolism. 
 
Other: anaphylactoid or hypersensitivity reactions, thromboembolism, weight gain, increased 
appetite, nausea, malaise, hiccups. 
 
The following additional adverse reactions are related to parenteral corticosteroid therapy: rare 
instances of blindness associated with intralesional therapy around the face and head; 
hyperpigmentation or hypopigmentation; subcutaneous and cutaneous atrophy; sterile abscess; 
post-injection flare (following intra-articular use); Charcot-like arthropathy. 
 
6.2Toxicity Management and Dose Modifications/Delays  
 
6.2.1Ixazomib 
 


 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
 
54 
Treatment with ixazomib will use a cycle length of 28 days during induction and 8 weeks during 
maintenance. For a new cycle of treatment to begin, the patient must meet the following criteria: 
 
• ANC must be ≥ 1,000/mm3. 
• Platelet count must be ≥ 75,000/mm3. 
• All other non-hematologic toxicity (except for alopecia) must have resolved to ≤ Grade 1 
or to the patient’s baseline condition 
 
Transfusion of blood products and G-CSF administration is not permissible on treatment days to 
meet the above requirements.  If the patient fails to meet the above-cited criteria for initiation of 
the next cycle of treatment, dosing of ixazomib, rituximab, and dexamethasone should be 
delayed for 1 week. At the end of that time, the patient should be re-evaluated to determine 
whether the criteria have been met. If the patient continues to fail to meet the above-cited 
criteria, delay therapy and continue to re evaluate. The maximum delay before treatment should 
be discontinued will be 28 days or at the discretion of the Principal Investigator.   
 
For dosing recommendations upon recovery, refer to Table 6-2 and Table 6-3. 
 
Table 6-1 MLN908 Dose Adjustments 
 
Dose Level 
Dose (mg) 
Starting Dose 
4.0 mg 
-1 
3.0 mg 
-2 
2.3 mg 
-3 
Discontinue 
 
6.2.1.1Dose Reductions for Hematologic Toxicities  
 
Dosage adjustments for hematologic toxicity are outlined in Table 6-2. 
Table 6-2    Ixazomib Dose Adjustments for Hematologic Toxicities 
Ixazomib can be held for maximum of 28 days except at discretion of PI 
Criteria 
Action 
Within-Cycle Dose Modifications 
 
If platelet count  30  109/L or ANC ≤ 0.50 
 109/L on a ixazomib dosing day (other 
than Day 1) 
Ixazomib dose should be withheld.   
Complete blood count (CBC) with 
differential should be repeated at least every 
other day until the ANC and/or platelet 
counts have exceeded the prespecified values 
(see Section 6.2.1) on at least 2 occasions.   
Upon recovery, ixazomib may be reinitiated 
with 1 dose level reduction.  


 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
 
55 
Dosage adjustments for hematologic toxicity are outlined in Table 6-2. 
Table 6-2    Ixazomib Dose Adjustments for Hematologic Toxicities 
Ixazomib can be held for maximum of 28 days except at discretion of PI 
Criteria 
Action 
Dose Modifications for Subsequent 
Treatment Cycles 
 
Delay of > 2 weeks in the start of a 
subsequent cycle due to lack of toxicity 
recovery as defined in Section 6.3.1.  
ANC < 1.0  109/L, platelet count < 75  
109/L, or other nonhematologic toxicities > 
Grade 1 or not to the patient’s baseline 
condition 
Hold ixazomib until resolution as per criteria 
Section 6.2. 
Upon recovery, reduce ixazomib 1 dose 
level. 
The maximum delay before treatment should 
be discontinued will be 28 days or at the 
discretion of the PI. 
Dose Modifications for Subsequent 
Treatment Cycles 
 
All hematologic toxicities 
For hematologic toxicity that occurs during a 
cycle but recover in time for the start of the 
next cycle,: 
 If dose was reduced within the cycle, start 
the next cycle at that same dose. 
If due to toxicity timing, ie, after Day 15 
dosing thus a dose reduction was not 
required at that point in the cycle, reduce 
ixazomib by 1 dose level at the start of that 
cycle. 
Do not reduce the dose both within a cycle 
and at the start of the cycle for the same 
most severe toxicity. 
 
 
 
 
6.2.1.2Dose Reductions for Non-Hematologic Toxicities 
 


 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
 
56 
Table 6-3    Ixazomib Treatment Modification (Delays, Reductions, and 
Discontinuations) Due to Adverse Events (Non-Hematologic Toxicities) 
Ixazomib can be held for maximum of 28 days except at discretion of PI 
Adverse Event (Severity) 
Action on Study Drug 
Further Considerations 
Peripheral Neuropathy: 
Grade 1 peripheral neuropathy 
 
• No action 
 
Grade 1 signs and symptoms:  
asymptomatic; without pain or loss 
of function; clinical or diagnostic 
observations only [14] 
 
 
New or worsening Grade 1 
peripheral neuropathy with pain or 
Grade 2 
• Hold study drug until 
resolution to Grade ≤ 1 or 
baseline 
Grade 2 signs and symptoms:  
Moderate symptoms; limiting 
instrumental activities of daily 
living (ADL) [14] 
 
 
New or worsening Grade 2 
peripheral neuropathy with pain or 
Grade 3 
• Hold study drug until 
resolution to Grade ≤ 1 or 
baseline 
• Reduce study drug to next 
lower dose upon recovery 
 
Grade 3 signs and symptoms:  
severe symptoms; limiting self-
care ADL; assistive device 
indicated [14] 
New or worsening Grade 4 
peripheral neuropathy 
• Discontinue study drug 
 
 
 
Grade 2 Rash 
• 
Symptomatic 
recommendations as per 
section 6.6 
The investigator and project 
clinician may discuss 
considerations for dose 
modifications and symptom 
management. 
 
Grade 3 nonhematologic toxicity 
judged to be related to study drug 
 
• Hold study drug until 
resolution to Grade < 1 or 
baseline 
 
Symptomatic recommendations 
noted in Section 6.6 
If not recovered to 
< Grade 1 or baseline 
within 4 weeks 
 
• Reduce study drug 1 to next 
lower dose upon return to 
< Grade 1 or baseline 
 
Subsequent recurrence 
Grade 3 that does not 
recover to < Grade 1 or 
baseline within 4 weeks 
• Hold study drug until 
resolution to Grade < 1 or 
baseline 
• Reduce study drug to next 
lower dose  
Monitor closely, take appropriate 
medical precautions, and provide 
appropriate symptomatic care 
 
 
 


 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
 
57 
Table 6-3    Ixazomib Treatment Modification (Delays, Reductions, and 
Discontinuations) Due to Adverse Events (Non-Hematologic Toxicities) 
Ixazomib can be held for maximum of 28 days except at discretion of PI 
Adverse Event (Severity) 
Action on Study Drug 
Further Considerations 
Grade 4 nonhematologic toxicities 
judged to be related to study drug 
• Consider permanently 
discontinuing study drug 
Exceptions are cases in which the 
investigator determines the patient 
is obtaining a clinical benefit  
 
Once ixazomib is reduced for any toxicity, the dose may not be re-escalated. 
 
6.2.1.3Missed Doses 
 
Missed doses will not be replaced during a cycle.  If a participant misses more than 2 doses of 
any cycle for reasons other than toxicity, the participant will be discontinued.  
 
6.2.1.4Changes in Body Surface Area (BSA)  
 
Dose adjustments do not need to be made based on BSA changes. 
 
6.2.1.5Management of Adverse Events due to Rituximab 
 
In the event that patients experience a fever spike (>101o F), rigors, mucosal congestion or 
edema, or a decline in blood pressure (>30 mm systolic drop) during infusion with rituximab, the 
infusion should be temporarily discontinued and the patient observed. When the patient has 
recovered, the infusion should be restarted at half the previous rate. Treatment of infusion-related 
symptoms with additional IV diphenhydramine, acetaminophen, IV corticosteroids, IV 
cimetidine or famotidine is recommended. Additional treatment with bronchodilators or IV 
saline may be indicated. Medications for treatment of hypersensitivity reactions, such as 
epinephrine, antihistamines, famotidine or cimetidine, and corticosteroids should be available for 
immediate use in the event of a reaction during administration. Infusions should be discontinued 
in the event of serious or life-threatening cardiac arrhythmias. Patients who develop clinically 
significant arrhythmias should undergo cardiac monitoring during and after subsequent infusions 
of rituximab. Patients with pre-existing cardiac conditions including arrhythmias and angina 
have had recurrences of these events during rituximab therapy and should be monitored 
throughout the infusion and immediate post-infusion period. 
 
No dose reductions of rituximab will be permitted in this study. However, for patients who 
experience toxicities, delay in whole or in part for rituximab will be permitted. In the event a 
patient cannot receive their intended rituximab infusion due to an infusion related reaction or 
toxicity to rituximab, then their therapy may be delayed for up to 7 days. Patients who 
experience infusion related reactions and are unable to complete their rituximab therapy on the 
day they experience such a reaction, may be rescheduled to return to receive the balance of their 
therapy within 7 days. The timing for future rituximab infusions will remain on track should a 
patient experience delay in receiving therapy. Patients who experience an anaphylactic reaction 


 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
 
58 
or are unable to tolerate rituximab will have their rituximab omitted, but continue receiving 
therapy otherwise as per protocol. Plasmapheresis is strongly encouraged for those patients at 
increased risk for hyperviscosity. Rituximab will be omitted for Cycles 1 and/or 2 in all patients. 
 
CBC and differential will be obtained regularly as indicated in study calendar. Erythropoietin 
and transfusion support are permitted. Same day treatment with platelets is allowed as long as 
eligibility is met. Drug toxicities will be reported using common toxicity criteria. 
 
Carriers of hepatitis B should be closely monitored for clinical and laboratory signs of active 
HBV infection and for signs of hepatitis throughout their study participation. Any participant 
who develops active HBV infection or hepatitis should not be treated with any further rituximab 
therapy. 
 
6.2.1.6Modification of Rate for Infusion of Rituximab 
 
In the event that patients develop an infusion related or hypersensitivity reaction to rituximab 
then the rate of drug administration is altered as described above in “Management of Adverse 
Events due to rituximab”. The total dose administered remains the same in such cases. In the 
event of serious or life threatening reactions, the infusion should be terminated and such adverse 
events reported. In the event of serious or life threatening events attributed to rituximab, patients 
may be removed from this study after consultation with the overall or institutional protocol 
chairperson. 
 
7.DRUG FORMULATION AND ADMINISTRATION  
 
7.1Ixazomib 
 
7.1.1Description 
 
Research Name 
MLN9708 
Chemical Name 
2,2'-{2-[(1R)-1-({[(2,5-dichlorobenzoyl)amino]acetyl}amino)-3-
methylbutyl]-5-oxo-1,3,2-dioxaborolane-4,4-diyl}diacetic acid 
Common name 
2,2'-{2-[(1R)-1-({[(2,5-dichlorobenzoyl)amino]acetyl}amino)-3-
methylbutyl]-5-oxo-1,3,2-dioxaborolane-4,4-diyl}diacetic acid 
Proprietary Name 
Not available 
USAN Name 
Ixazomib citrate 
CAS Registry Number 
1239908-20-3 
Classification 
Proteasome inhibitor (as the boronic acid). 
Molecular Formula 
C20H23BCl2N2O9 
Molecular Weight 
517.12 
 
Figure 7-1 
Structure of ixazomib 
 


 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
 
59 
 
 
7.1.2Form 
 
All later phase studies are conducted with the Capsule formulation. The Ixazomib Capsule 
formulation consists of the Ixazomib drug substance and the inactive ingredients microcrystalline 
cellulose, talc, and magnesium stearate in a hard gelatin. Seven different capsule strengths have 
been developed: 0.2-, 0.5-, 2.0-, 2.3-, 3.0-, 4.0-, and 5.5 mg; each capsule strength has a unique 
color. Dosage strength is stated as the active boronic acid (MLN2238). Ixazomib Capsules are 
individually packaged in foil-foil blisters with a paper backing for child resistance. The study drug 
ixazomib capsules will be provided by Millennium.  The study drug will be labeled and handled 
as open-label material, and packaging labels will fulfill all requirements specified by governing 
regulations.   
 
7.1.3Storage 
 
Ixazomib capsules should be stored unopened at 2°C to 8°C (36°F-46°F).  The capsules are 
individually packaged in cold form foil-foil blisters in a child-resistant package.  The 2.3-, 3.0-, 
and 4.0 mg capsules are supplied as a 1 x 3 blister card in a child-resistant cardboard wallet.  The 
permissible storage condition excursion range is 8°C to 40°C for a maximum period of 30 days; 
and from 0-50°C for up to 3 days. 
 
7.1.4Handling 
 
Ixazomib drug product is a cytotoxic anticancer drug. As with other potentially toxic 
compounds, caution should be exercised when handling Ixazomib. Please refer to published 
guidelines regarding the proper handling and disposal of cytotoxic agents. Ixazomib Capsules 
must be administered as intact capsules and are not intended to be opened or manipulated in any 
way. 
 
Upon receipt at the investigative site, ixazomib should remain in the blister and carton provided 
until use or until drug is dispensed. The container should be stored at the investigative site 
refrigerated (36°F to 46°F, 2°C to 8°C). Ensure that the drug is used before the retest expiry date 
provided by Millennium. Expiry extensions will be communicated accordingly with updated 
documentation to support the extended shelf life. 


 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
 
60 
 
In countries where local regulations permit, ixazomib capsules dispensed to the patient for take-
home dosing should remain in the blister packaging and refrigerated as noted above until the point 
of use. The investigative site is responsible for providing the medication to the patient in the correct 
daily dose configurations. Comprehensive instructions should be provided to the patient in order 
to ensure compliance with dosing procedures. Patients who are receiving take-home medication 
should be given only 1 cycle of medication at a time. Patients should be instructed to store the 
medication refrigerated (36°F to 46°F, 2°C to 8°C) for the duration of each cycle. Patients should 
be instructed to return their empty blister packs to the investigative site, rather than discarding 
them. Reconciliation will occur accordingly when the patient returns for their next cycle of take-
home medication. Any extreme in temperature should be reported as an excursion and should be 
dealt with on a case-by-case basis. 
 
Because ixazomib is an investigational agent, it should be handled with due care. Patients should 
be instructed not to chew, break, or open capsules. In case of contact with broken capsules, raising 
dust should be avoided during the clean-up operation. The product may be harmful by inhalation, 
ingestion, or skin absorption. Gloves and protective clothing should be worn during cleanup and 
return of broken capsules and powder to minimize skin contact. 
The area should be ventilated and the site washed with soap and water after material pick-up is 
complete. 
 
In case of contact with the powder (eg, from a broken capsule), skin should be washed immediately 
with soap and copious amounts of water for at least 15 minutes. In case of contact with the eyes, 
copious amounts of water should be used to flush the eyes for at least 15 minutes. Medical 
personnel should be notified. Patients are to be instructed on proper storage, accountability, and 
administration of ixazomib, including that ixazomib is to be taken as intact capsules. 
 
7.1.5Availability 
 
The study drug ixazomib capsules will be provided by Millennium.  The study drug will be 
labeled and handled as open-label material, and packaging labels will fulfill all requirements 
specified by governing regulations.  
 
Ixazomib capsules should be stored unopened at 2°C to 8°C (36°F-46°F).  The capsules are 
individually packaged in cold form foil-foil blisters in a child-resistant package.    The capsules 
are individually packaged using cold-form foil-foil blisters that are in a child-resistant carton.  
There are 3 capsules in each wallet/carton. 
 
7.1.6Ordering 
 
Ixazomib will be ordered directly from Millennium Pharmaceuticals via a drug order form that is 
faxed from the pharmacist.   
 
7.1.7Accountability 
 


 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
 
61 
The investigator, or a responsible party designated by the investigator, must maintain a careful 
record of the inventory and disposition of the agent (investigational or free of charge) using the 
NCI Drug Accountability Record or another comparable drug accountability form. (See the 
CTEP website at http://ctep.cancer.gov/protocolDevelopment  for the “Policy and Guidelines for 
Accountability and Storage of Investigational Agents” or to obtain a copy of the drug 
accountability form.) 
 
Millennium Pharmaceuticals and the Pharmacy will maintain records of each shipment of 
investigational product.  The records will document shipment dates, batch numbers, and quantity 
of vials contained in the shipment.  Upon receipt of the investigational product, the designated 
recipient at the study site will inspect the shipment, verify the number and condition of the vials, 
and prepare an inventory or drug accountability record.  
 
Drug accountability records must be readily available for inspection by representatives of 
Millennium Pharmaceuticals and by regulatory authorities.  
 
7.1.8Destruction and Return 
 
Investigational ixazomib (expired or end of study) should be destroyed on site according to the 
institution’s standard operating procedure.  Be sure to document removal and destruction on drug 
accountability logs. 
 
7.2Rituximab 
 
7.2.1Description 
 
Rituximab is a genetically engineered chimeric murine/human monoclonal antibody directed 
against the CD20 cell surface antigen. The antibody is an IgG kappa immunoglobulin 
containing murine light- and heavy-chain variable region sequences and human constant region 
sequences. Rituximab is a composed of two heavy chains of 451 amino acids and two light 
chains of 213 amino acids (based on cDNA analysis) and has an approximate molecular weight 
of 145 kD. Rituximab has a binding affinity for the CD20 antigen of approximately 8 nM. The 
chimeric anti-CD20 antibody is produced by mammalian cell (Chinese Hamster ovary) 
suspension culture in a nutrient medium containing the antibiotic gentamicin. Gentamicin is not 
detectable in the final product. Rituximab is purified by affinity and ion exchange 
chromatography. The purification process includes specific viral inactivation and removal 
procedures. 
 
Hepatitis B virus (HBV) reactivation with fulminant hepatitis, hepatic failure, and death has 
been reported in some patients with hematologic malignancies treated with rituximab.  The 
majority of patients received rituximab in combination with chemotherapy.  The median time to 
the diagnosis of hepatitis was approximately 4 months after the initiation of rituximab and 
approximately one month after the last dose. 
 
7.2.2Form 
 


 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
 
62 
Rituximab is supplied as a sterile, colorless, preservative free liquid concentrate for intravenous 
(IV) administration. Rituximab is supplied at a concentration of 10 mg/ml in either 100 mg (10 
mL) or 500 mg (50 mL) single-use vials. The product is formulated for IV administration in 
9mg/ml sodium chloride, 7.35-mg/mL sodium citrate dehydrate, 0.7 mg/mL polysorbate 80, and 
sterile water for injection. The pH is adjusted to 6.5. 
 
7.2.3Storage and Stability 
 
Rituximab vials are stable at 2-8 C. Vials of rituximab beyond expiration date on the carton 
should not be used. Rituximab vials should be protected from direct sunlight. 
 
7.2.4Handling 
 
Rituximab is diluted to a final concentration of 1 to 4 mg/ml into an infusion bag containing 
either 0.9% sodium chloride USP or 5% dextrose in water USP. Rituximab solutions for 
infusion are stable at 2 to 8 C for 24 hours and at room temperature for an additional 12 hours. 
No incompatibilities between rituximab and polyvinylchloride or polyethylene bags have been 
reported.  
 
7.2.5Availability 
 
Rituximab is commercially available. 
 
7.2.6Administration 
 
Rituximab is administered intravenously. To prevent infusion related or hypersensitivity events, 
rituximab is not to be administered as an intravenous push or bolus. See section 5.2.2.6 for 
details on administration of rituximab. 
 
7.3Dexamethasone 
 
7.3.1 Description 
 
Dexamethasone is a potent synthetic member of the glucocorticoid class of steroid hormones. It 
acts as an anti-inflammatory and immunosuppressant. Its potency is about 20-30 times that of 
hydrocortisone and 4-5 times of prednisone. 
 
Figure 7-2 Structure of dexamethasone 
 


 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
 
63 
 
 
7.3.2Form 
 
Each mL of clear, colorless sterile solution contains: dexamethasone sodium phosphate 
equivalent to dexamethasone phosphate 4 mg (equal to 3.33 mg of dexamethasone or roughly 
about 100 mg of hydrocortisone). Non-medicinal ingredients: creatinine, sodium citrate, sodium 
hydroxide (to adjust pH) and water for injection with sodium bisulfite, methylparaben, and 
propylparaben are added as preservatives. 
 
7.3.3Storage and Stability 
 
Store below 25°C. Do not freeze. Protect from light. 
 
7.3.4Availability 
 
Dexamethasone is a commercially available agent.  
 
7.3.5Administration 
 
Patients will receive dexamethasone 20 mg IV, with each infusion of ixazomib and rituximab. 
Dexamethasone should be given prior to ixazomib and rituximab. The administration of IV 
Dexamethasone will suffice for steroid for premedication for rituximab. 20 mg oral 
dexamethasone may be substituted in the event of a drug supply shortage of IV dexamethasone 
and on days 8 and 15 of induction and maintenance for dosing outside of clinic. Administration 
method will be documented. 
 
7.3.6Contraindications for Dexamethasone therapy 
 
Dexamethasone will be omitted from therapy in the following circumstances: 
• History of tuberculosis or other granulomatous disease 
• Systemic fungal infection 
• History of or development of uncontrollable steroid related glucose intolerance 
• History of or development of steroid related hypersensitivity 
• Intolerance due to gastric and duodenal ulcers despite adequate upper gastrointestinal 
prophylactic therapy 
• Recipient of a live virus vaccine within 30 days 


 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
 
64 
• Pregnancy and lactation 
• Development of moderate to severe acute infections 
 
In the event dexamethasone is omitted, patients will not be removed from study treatment and 
will continue to receive all other intended therapy on study. 
 
7.4Study compliance 
 
Study drug will be administered or dispensed only to eligible patients under the supervision of 
the investigator or identified sub-investigator(s).  The appropriate study personnel will maintain 
records of study drug receipt and dispensing. 
 
7.5Termination of Treatment and/or Study Participation 
Patients will be informed that they have the right to withdraw from the study at any time for any 
reason, without prejudice to their medical care.  The investigator also has the right to withdraw 
patients from the study for any of the following reasons: 
• Adverse event 
• Protocol violation 
• Lost to follow-up 
• Progressive disease 
• Study terminated  
• Other 
 
At the time of withdrawal, all study procedures outlined for the End of Study visit should be 
completed. The primary reason for patient’s withdrawal from the study should be recorded in the 
source documents and CRF. 
 
 
8.CORRELATIVE/SPECIAL STUDIES  
 
8.1Determination of MYD88 and CXCR4 mutational status 
 
The MYD88 L265P mutational analysis will be assessed by allele-specific PCR and CXCR4 
mutational analysis by Sanger sequencing. The Brigham & Women’s Hospital Advanced 
Molecular Laboratory will perform the MYD88 mutational analysis. The CXCR4 mutational 
analysis and FcγRIIIA-158 polymorphisms analysis will be performed by the Bing Center for 
Waldenström’s Macroglobulinemia Research Laboratory. 
 
 


 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
 
65 
9.STUDY CALENDAR 
 
Screening 
≤30 days 
from study 
entry 
Induction Phase 
q28 days +/- 3 Days*,** 
Inter-phase 
Visit 
Within 4 
weeks +/- 2 
weeks of 
completion of 
Cycle 6 of 
induction 
Maintenance Phase 
(Beginning 8 weeks 
+/- 2 weeks after 
Induction C6D1) 
q 8 weeks +/- 
2 weeks 
Off Treatment 
Visit 
within 4 weeks 
+/- 2 weeks of 
completion of 
all treatment  or 
removal from 
trial 
Follow-up 
Q6 months 
+/- 2 weeks 
for 2 years6 
Cycles 1 and 2 
Cycles 3-6 
Cycles 1-6 
D1 D8 D15 D1 D88 D158 
D1** 
D8 
D15 
Dexamethasone 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
 
Ixazomib 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
 
Rituximab 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Physical exam 
(Ht, Wt, BSA, VS) 
X 
X 
 
 
 
X 
 
 
X 
X 
 
 
X 
X 
History 
X 
X 
 
 
 
 
 
X 
X 
 
 
X 
X 
Concurrent meds 
X 
X 
 
 
X 
 
 
X 
X 
 
 
X 
X 
ECOG Performance Status 
X 
X 
 
 
X 
 
 
X 
X 
 
 
X 
X 
CBC w/diff, platelets 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
Serum chemistry1,  
X 
X 
X 
X 
X 
X 
X 
X 
X1 
 
 
X 
X 
Coagulation Profile 
(PT, PTT, INR) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Quantitative IgM, IgA, IgG 
X 
X 
 
 
X 
 
 
X 
X 
 
 
X 
X 
SPEP and immunofixation2 
X 
X 
 
 
X 
 
 
X 
X 
 
 
X 
X 
Beta-2-Microglobulin 
X 
 
 
 
 
 
 
 
 
 
 
 
 
B-HCG3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis B and C Screening 
X 
 
 
 
 
 
 
 
 
 
 
 
 
MYD88 L265P status bone 
marrow (PCR) 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
MYD88 L265P status 
peripheral blood (qPCR) 
X7 
 
 
 
 
 
 
 
 
 
 
 
 
CXCR4 mutational status 
(Sanger) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse event evaluation 
X 
X 
 
 
X 
 
 
X 
X 
 
 
X 
 
Neuropathy Assessment 
X 
X 
 
 
X 
 
 
X 
X 
 
 
X 
 
CT scan w/ contrast 
Chest/Abdomen/Pelvis5 
X4 
 
 
 
 
 
 
X5 
 
 
 
X5 
 
Bone Marrow Biopsy and 
Aspiration2  
X4 
 
 
 
 
 
 
X 
 
 
 
X 
 
*: Peripheral Neuropathy questionnaire and labs do not need to be repeated if Day 1 of induction treatment within 10 days of screening. If labs are 
repeated on C1D1 they must be reviewed prior to study drug administration and meet eligibility. 
**: For criteria for administration of treatment see Section 6.2 
1: Comprehensive chemistry panel: Albumin, total bilirubin, BUN, creatinine, calcium, chloride, glucose, potassium, total protein, sodium, SGOT, 
SGPT, alkaline phosphatase, magnesium 
2: Bone Marrow Biopsy and Aspiration will be required at Screening, Interphase visit, and Off-Treatment Visit. May be Repeated at other time 
points to confirm a suspected complete remission and at the Principal Investigator’s discretion 
3: Serum pregnancy test for women of childbearing potential 
4: If done within 90 days of screening, this will not be required at the screening visit 
5: Repeat to assess disease response or confirm a suspected complete remission if participant had lymphadenopathy, hepatosplenomegaly, or an 
extramedullary mass at baseline defined as adenopathy >1.5 cm in any axis, and splenomegaly >15 cm in the craniocaudal axis. 
6. Follow-up visits will be required every 6 months +/- 2 weeks after EOT visit.  3 month follow-up visits are recommended. 
7. MYD88 L265P mutational status by qPCR at screening and, if mutant, subsequently every 3 months while on therap. 
8.  Safety Laboratories do not need to be performed on Day 8 and 15 of Induction Cycles 4-6, or any Maintenance cycles. 
 
 
 


 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
 
66 
10.MEASUREMENT OF EFFECT  
 
10.1Response Criteria  
 
Response criteria are based on modified response criteria updated at the Third International 
Workshop on Waldenstrom’s macroglobulinemia (Kimby 2006; Treon 2011). 
 
For participants who undergo TPE (total plasmapheresis), IgM will be considered unevaluable 
for 4-6 weeks following the last TPE treatment.  For response assessment, post-pheresis IgM 
values will not be considered as nadir values.   
 
When rituximab induced IgM flare is suspected, serum IgM response will be determined to be 
unevaluable by the investigator and not considered to be progressive disease. 
 
Complete Response (CR): A complete response (CR) is defined as having resolution of all 
symptoms, normalization of serum IgM levels with complete disappearance of IgM paraprotein 
by immunofixation, and resolution of any adenopathy or splenomegaly. A near CR (nCR) is 
defined as fulfilling all CR criteria in the presence of positive immunofixation test for an IgM 
paraprotein. 
 
Very Good Partial Response (VGPR): is defined as >90% reduction in serum IgM levels.   
 
Partial Response (PR): Partial response (PR) is defined as achieving a >50% reduction in 
serum IgM levels. 
 
Minor Response (MR): A minor response (MR) is defined 25-49% reduction in serum IgM 
levels. 
                       
Progressive Disease (PD): Progressive disease (PD) is defined as occurring when a greater than 
25% increase in serum IgM and an absolute 500mg/dL increase in IgM level occurs from the 
lowest attained response value(except as specfied above) or progression of clinically significant 
disease related symptom(s). When PD is suspected on the basis of increasing serum IgM, repeat 
of these studies within 2 + 1 week(s) will be required to confirm PD. 
 
Stable Disease (SD): Stable disease is defined as having < 25% change in serum IgM levels, in 
the absence of new or increasing adenopathy or splenomegaly and/or other progressive signs or 
symptoms of WM. 
 
10.2Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started, except in cases of TPE, specified in section 
10.1). The participant's best response assignment will depend on the achievement of both 
measurement and confirmation criteria. 
 


 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
 
67 
10.3Duration of Response 
 
Duration of overall response: The duration of overall response is measured from the time 
measurement criteria are met for an objective response i.e. CR, PR or MR (whichever is first 
recorded) until the first date that recurrence or PD is objectively documented, taking as 
reference for PD the smallest measurements recorded since the treatment started (except in 
cases of TPE, specified in section 10.1). 
 
Duration of overall complete response: The duration of overall CR is measured from the time 
measurement criteria are first met for CR until the first date that recurrent disease is 
objectively documented. 
 
Duration of stable disease: Stable disease is measured from the start of the protocol treatment 
until the criteria for progression are met, taking as reference the smallest measurements recorded 
since the treatment started (except in cases of TPE, specified in section 10.1). 
 
10.4Time to Progression 
 
Time to Progression (TTP) is defined as the duration of time from start of treatment to time of 
disease progression as defined in section 10.1. Death from any cause or initiation of a new anti-
neoplastic therapy will also be considered a progression event.   
 
     10.5   Time to Next Therapy 
 
Time to Next Therapy (TNT) is defined as the duration from start of protocol treatment to time 
of initiation of any new anti-neoplastic therapy, including radiation or intrathecal therapy.    
 
11.ADVERSE EVENT REPORTING REQUIREMENTS 
 
11.1Definitions 
 
 
11.1.1Adverse Event (AE) Definition 
 
Adverse event (AE) means any untoward medical occurrence in a patient or subject administered 
a pharmaceutical product; the untoward medical occurrence does not necessarily have a causal 
relationship with this treatment.  An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of a medicinal (investigational) product whether or not it is related to the medicinal product.  
This includes any newly occurring event, or a previous condition that has increased in severity or 
frequency since the administration of study drug. 
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.   
 


 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
 
68 
11.1.2Serious adverse event (SAE) Definition 
 
Serious AE (SAE) means any untoward medical occurrence that at any dose: 
• Results in death. 
• Is life-threatening (refers to an AE in which the patient was at risk of death at the time of 
the event.  It does not refer to an event which hypothetically might have caused death if it 
were more severe). 
• Requires inpatient hospitalization or prolongation of an existing hospitalization (see 
clarification in the paragraph below on planned hospitalizations). 
• Results in persistent or significant disability or incapacity. (Disability is defined as a 
substantial disruption of a person’s ability to conduct normal life functions). 
• Is a congenital anomaly/birth defect. 
• Is a medically important event.  This refers to an AE that may not result in death, be 
immediately life threatening, or require hospitalization, but may be considered serious 
when, based on appropriate medical judgment, may jeopardize the patient, require 
medical or surgical intervention to prevent 1 of the outcomes listed above, or involves 
suspected transmission via a medicinal product of an infectious agent.   Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse; any 
organism, virus, or infectious particle (eg, prion protein transmitting Transmissible 
Spongiform Encephalopathy), pathogenic or nonpathogenic, is considered an infectious 
agent.   
 
Clarification should be made between a serious AE (SAE) and an AE that is considered severe in 
intensity (Grade 3 or 4), because the terms serious and severe are NOT synonymous.  The 
general term severe is often used to describe the intensity (severity) of a specific event; the event 
itself, however, may be of relatively minor medical significance (such as a Grade 3 headache).  
This is NOT the same as serious, which is based on patient/event outcome or action criteria 
described above, and is usually associated with events that pose a threat to a patient’s life or 
ability to function.  A severe AE (Grade 3 or 4) does not necessarily need to be considered 
serious.  For example, a white blood cell count of 1000/mm3 to less than 2000 is considered 
Grade 3 (severe) but may not be considered serious.  Seriousness (not intensity) serves as a guide 
for defining regulatory reporting obligations. 
 
 
11.1.3Expectedness 
 
Adverse events can be “Expected” or “Unexpected.”  
 
11.1.3.1Expected adverse event 
 
Expected adverse events are those that have been previously identified as resulting from 
administration of the agent. For the purposes of this study, an adverse event is considered 


 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
 
69 
expected when it appears in the current adverse event list, the Investigator’s Brochure, the 
package insert or is included in the informed consent document as a potential risk.   
 
Refer to Section 6.1 for a listing of expected adverse events associated with the study 
agent(s). 
 
11.1.3.2Unexpected adverse event 
 
 
For the purposes of this study, an adverse event is considered unexpected when it varies in 
nature, intensity or frequency from information provided in the current adverse event list, the 
Investigator’s Brochure, the package insert or when it is not included in the informed consent 
document as a potential risk.   
 
11.1.4Attribution 
 
Attribution is the relationship between an adverse event or serious adverse event and the study 
treatment. Attribution will be assigned as follows: 
 
• Definite – The AE is clearly related to the study treatment. 
• Probable – The AE is likely related to the study treatment. 
• Possible – The AE may be related to the study treatment.  
• Unlikely - The AE is doubtfully related to the study treatment. 
• Unrelated - The AE is clearly NOT related to the study treatment. 
 
11.2Procedures for AE and SAE Recording and Reporting 
 
AEs may be spontaneously reported by the patient and/or in response to an open question from 
study personnel or revealed by observation, physical examination, or other diagnostic 
procedures.  Any clinically relevant deterioration in laboratory assessments or other clinical 
finding is considered an AE.  When possible, signs and symptoms indicating a common 
underlying pathology should be noted as one comprehensive event.  For serious AEs, the 
investigator must determine both the intensity of the event and the relationship of the event to 
study drug administration. For serious pretreatment events, the investigator must determine both 
the intensity of the event and the relationship of the event to study procedures. 
 
AEs which are serious must be reported to Millennium Pharmacovigilance (or designee) 
from the first dose of study drug through 30 days after administration of the last dost of 
ixazomib.  Any SAE that occurs at any time after completion of ixazomib treatment or after the 
designated follow-up period that the sponsor-investigator and/or sub-investigator considers to be 
related to any study drug must be reported to Millennium Pharmacovigilance (or designee).  In 
addition, new primary malignancies that occur during the follow-up periods must be reported, 
regardless of causality to study regimen, for a minimum of three years after the last dose of the 
investigational product, starting from the first dose of study drug. All new cases of primary 
malignancy must be reported to Millennium Pharmacovigilance (or designee). 
 


 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
 
70 
Planned hospital admissions or surgical procedures for an illness or disease that existed before 
the patient was enrolled in the trial are not to be considered AEs unless the condition deteriorated 
in an unexpected manner during the trial (e.g., surgery was performed earlier or later than 
planned).  All SAEs should be monitored until they are resolved or are clearly determined to be 
due to a patient’s stable or chronic condition or intercurrent illness(es). 
 
Since this is an investigator-initiated study, the principal investigator Jorge J. Castillo, MD, also 
referred to as the sponsor-investigator, is responsible for reporting serious adverse events (SAEs) 
to any regulatory agency and to the sponsor- investigator’s EC or IRB.    
 
Regardless of expectedness or causality, all SAEs (including serious pretreatment events) must 
also be reported to Millennium Pharmacovigilance: 
 
Fatal and Life Threatening SAEs within 24 hours of the sponsor-investigator’s observation or 
awareness of the event 
 
All other serious (non-fatal/non life threatening) events within 4 calendar days of the sponsor-
investigator’s observation or awareness of the event 
 
See below for contact information for the reporting of SAEs to Millennium Pharmacovigilance.   
The sponsor-investigator must fax or email the SAE Form per the timelines above.  A sample of 
an SAE Form will be provided. The SAE report must include at minimum: 
• Event term(s) 
• Serious criteria 
• Intensity of the event(s): Sponsor-investigator’s or sub-investigator’s 
determination.  Intensity for each SAE, including any lab abnormalities, will 
be determined by using the NCI CTCAE version specified in the protocol, as a 
guideline, whenever possible.  The criteria are available online at 
http://ctep.cancer.gov/reporting/ctc.html. 
• Causality of the event(s): Sponsor-investigator’s or sub-investigator’s 
determination of the relationship of the event(s) to study drug administration.  
 
Follow-up information on the SAE may be requested by Millennium.   
 
Intensity for each SAE, including any lab abnormalities, will be determined by using the NCI 
CTCAE version used at your institution, as a guideline, whenever possible.  The criteria are 
available online at http://ctep.cancer.gov/reporting/ctc.html. 
 
In the event that this is a multisite study, the sponsor-investigator is responsible to ensure that the 
SAE reports are sent to Millennium Pharmacovigilance (or designee) from all sites participating 
in the study.  Sub-investigators must report all SAEs to the sponsor-investigator so that the 
sponsor-investigator can meet his/her foregoing reporting obligations to the required regulatory 
agencies and to Millennium Pharmacovigilance, unless otherwise agreed between the sponsor-
investigator and sub-investigator(s).   
 
Relationship to all study drugs for each SAE will be determined by the investigator or sub-


 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
 
71 
investigator by responding yes or no to the question: Is there a reasonable possibility that the AE 
is associated with the study drug(s)? 
 
Sponsor-investigator must also provide Millennium Pharmacovigilance with a copy of all 
communications with applicable regulatory authorities related to the study product(s), as soon as 
possible but no later than 4 calendar days of such communication. 
 
SAE and Pregnancy Reporting Contact Information 
 
Fax Number: 1-800-963-6290 
Email: TakedaOncoCases@cognizant.com 
 
Suggested Reporting Form:   
• SAE Report Form (provided by Millennium) 
• US FDA MedWatch 3500A:  
http://www.fda.gov/Safety/MedWatch/HowToReport/DownloadForms/default.htm 
 
 
 
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 or 
within 90 days after the last dose, she must inform the investigator immediately and 
permanently discontinue study drug.  The sponsor-investigator must immediately fax a 
completed Pregnancy Form to the Millennium Department of Pharmacovigilance or designee 
(see Section 8.2).  The pregnancy must be followed for the final pregnancy outcome. 
 
If a female partner of a male patient becomes pregnant during the male patient’s participation in 
this study, the sponsor-investigator must also immediately fax a completed Pregnancy Form to 
the Millennium Department of Pharmacovigilance or designee (see Section 8.2).  Every effort 
should be made to follow the pregnancy for the final pregnancy outcome. 
 
11.3Reporting to the Institutional Review Board (IRB) 
 
Investigative sites within DF/HCC will report all serious adverse events directly to the DFCI 
Office for Human Research Studies (OHRS). 
 
11.4Reporting to the Food and Drug Administration (FDA) 
 
The DF/HCC Overall Principal Investigator, as holder of the IND, will be responsible for all 
communication with the FDA. The DF/HCC Overall Principal Investigator will report to the 
FDA, regardless of the site of occurrence, any adverse event that is serious, unexpected and 
reasonably related (i.e., possible, probable, definite) to the study treatment. 
 


 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
 
72 
Unexpected fatal or life-threatening experiences associated with the use of the study treatment 
will be reported to FDA as soon as possible but in no event later than 7 calendar days after initial 
receipt of the information. 
 
All other serious unexpected experiences associated with the use of the study treatment will be 
reported to FDA as soon as possible but in no event later than 15 calendar days after initial 
receipt of the information. 
 
  
Events will be reported to the FDA by telephone (1-800-FDA-1088) or by fax (1-800-FDA-
0178) using Form FDA 3500A (Mandatory Reporting Form for investigational agents) or FDA 
Form 3500 (Voluntary Reporting Form for commercial agents). Forms are available at 
http://www.fda.gov/medwatch/getforms.htm.  
 
11.5Reporting to Hospital Risk Management 
 
Participating investigators will report to their local Risk Management office any participant 
safety reports or sentinel events that require reporting according to institutional policy. 
 
11.6Pregnancy Reporting 
 
If a woman becomes pregnant or suspects that she is pregnant while participating in this study, 
she must inform the investigator immediately and permanently discontinue study drug.  The 
sponsor-investigator must immediately fax a completed Pregnancy Form to the Millennium 
Department of Pharmacovigilance or designee (see Section 11.2).  The pregnancy must be 
followed for the final pregnancy outcome. 
 
If a female partner of a male patient becomes pregnant during the male patient’s participation in 
this study, the sponsor-investigator must also immediately fax a completed Pregnancy Form to 
the Millennium Department of Pharmacovigilance or designee (see Section 11.2).  Every effort 
should be made to follow the pregnancy for the final pregnancy outcome. 
 
11.7Monitoring of Adverse Events and Period of Observation 
 
All adverse events, both serious and non-serious, and deaths that are encountered from initiation 
of study intervention, throughout the study, and within 30 days of the last study intervention 
should be followed to their resolution, or until the participating investigator assesses them as 
stable, or the participating investigator determines the event to be irreversible, or the participant 
is lost to follow-up. The presence and resolution of AEs and SAEs (with dates) should be 
documented on the appropriate case report form and recorded in the participant’s medical record 
to facilitate source data verification.  
 
For some SAEs, the study sponsor (Dr. Jorge J. Castillo) or designee may follow-up by 
telephone, fax, and/or monitoring visit to obtain additional case details deemed necessary to 
appropriately evaluate the SAE report (e.g., hospital discharge summary, consultant report, or 
autopsy report).  
 


 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
 
73 
Participants should be instructed to report any serious post-study event(s) that might reasonably 
be related to participation in this study.  
 
11.8 Product Complaints   
 
A product complaint is a verbal, written, or electronic expression that implies dissatisfaction 
regarding the identity, strength, purity, quality, or stability of a drug product.  Individuals who 
identify a potential product complaint situation should immediately contact MedComm Solutions 
(see below) and report the event.  Whenever possible, the associated product should be 
maintained in accordance with the label instructions pending further guidance from a Millennium 
Quality representative. 
 
For Product Complaints, 
call MedComm Solutions at 
877-674-3784 (877 MPI DRUG) 
(US and International) 
 
Product complaints in and of themselves are not AEs.  If a product complaint results in an SAE, 
an SAE form should be completed and sent to Millennium Pharmacovigilance (refer to Section 
8.2). 
 
 
12.DATA AND SAFETY MONITORING 
 
12.1Data Reporting 
 
12.1.1Method  
 
The QACT will collect, manage, and monitor data for this study.  
 
12.1.2Data Submission  
 
The schedule for completion and submission of case report forms (paper or electronic) to the 
QACT is as follows: 
 
Form 
Submission Timeline 
Eligibility Checklist 
Complete prior to registration with QACT 
On Study Form 
Within 14 days of registration 
Baseline Assessment Form 
Within 14 days of registration 
Treatment Form 
Within 10 days of the last day of the cycle 
Adverse Event Report Form 
Within 10 days of the last day of the cycle 
Response Assessment Form 
Within 10 days of the completion of the 
cycle required for response evaluation 
Off Treatment/Off Study 
Form 
Within 14 days of completing treatment or 
being taken off study for any reason 


 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
 
74 
Follow up/Survival Form 
Within 14 days of the protocol defined 
follow up visit date or call 
 
12.2Safety Meetings 
 
The DF/HCC Data and Safety Monitoring Committee (DSMC) will review and monitor toxicity 
and accrual data from this trial. The committee is composed of clinical specialists with 
experience in oncology and who have no direct relationship with the study. Information that 
raises any questions about participant safety will be addressed with the Principal Investigator and 
study team. 
 
The DSMC will meet quarterly and/or more often if required to review toxicity and accrual data.  
Information to be provided to the committee may include:  up-to-date participant accrual; current 
dose level information; DLT information; all grade 2 or higher unexpected adverse events that 
have been reported; summary of all deaths occurring within 30 days for Phase I or II protocols; 
for gene transfer protocols, summary of all deaths while being treated and during active follow-
up; any response information; audit results, and a summary provided by the study team. Other 
information (e.g. scans, laboratory values) will be provided upon request.  
 
12.3Monitoring  
 
Involvement in this study as a participating investigator implies acceptance of potential audits or 
inspections, including source data verification, by representatives designated by the DF/HCC 
Overall Principal Investigator (or Protocol Chair) or DF/HCC. The purpose of these audits or 
inspections is to examine study-related activities and documents to determine whether these 
activities were conducted and data were recorded, analyzed, and accurately reported in 
accordance with the protocol, institutional policy, Good Clinical Practice (GCP), and any 
applicable regulatory requirements.  
 
All data will be monitored for timeliness of submission, completeness, and adherence to protocol 
requirements. Monitoring will begin at the time of participant registration and will continue 
during protocol performance and completion.  
 
 
13.REGULATORY CONSIDERATIONS 
 
13.1Protocol Review and Amendments 
 
This protocol, the proposed informed consent and all forms of participant information related 
to the study (e.g., advertisements used to recruit participants) and any other necessary 
documents must be submitted, reviewed and approved by a properly constituted IRB 
governing each study location.  
 
Any changes made to the protocol must be submitted as amendments and must be approved 
by the IRB prior to implementation. Any changes in study conduct must be reported to the 


 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
 
75 
IRB. The DF/HCC Overall Principal Investigator (or Protocol Chair) will disseminate 
protocol amendment information to all participating investigators.  
 
All decisions of the IRB concerning the conduct of the study must be made in writing. 
 
13.2Informed Consent 
 
All participants must be provided a consent form describing this study and providing 
sufficient information for participants to make an informed decision about their 
participation in this study. The formal consent of a participant, using the IRB approved 
consent form, must be obtained before the participant is involved in any study-related 
procedure. The consent form must be signed and dated by the participant or the 
participant’s legally authorized representative, and by the person obtaining the consent. The 
participant must be given a copy of the signed and dated consent document. The original 
signed copy of the consent document must be retained in the medical record or research file.  
 
13.3Ethics and Good Clinical Practice (GCP) 
 
This study is to be conducted according to the following considerations, which represent 
good and sound research practice: 
• US Code of Federal Regulations (CFR) governing clinical study conduct and ethical 
principles that have their origin in the Declaration of Helsinki 
• Title 21 Part 50 – Protection of Human Subjects 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr50_02.html  
• Title 21 Part 54 – Financial Disclosure by Clinical Investigators 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr54_02.html  
• Title 21 Part 56 – Institutional Review Boards 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr56_02.html  
• Title 21 Part 312 – Investigational New Drug Application 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr312_02.html  
• 
State laws 
• 
DF/HCC research policies and procedures:  
http://www.dfhcc.harvard.edu/clinical-research-support/clinical-research-unit-cru/policies-
and-procedures/  
 
It is understood that deviations from the protocol should be avoided, except when necessary to 
eliminate an immediate hazard to a research participant. In such case, the deviation must be 
reported to the IRB according to the local reporting policy.  
 
13.4Study Documentation 
 
The investigator must prepare and maintain adequate and accurate case histories designed to 
record all observations and other data pertinent to the study for each research participant. This 
information enables the study to be fully documented and the study data to be subsequently 
verified. 


 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
 
76 
 
Original source documents supporting entries in the case report forms include but are not limited 
to hospital records, clinical charts, laboratory and pharmacy records, recorded data from 
automated instruments, microfiches, photographic negatives, microfilm or magnetic media, 
and/or x-rays.  
 
13.5Records Retention 
 
All study-related documents must be retained for the maximum period required by applicable 
federal regulations and guidelines or institutional policies.  
 
13.6IND Annual Reports 
 
 
The sponsor investigator or his designee will submit the annual report for this PI-initiated trial 
within 60 days of the IND anniversary date in accordance with 21 CFR 312.33.  The data 
elements that are to be submitted in the report are provided in 21 CFR 312.33.  The Annual 
Report should be filed in the study's Regulatory Binder.  
 
 
14.STATISTICAL CONSIDERATIONS  
 
14.1Study Design/Endpoints 
 
Following Fleming’s single phase approach and with a one-sided alpha set at 0.05 and beta at 0.20 
(80% power) assuming a null VGPR or better of 18% and a successful VGPR or better of 40%, 
we will need to accrue 23 participants.  In a previous study, the combination of bortezomib, 
rituximab and dexamethasone induced VGPR or better of 35% [22]. If at least 9 participants are 
found to have a response of VGPR or better, the trial will be deemed a success and IDR will 
warrant further testing in patients with WM. Accounting for 10% of non-evaluable patients, the 
total sample size will be 26 patients. In addition, with a sample size of 26 participants, the 
probability of observing at least one adverse event will be 93% when the actual probability of this 
event is 10%. Counting 1 patient who was registered but never started, 27 patients were accrued 
to this study. 
 
 
14.2Populations for analysis   
 
The population for all safety analyses is the Safety Analysis Set (SAS). All participants who 
receive at least one dose of any test material during the study will be included in the SAS 
population and included in the safety analysis.  
 
Participants will be included in the Full Analysis Set (FAS) for the primary assessment of 
efficacy. The FAS will include those participants who have measurable disease present at 
baseline, have received at least one cycle of therapy, and have had their disease re-
evaluated.   
 


 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
 
77 
The Per-Protocol Analysis Set (PPS) is defined as all participants from the FAS set who 
complete the study and are deemed to be protocol-compliant. To be protocol-compliant, a 
participant must not have any major protocol deviations during the study period. Protocol 
deviations will be identified prior to database lock and will be listed in the clinical study report. 
The PPS will be used for a secondary assessment of efficacy endpoints. 
 
14.3Participant Disposition 
 
The total number of participants screened, completed, and prematurely discontinued from the 
study will be summarized.  The reason for termination for all participants who discontinued will 
also be presented.  A listing of participants with major protocol deviations will also be presented. 
 
14.4Participants Baseline Characteristics 
 
Descriptive summaries of demographic and baseline characteristics will be presented for all 
participants. 
 
14.5Exposure to Investigational Material 
 
Exposure to all test material will be tabulated by presenting number of days on study, defined as 
number of days from day of first dose to day of last infusion. Total amount of investigational 
material taken will also be presented. 
 
14.6Safety Analysis 
 
Safety evaluations will be presented by escalating dose and based on the incidence, intensity and 
type of adverse events (AEs).  
 
All AEs occurring on study will be listed in by-participant data listings. A by-dose tabulation 
will be provided that enumerates AEs by maximum severity.  Deaths, SAEs and events resulting 
in study discontinuation will be tabulated. 
 
14.7Efficacy Analyses 
 
Primary and secondary analyses will be performed in both the FAS and PPS populations and will 
include calculating the proportion of patients having an overall response (MR or better) and 
major response (CR or VG). Confidence intervals (95%) about these point estimates will be 
presented. Time to progression (TTP) and time to next therapy (TNT) as defined in sections 10.4, 
and 10.5, respectively will be estimated using Kaplan and Meier methodology with median time 
plus 25th and 75th percentile time to progression free survival along with 95% confidence 
intervals being provided, as appropriate. In addition, landmark analysis for 2 and 4 year 
progression free survival will be performed. 
 
14.8Sample Size/Accrual Rate 
 


 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
 
78 
Following Fleming’s single phase approach and with a one-sided alpha set at 0.05 and beta at 0.20 
(80% power) assuming a null VGPR or better of 18% and a successful VGPR or better of 40%, 
we will need to accrue 30 participants.  In a previous study, the combination of bortezomib, 
rituximab and dexamethasone induced VGPR or better of 35% [22]. If at least 10 participants are 
found to have a response of VGPR or better, the trial will be deemed a success and IDR will 
warrant further testing in patients with WM. Accounting for 10% of non-evaluable patients, the 
total sample size will be 33 patients. In addition, with a sample size of 33 participants, the 
probability of observing at least one adverse event will be 97% when the actual probability of this 
event is 10%.  
 
The accrual expectation is 2-3 patients per month with a total accrual time of 12-15 months. 
 
14.9Stratification Factors 
 
There will be no stratification employed in the current study. 
 
14.10Analysis of Secondary Endpoints 
 
The secondary objectives of determining the impact of MYD88 and CXCR4 gene mutations, and 
FcγRIIIA-158 polymorphisms in predicting overall and categorical response to treatment, as well 
as progression-free survival, will be assessed by presenting these outcomes by 
mutation/polymorphism type. If there are sufficient numbers in each category, appropriate 
inferential statistics may be performed.  These analyses would be considered exploratory in 
nature. 
 
14.11Evaluation of toxicity 
 
All participants will be evaluable for toxicity from the time of their first treatment. 
 
14.12Evaluation of response 
 
All participants included in the study will be assessed for response to treatment according to 
criteria set forth in section 10.1. 
 
 
15.PUBLICATION PLAN 
 
Any formal presentation or publication of data from this trial may be published after review and 
comment by Millennium Pharmaceuticals and prior to any outside submission. Millennium 
Pharmaceuticals must receive copies of any intended communication in advance of publication 
(at least fifteen working days for presentational materials and abstracts and thirty working days 
for manuscripts). These requirements acknowledge Millennium Pharmaceuticals’ responsibility 
to provide peer input regarding the scientific content and conclusions of such publications or 
presentations.  Principal Investigator/Institution shall have the final authority to determine the 
scope and content of its publications, provided such authority shall be exercised with reasonable 
regard for the interests of Millennium Pharmaceuticals and, in accord with the trial contract and 


 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
 
79 
shall not permit disclosure of Millennium Pharmaceuticals’ confidential or proprietary 
information. 
 
 
16.REFERENCES  
 
1. Owen RG, Treon SP, Al-Katib A, et al. Clinicopathological definition of Waldenström’s 
Macroglobulinemia: consensus panel recommendations from the Second International 
Workshop on Waldenström’s Macroglobulinemia. Semin Oncol 2003; 30: 110-115. 
2. Waldenström J. Incipient myelomatosis or "essential" hyperglobulinemia with 
fibrinogenopenia - A new syndrome? Acta Med Scand 1944; 117: 216-47. 
3. Treon SP, Gertz MA, Dimopoulos M, et al. Update on treatment recommendations from the 
Third International Workshop on Waldenstrom’s Macroglobulinemia. Blood 2006; 
107:3442-6.  
4. Dimopoulos MA, Gertz MA, Kastritis E, et al. Update on treatment recommendations from 
the fourth international workshop on Waldenstrom’s macroglobulinemia. J Clin Oncol 2008; 
27:120-6 
5. Treon SP. How I Treat Waldenstrom’s Macroglobulinemia. Blood 2009a; 114(12) :2375-85.  
6. Leleu X, Tamburini J, Roccaro A, et al. Balancing risk versus benefit in the treatment of 
Waldenström's Macroglobulinemia patients with nucleoside analogue-based therapy. Clin 
Lymphoma Myeloma 2009 Mar;9(1):71-3.  
7. Treon SP, Emmanouilides C, Kimby E, et al. Extended rituximab therapy in Waldenström’s 
Macroglobulinemia. Ann Oncol 2005a; 16:132-8.  
8. Dimopoulos MA, Anagnostopoulos A, Zervas C, et al. Predictive factors for response to 
rituximab in Waldenstrom’s macroglobulinemia. Clin Lymphoma 2005; 5:270-2. 
9. Treon SP, Hansen M, Branagan AR, et al. Polymorphisms in FcγRIIIA (CD16) receptor 
expression are associated with clinical responses to Rituximab in Waldenstrom’s 
Macroglobulinemia. J Clin Oncol 2005b; 23: 474-81.  
10. Treon SP, Ioakimidis L, Soumerai JD, et al. Primary therapy of Waldenstrom’s 
Macroglobulinemia with Bortezomib, Dexamethasone and Rituximab: Results of WMCTG 
Clinical Trial 05-180. J Clin Oncol 2009b; 27(23):3830-5.  
11. Ghobrial IM, Xie W, Padmanabhan S, et al. Phase II trial of weekly bortezomib in 
combination with rituximab in untreated patients with Waldenström Macroglobulinemia. Am 
J Hematol. 2010;85(9):670-4. 
12. Treon SP, et al. Prospective phase II clinical trial of carfilzomib, rituximab and 
dexamethasone (CARD) in Waldenström’s Macroglobulinemia (WM). ASH Annual Meeting 
abstract, 2013. 
13. Treon SP, Xu L, Yang G, et al. MYD88 L265P somatic mutation in Waldenström's 
macroglobulinemia. N Engl J Med 2012; 367(9): 826-33. 
14. Ondrejka SL, Lin JJ, Warden DW, et al. MYD88 L265P Somatic Mutation: Its Usefulness in 
the Differential Diagnosis of Bone Marrow Involvement by B-Cell Lymphoproliferative 
Disorders. Am J Clin Pathol. 2013 Sep;140(3):387-94. 
15. Cartron G, Dacheux L, Salles G, Solal-Celigny P, Bardos P, Colombat P, Watier H. 
Therapeutic activity of humanized anti-CD20 monoclonal antibody and polymorphism in 
IgG Fc receptor Fcgamma RIIIA gene. Blood. 2002; 99:754-8. 
16. Poulain S, Roumier C, Decambron A, et al. MYD88 L265P mutation in Waldenstrom 


 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
 
80 
macroglobulinemia. Blood. 2013 May 30;121(22):4504-11. 
17. Varettoni M, Arcaini L, Zibellini S, et al. Prevalence and clinical significance of the MYD88 
(L265P) somatic mutation in Waldenstrom's macroglobulinemia and related lymphoid 
neoplasms. Blood. 2013 Mar 28;121(13):2522-8. 
18. Xu L, Hunter ZR, Yang G, et al. MYD88 L265P in Waldenström macroglobulinemia, 
immunoglobulin M monoclonal gammopathy, and other B-cell lymphoproliferative disorders 
using conventional and quantitative allele-specific polymerase chain reaction. Blood. 2013 
Mar 14;121(11):2051-8. 
19. Cao Y, Xu L, Liu X, et al. Whole Genome Sequencing Identifies Recurring Somatic 
Mutations in the C-Terminal Domain of CXCR4, Including a Gain of Function Mutation in 
Waldenstrom's Macroglobinemia. Blood (ASH Annual Meeting Abstracts) 2012. 120: 
abstract 2715. 
20. Hunter Z, Xu L, Yang G, et al. Recurring activation mutations and somatic deletions revealed 
through whole genome sequencing in Waldenstrom’s Macroglobulinemia. Hematological 
Oncol. 2013 June; 31(1S): abstract 093. 
21. Weng WK, Levy R. Two Immunoglobulin G Fc receptor polymorphisms independently 
predict response to rituximab in patients with follicular lymphoma. J Clin Oncol 2003; 
21:3940-3947. 
22. Treon et al. The attainment of CR/VGPR is associated with significantly longer progression 
free survival in rituximab naïve WM patients undergoing rituximab based therapy, and is 
predicted by polymorphisms in FcRIIIA-158. Br J Haematol, 2011. 
23. Kyle R, Treon SP, Alexanian R, et al. Prognostic markers and criteria to initiate therapy in 
Waldenström's macroglobulinemia: consensus panel recommendations from the Second 
International Workshop on Waldenström's Macroglobulinemia. Semin Oncol. 2003; 30: 116-
20.  
24. Kimby E, Treon SP, Anagnostopoulos A. Dimopoulos M, Garcia-Sanz R et al. Update on 
recommendations for assessing response from the Third International Workshop 
onWaldenstrom's Macroglobulinemia. Clin Lymphoma Myeloma. 2006; 6(5): 380-3. 
 
 
 
 


 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
 
81 
 
17.APPENDICES  
 
Appendix A: Performance Status Criteria 
 
 
ECOG Performance Status Scale 
 
 
Karnofsky Performance Scale 
Grade 
Description 
Percent 
Description 
0 
Normal activity. Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no 
evidence of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of 
disease. 
1 
Symptoms, but ambulatory. 
Restricted in physically strenuous 
activity, but ambulatory and able to 
carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; 
some signs or symptoms of 
disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active 
work. 
2 
In bed < 50% of the time. 
Ambulatory and capable of all self-
care, but unable to carry out any 
work activities. Up and about more 
than 50% of waking hours. 
60 
Requires occasional assistance, 
but is able to care for most of 
his/her needs. 
50 
Requires considerable assistance 
and frequent medical care. 
3 
In bed >50% of the time. Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care 
and assistance. 
30 
Severely disabled, 
hospitalization indicated. Death 
not imminent. 
4 
100% bedridden. Completely 
disabled. Cannot carry on any self-
care. Totally confined to bed or 
chair. 
20 
Very sick, hospitalization 
indicated. Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly.  
5 
Dead. 
0 
Dead. 
Source:  Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET et al. Toxicity 
and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982; 5 
(6):649-55. 
 
 
 


 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
 
82 
Appendix B: IDR Neuropathy Assessment Questionnaire 
 
Patient Name:______________________  
MRN______________    
 
Patient Signature:___________________  
Date___________ 
 
Please circle one (1) number to indicate how true each of the following statements has been 
for you in the past 7 days.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
I have numbness or tingling in my hands  
 
 
0  
 
1  
 
 2  
 
 
 3  
 
 
  4  
I have numbness or tingling in my feet  
 
 
 
0  
 
1  
 
 2  
 
 
 3  
 
 
  4 
I feel discomfort in my hands  
 
 
 
 
 
 
0  
 
1  
 
 2  
 
 
 3  
 
 
  4 
I feel discomfort in my feet  
 
 
 
 
 
 
0  
 
1  
 
 2  
 
 
 3  
 
 
  4 
I have joint pain or muscle cramps  
 
 
 
 
0  
 
1  
 
 2  
 
 
 3  
 
 
  4 
I feel weak all over  
 
 
 
 
 
 
 
 
 
0  
 
1  
 
 2  
 
 
 3  
 
 
  4 
I have trouble hearing  
 
 
 
 
 
 
 
 
0  
 
1  
 
 2  
 
 
 3  
 
 
  4 
I get ringing or buzzing in my ears  
 
 
 
 
0  
 
1  
 
 2  
 
 
 3  
 
 
  4 
I have trouble with buttons 
 
 
 
 
 
 
 
0  
 
1  
 
 2  
 
 
 3  
 
 
  4 
I have trouble feeling the shape of small objects 
0  
 
1  
 
 2  
 
 
 3  
 
 
  4 
I have trouble walking  
 
 
 
 
 
 
 
 
0  
 
1  
 
 2  
 
 
 3  
 
 
  4  
 
Adapted from “Neurotoxicity Assessment Tool” Millennium. Cella DF, Tulsky DS, Gary G et al. The functional assessment of cancer therapy (FACT) scale: 
development and validation of the general measure. J Clin Oncol 1993:11(3):570-79. Calhoun EA, Fishman A, Roland PY et al. Validity and selective sensitivity of 
the FACT/GOG-Ntx. Abstract 1751. 36th Annual Meeting of the American Society of Clinical Oncology, May 2000, New Orleans, LA. 
None    A little bit  Somewhat 
Quite a bit 
Very much 
Screening/Off Study 
Induction/Maintenance 
Cycle_____ Day____