Phase II Study of Ibrutinib in Combination With Ixazomib in Patients With Waldenström Macroglobulinemia
Phase: PHASE2
Conditions: Recurrent Waldenstrom Macroglobulinemia, Refractory Waldenstrom Macroglobulinemia, Waldenstrom Macroglobulinemia
Sponsor: Mayo Clinic

MC178B / 18-000580 
Phase II Study of Ibrutinib in Combination With Ixazomib in 
Patients With Waldenstrom Macroglobulinemia 
NCT03506373 
Document Date: 02/16/2022 

Version Date:07May2021 
1 
 
 
Mayo Clinic Cancer Center 
 
Phase II study of Ibrutinib in combination with Ixazomib in patients with Waldenström 
Macroglobulinemia 
 
Sponsor/Principal Investigator: Asher Chanan-Khan, MD 
Mayo Clinic Jacksonville 
4500 San Pablo Rd 
Jacksonville, FL 32224 
Phone: 
904/953-2708 
Fax: 
904/953-2315 
 
Co-Investigators: 
Aneel Paulus, MD 
 
Vivek Roy, MD 
Taimur Sher, M.D. 
 
Statistician: 
Betsy LaPlant, MS √ 
FDA IND #: Exempt 
Trial Supported by: Takeda Pharmaceuticals 
Funding: Takeda Pharmaceuticals 
Drug Availability: 
Commercial Agents: Ibrutinib 
Drug Company Supplied: Ixazomib 
√Study contributor(s) not responsible for patient care 
 
Document History 
(Effective Date) 
Activation 
Addendum 1 
Addendum 2 
Addendum 3 
   Addendum 4 
   Addendum 5 
   Addendum 6 
 
 
2018May05 
2019Jan02 
2019Sep20 
2019Oct16 
2020Jan29 
      2021Jul01 
      2022Feb16  
 
 
 
Site Investigators & Participating sites:  
Mayo Clinic Rochester: 
Stephen M. Ansell, M.D., Ph.D 
Mayo Clinic  
200 First Street SW  
Rochester, MN 55905  
507/284-2511 
 

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Protocol Resources 
 
 
Questions: 
Contact Name: 
Patient eligibility*, test schedule, 
treatment delays/interruptions/adjustments, 
dose modifications, adverse events, 
forms completion and submission 
Heidi Ganz, Quality Assurance Specialist 
Phone: 507/293-1465 
E-mail: ganz.heidi@mayo.edu 
Forms completion and submission 
Kathleen Burke, R.N, CCRP 
(MCF) Phone: 904-953-7563 
Email: Burke.Kathleen@mayo.edu  
 
Kelly Chisholm, CRC (MCR) 
Phone: 507/266-6333 
Email: Chisholm.kelly@mayo.edu 
Protocol document, consent form, 
regulatory issues 
  Nichole Plouffe (MCF RPS Lead) 
  Phone: 904/953-0314 
  Email: plouffe.nichole@mayo.edu  
 
  Jean M. Hanson, CCRP (MCR RPS) 
Phone: 507/284-8665 
Email: hansonj@mayo.edu  
Non-paraffin biospecimens 
FLA BAP 
Phone: 904/953-6015 
Email: dlflabap@mayo.edu   
Serious Adverse Event Reporting 
Patricia G McNamara, SAE Coordinator 
Phone: 507/266-3028 
E-mail: RSTP2CSAES@mayo.edu 
*No waivers of eligibility allowed 

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Table of Contents 
 
Title of Protocol .............................................................................................................................................. 
Protocol Resources ........................................................................................................................................ 2 
Table of Contents .......................................................................................................................................... 3 
Schema .......................................................................................................................................................... 4 
1.0 
Background ................................................................................................................................... 5 
2.0 
Goals ............................................................................................................................................. 9 
3.0 
Registration Patient Eligibility .................................................................................................... 10 
4.0 
Test Schedule .............................................................................................................................. 13 
5.0 
Stratification Factors OR Grouping Factor ................................................................................. 16 
6.0 
Registration/Randomization Procedures ..................................................................................... 16 
7.0 
Protocol Treatment ...................................................................................................................... 18 
8.0 
Dosage Modification Based on Adverse Events ......................................................................... 18 
9.0 
Ancillary Treatment/Supportive Care ......................................................................................... 24 
10.0 
Adverse Event (AE) Monitoring and Reporting ......................................................................... 26 
11.0 
Treatment Evaluation/Measurement of Effect ............................................................................ 37 
12.0 
Descriptive Factors ..................................................................................................................... 38 
13.0 
Treatment/Follow–up Decision at Evaluation of Patient ............................................................ 38 
14.0 
Body Fluid Biospecimens ........................................................................................................... 40 
15.0 
Drug Information ........................................................................................................................ 47 
16.0 
Statistical Considerations and Methodology ............................................................................... 54 
17.0 
Pathology Considerations/Tissue Biospecimens ......................................................................... 62 
18.0 
Records and Data Collection Procedures .................................................................................... 62 
19.0 
Budget ......................................................................................................................................... 63 
20.0 
References ................................................................................................................................... 64 
Appendix I 
ECOG Performance Status ............................................................................................... 65 
Appendix II 
Patient Medication Diary .................................................................................................. 66 
Appendix III 
Response Assessment Criteria ......................................................................................... 68 

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Schema 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Generic name: Ixazomib  
Brand name(s): Ninlaro® 
Mayo Abbreviation:MLN9708 
Availability: Mayo Clinic Pharmacy 
Generic name: Ibrutinib  
Brand name(s):Imbruvica® 
Mayo Abbreviation: PCI-32765 
Availability: Commercial 
Registration 
Treatment (Active Treatment Phase) 
Ixazomib: PO Days 1, 8, 15 every cycle* 
Ibrutinib: PO Days 1-28 every cycle* 
Response assessment: Every cycle* 
Duration of therapy: 24 cycles* 
Clinical Follow-up 
Q 3 months X 2 years 
At any time: 
Disease Progression 
Intolerable adverse events 
Patient refusal 
Subsequent treatment 
Survival Follow-up 
*Every cycle = 28 days (4 weeks - except at treatment completion where cycle length will be the 
number of treatment days in that cycle + 28 days)  

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1.0 
Background 
 
1.1 
Waldenström macroglobulinemia 
Waldenström macroglobulinemia (WM) is an incurable indolent B-cell neoplasm 
manifested 
by 
the 
accumulation 
of 
clonal 
immunoglobulin 
(Ig)M-secreting 
lymphoplasmacytic cells (Treon, Xu et al. 2015). WM is a rare disorder, with an incidence 
rate of about 3 cases per million people per year in the United States (ACS website). 
 
Clinical Presentation: patients may have variable clinical presentation and the symptoms 
can be divided into three major clinical groups: (a) symptoms related to the underlying 
lymphoproliferative process (e.g., constitutional symptoms, cytopenias, or tissue 
infiltration), (b) hyperviscosity related to the overproduction of IgM, and (c) paraneoplastic 
neuropathy. 
 
Patients with disease-related hemoglobin <10 g/L, platelets <100 × 109/L, bulky 
adenopathy and/or organomegaly, symptomatic hyperviscosity, peripheral neuropathy, 
amyloidosis, cryoglobulinemia, cold-agglutinin disease, or transformed disease are often 
considered for therapy while asymptomatic patients can be monitored. 
 
1.11 
Disease biology 
Understanding the biology of WM has revealed two critical survival pathways 
that exposed the vulnerability of the malignant cells. 
 
The proteasome system: 
WM cell survival is critically anchored to the viability of proteasomes, which form 
the principle component of the ubiquitin proteasome degradation system (UPS). 
The UPS regulates stability of numerous proteins such as p53, cyclin- dependent 
kinase inhibitors and nuclear transcription factor kappa-B (NFkB), all whose 
balance is crucial to the maintenance of normal cellular homeostasis. (LQ. 2012) 
Moreover, in WM cells that have a high protein turnover, UPS machinery is 
upregulated to prevent accumulation of misfolded proteins. (Assouline 2012). 
Proteasomes are comprised of a 26S barrel shaped structure that is flanked on both 
sides with two regulatory 19S caps. The ß rings of the 26S core form the catalytic 
components. Disruption of the catalytic core by proteasome inhibitors (PI) such as 
bortezomib, carfilzomib and ixazomib inhibits chymotrypsin-like activity at the ß5 
subunits and this results in loss of WM cell viability. Importantly, the pleiotropic 
effects of the pro survival complex NFkB, which is expressed at high levels in WM 
cells (Lonial 2012), is attenuated by PI through the stabilization of its inhibitor 
(IkB) (Kumar 2011). It is therefore not surprising that inhibition of the UPS with 
PIs such as the first in class agent bortezomib has resulted in significant clinical 
benefit in over 80% of WM patients treated. Ixazomib is a newer, more tolerable 
and more patient convenient PI that effectively targets the proteasome and has 
demonstrated impressive anti-multiple myeloma (MM) activity in plasma cell 
cancers. Our preclinical evaluations have demonstrated its activity in models of 
WM. 

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BCR signaling: 
More recently, it has been demonstrated that the pathological behavior of WM 
cells is a consequence of aberrant B-cell receptor (BCR) signaling due to 
activating mutations of the myeloid differentiation primary response gene 88 
(MYD88L265P) and hyper-activation of Brutons tyrosine kinase (BTK) (Treon, 
Cao et al. 2014, Treon, Xu et al. 2015). Although individually distinct and 
qualified to drive WM pathogenesis, these molecular abnormalities often 
converge on the common effector element of NFkB. Together, the 
MYD88L265P/ IRAK1/4/ BTK complexes induce a signaling cascade that 
activates NFkB and the Signal Transducers and Activators of Transcription 
(STAT) family of factors (Kumar 2012). NFkB and STATs in turn regulate the 
expression and stability of several tumor promoting genes (c-MYC, IL-6, Bcl-xL, 
Gadd45b, IAPs) (Kumar 2011). Ibrutinib is an irreversible small molecule 
inhibitor of BTK that blocks signal transduction activity of the B-cell receptor 
(BCR) by disengaging BTKs interactions with PLC and MYD88 (Richardson 
2012). Thus, downstream activation of NFkB and STAT signaling is mitigated 
resulting in decreased pro survival signals, direct induction of apoptosis and 
inhibition of cell homing towards chemokine’s that facilitate adhesion 
(Richardson 2011., San Miguel 2012). Several lines of preclinical evidence in 
various B-cell lymphoma cell lines and now also in WM models attests to the 
tumoricidal effects of ibrutinib. 
 
1.2 
Treatment for WM 
Up until 2015 there was no standard FDA therapy for the treatment of symptomatic WM. 
The therapeutic strategies for treatment of WM were primarily derived from experience in 
other plasma cell / B cell cancers with the use of steroids, chemotherapeutics 
(cyclophosphamide, doxorubicin), biologics (rituximab) and novel agents (such as the 
proteasome inhibitor bortezomib). Among these the highest single agent response rate was 
reached with bortezomib. 
 
In January of 2015, ibrutinib was the first drug to receive FDA approval for treatment of 
WM. This approval was based on the demonstration of durable responses in a single arm, 
multi-center phase II clinical trial enrolling 63 patients with previously treated WM. The 
overall response rate (inclusive of complete response (CR), very good partial response 
(VGPR), and partial response (PR)) was 61.9% (95%CI 48.8, 73.9). Among these the 
responses consisted of VGPR (11.1%) and PR (50.8%) with none of the patients 
achieving a CR. The median duration of response has not been reached at the time of 
drug approval (range of 2.8+ to 18.8+ months) with a median time to response of 1.2 
months. 
 
 
1.3 
Rationale 
Waldenström macroglobulinemia (WM) is a rare and incurable indolent B-cell neoplasm 
manifested by the accumulation of clonal immunoglobulin (Ig) M-secreting 
lymphoplasmacytic cells. Since 2015, the Bruton tyrosine kinase (BTK) inhibitor 
ibrutinib has been approved for the treatment of WM. Over 80% of patients with 
Waldenström Macroglobulinemia (WM) demonstrate clinical benefit from treatment with 
ibrutinib. However, most of the clinical responses are limited to partial remission, which 
is consistent with ibrutinib’s clinical activity in other B-cell cancers as well. Therefore, 

Version Date:07May2021 
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opportunities remain to enhance the response rates through combination therapies. The 
proteasome inhibitor ixazomib (MLN-9708) is an attractive combination partner because 
it complements the biological activity of ibrutinib, may synergistically enhance its anti- 
WM effects and does not have an overlapping toxicity profile. 
 
1.4 
Study Design 
This is a Phase II, single arm, open-label study to assess the efficacy, safety, tolerability, 
pharmacokinetics and pharmacodynamics of the combination of ibrutinib and ixazomib 
administered to patients with WM. The study consists of a treatment phase, followed by 
an event-monitoring follow-up phase: 
 
In the treatment phase, patients will receive ixazomib 4 mg PO on days 1, 8 and 15 and 
ibrutinib 420 mg PO daily in 4-weekly cycles. The response to therapy will be assessed 
every cycle, with imaging done every 2 cycles as necessary. Patients will receive additional 
cycles of treatment up to a maximum of 24 cycles or until progressive disease (PD), 
subsequent treatment, intolerable adverse effects, patient refusal, withdrawal of consent, or 
death. 
 
After the patient has completed the treatment phase an end-of-treatment (EOT) visit will 
be scheduled 4 weeks after the last intake of study medication. After the EOT visit, the 
patients will go to clinical follow-up, followed by the survival follow-up phase in which 
patients will be followed up for survival status and start of new lines of therapy. 
 
 
1.5 
Correlative Research 
 
1.51 
To determine the role of members of the BTK signalosome in achievement or lack 
thereof of response to Ibrutinib and Ixazomib: The variability in extent of response to a 
therapeutic agent may suggest underlying adaptability of the WM clone through 
components of the BTK signalosome. Patients with B-cell malignancies treated with 
ibrutinib demonstrate upregulation of p-Akt and p-Erk (downstream mediators of BTK) 
in some (but not all) cases, suggesting that these pathways may contribute to survival of 
the malignant clone. It was also concluded in this work that these cells might not be 
dependent upon the proximal BTK pathways mediated apoptosis and thus, resistant to 
killing by Ibrutinib. To address this question we will establish the profile of BTK 
signalosome for each patient through determination of the mRNA (RT-PCR/nanostring 
assay; whole exome sequencing (WES), transcriptome analysis) and protein expression 
(western blot analysis) of members of the BTK signaling pathway and look for 
associations between this and eventual response (or lack thereof) to the treatment. The 
said tests will be done analyzing the lymphoplasmacytic cells enriched from the bone 
marrow samples collected at baseline, and then at the time of disease progression. This 
will help explore mechanisms of acquired resistance to ibrutinib when used with 
ixazomib. We will also look for pAKT, pS6 and pERK as indirect pharmacodynamic 
biomarkers analyzed in patient’s PBMC collected as a peripheral blood sample. 
 
 
1.52 
To explore biologic effects of ibrutinib and ixazomib on microenvironment in WM 
and correlate with response to treatment: In cancer redirection of host immunity from a 
predominant Th2 to Th1 response can deliver antitumor response. Ibrutinib can 

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bind to ITK, a member of the TEC-kinase family, which mediates TCR signaling through 
PLCg, NFAT, NF-kappaB and MAPK. This results in activation and proliferation of CD8+ 
cells. Our hypothesis is that ibrutinib with ixazomib alters the Th2:Th1 balance in the blood 
and bone marrow microenvironment, skewing towards a more Th1 profile and this may 
translate into clinical efficacy. We further hypothesize that the robustness of the Th1 
response will direct this combination’s depth of response. We will assess this in bone 
marrow samples comparing the baseline sample to one collected after 1 cycle of treatment 
with ibrutinib and ixazomib using the MultiOmyx Tumor Infiltrating Lymphocytes panel 
for T helper (CD4+), Treg (FOXP3+), T cytotoxic (CD8+), B cells (CD20+), macrophage 
(CD68+), NK cells (CD56+), immunosuppression (PD-L1), CD138+, CD38+, ITK and 
BTK. Furthermore, BTK/ITK occupancy by Ibrutinib has been associated with response 
rates in other B-cell malignancies where this is an effective agent (CLL) but this has never 
been tested in WM. This assay will be performed to assess target coverage in bone marrow 
samples obtained from patients at the end of 1 cycle of treatment with ibrutinib and 
ixazomib. In addition, PBMC samples (2 ml of whole blood with heparin) from baseline 
and after 1 cycle of treatment will be assessed for: 
Th1 cells (live+, CD19-, CD3+, CD4+, CD8-, IFNg+) 
Th2 cells (live+, CD19-, CD3+, CD4+, CD8-, IL4+) 
Th17 cells (live+, CD19-, CD3+, CD4+, CD8-, IL17+) 
Treg cells (live+, CD19-, CD14-, CD3+, CD4+, CD25+, CD127-, FOXP3, CCR4+) 
 
 
 

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2.0 
Goals 
2.1 
Primary Goal 
The primary objective of this study is to determine the efficacy (as assessed by complete 
response [CR] rate) of the combination of ixazomib and ibrutinib in WM patients. 
2.2 
Secondary Goals 
2.21 
To assess the overall response rate (ORR=PR or better) in WM patients treated 
with ixazomib and ibrutinib. 
2.22 
To assess the time to progression (TTP) in WM patients treated with ixazomib 
and ibrutinib. 
 
2.23 
To further characterize the safety and toxicity of the combination of ibrutinib and 
ixazomib. 
 
2.24 
To assess the overall survival (OS) in WM patients treated with ixazomib and 
ibrutinib. 
2.3 
Correlative Research 
2.31 
To determine the role of members of the BTK signalosome in achievement or 
lack thereof of response to ibrutinib and ixazomib. 
 
 
2.32 
To explore biologic effects of ibrutinib and ixazomib on microenvironment in 
WM and correlate with response to treatment. 
 

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3.0 
Registration Patient Eligibility 
 
3.1 Inclusion Criteria 
3.11 
Age ≥ 18 years 
3.12 
Histological confirmation of WM. Patients may have newly diagnosed, relapsed, 
or refractory disease. (Definition: Newly diagnosed; Patients previously 
untreated for WM, Relapse; patients who have received prior treatment for WM 
and now have disease recurrence. Refractory; patients who have received anti-
WM therapy and are noted to have progressive disease while on therapy, or those 
patients who demonstrated disease progression within 6 months of the last anti-
WM treatment). NOTE: Ibrutinib naïve patients are allowed. If previously 
treated with ibrutinib, subject must have reached a response of at least SD and 
cannot have progressed while on ibrutinib. If subject stopped taking ibrutinib for 
reasons other than progression, they cannot have progressed for at least 6 months 
post last dose of ibrutinib. 
3.13 
Presence of measurable disease as defined by: presence of IgM paraprotein, 
measurable lymphadenopathy on imaging studies and/or physical exam, and/or 
bone marrow infiltration >10%. (Kapoor, 2017) 
3.14 
ECOG Performance Status (PS) of 0, 1, or 2 (Appendix 1). 
3.15 
The following laboratory values obtained ≤14 days prior to registration: 
• 
ANC ≥1000/mm3 
• 
Platelet count ≥75,000/mm3 (NOTE: Platelet transfusions in order to help 
patients meet eligibility criteria are not allowed) 
• 
Hemoglobin ≥9.0 g/dL 
• 
Total bilirubin ≤1.5 x upper limit of normal (ULN) unless due to Gilbert’s 
syndrome, in which case the direct bilirubin must be ≤1.5 X ULN. 
• 
Aspartate transaminase (AST) and alanine aminotransferase (ALT) ≤3 x 
ULN 
• 
Calculated creatinine clearance must be ≥30 ml/min using the Cockcroft- 
Gault formula below: 
 
3.16 
Negative pregnancy test done at screening and ≤3 days (72 hours) prior to 
registration, for women of childbearing potential 
3.17 
Provide written informed consent. 
3.18 
Willingness to provide mandatory blood specimens and bone marrow specimens 
for correlative research. 
3.19 
Willingness to return to enrolling institution for follow-up 
3.2 Exclusion Criteria 
 
3.21 
Failure to have fully recovered (i.e., ≤Grade 1 toxicity) from the reversible 
effects of prior treatment for WM. 
Creatinine clearance for females = (140 – age [years])(weight in kg)(0.85) 
(72)(serum creatinine in mg/dL) 
(140 – age [years])(weight in kg) 
(72)(serum creatinine in mg/dL) 
Cockcroft-Gault Equation: 
Creatinine clearance for males = 

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3.22 
Major surgical procedure (including open biopsy, excluding central line IV and 
portacath placement) within ≤14 days prior to initiating study treatment, or 
anticipation of the need for major surgery during the course of the study treatment. 
3.23 
Radiotherapy ≤14 days prior to registration. If the involved field is small, 7 days 
will be considered a sufficient interval between treatment and administration of the 
Ixazomib. 
3.24 
Systemic treatment, ≤14 days before registration, with strong CYP3A inducers 
(rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital), or St. 
John’s wort. 
3.25 
Systemic anti-cancer therapy or participation in other clinical trials, including 
those with other investigational agents not included in this trial, ≤ 28 days of 
registration and throughout the duration of active treatment in this trial. 
3.26 
Patients that have previously been treated with ixazomib, or participated in a study 
with ixazomib whether treated with ixazomib or not. Prior bortezomib treatment 
is allowed as per: Patients with prior exposure to bortezomib will be allowed if 
they do not have disease refractory to bortezomib). 
3.27 
Central nervous system involvement (Bing-Neel syndrome). 
3.28 
Infection requiring systemic antibiotic therapy or other serious infection ≤7 days 
prior to registration. 
3.29 a Evidence of current uncontrolled cardiovascular conditions,  including  uncontrolled 
hypertension, serious cardiac arrhythmia requiring medication (other than 
adequately rate-controlled atrial fibrillation), symptomatic congestive heart failure, 
unstable angina, stroke/TIA within the past 6 months or myocardial infarction 
within the past 6 months. 
3.29b Known allergy to any of the study medications, their analogues, or excipients in  the 
various formulations of any agent. 
3.29c   Known GI disease or GI procedure that could interfere with the oral absorption   or 
tolerance of ixazomib or ibrutinib, including difficulty swallowing. 
3.29d History of any other prior malignancy. (NOTE: Exception to this are adequately 
treated non-melanoma skin cancers, any in situ cancer, adequately treated stage I 
or II cancer from which the patient is currently in complete remission, or any other 
cancer from which the patient has been disease free for at least two years prior to 
study enrollment). 
3.29e  Patient has ≥ Grade 2 peripheral neuropathy or Grade 1 peripheral neuropathy  with 
pain on clinical examination during the screening period. 
3.29 f Any of the following because this study involves an investigational agent whose 
genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn 
are unknown. 
• 
Pregnant women 
• 
Nursing women 
• 
Men or women of child bearing potential (WCBP) who are unwilling to employ 
effective contraception. Effective contraception would be defined as utilizing 2 
simultaneous methods of contraception from the time of signing consent through 
90 days after the last dose of the study drugs unless they agree to participate in true 
abstinence when this is in line with the preferred and usual lifestyle of the 

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subject. [WCBP: A female who is sexually mature and who: (1) has not undergone 
a hysterectomy or bilateral oophorectomy; or (2) has not been naturally 
postmenopausal for at least 24 consecutive months (i.e., has had menses at any 
time in the preceding 24 consecutive months)]. 
3.29g Evidence of any other serious medical condition (such as psychiatric illness, 
infectious diseases, physical or laboratory findings) that may interfere with the 
planned treatment, affect compliance or place the patient at high risk from 
treatment-related complications or potentially interfere with the completion of  the 
treatment as per the protocol. 
3.29h Ongoing, active hepatitis B or C virus infection, or known human immunodeficiency 
virus (HIV) positive. 
32.9i 
Liver disease with Child-Pugh class B or C liver dysfunction. 
3.29j 
Current treatment with a combination of ibrutinib and strong CYP3A inhibitors. 

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4.0 
Test Schedule 
4.1 
Test schedule for Waldenström Macroglobulinemia 
 
 
 
 
 
 
 
Tests and procedures 
 
 
 
 
≤ 28 days 
prior to 
registration 
 
 
 
≤ 14 days 
prior to 
registration 
 
Cycle 1 
Cycles 2-24 
(During course of 
treatment)11 
(End of 
treatment) 
 
Clinical 
Follow-up 
 
 
Day 
1 
 
 
Day 
8 
 
 
Day 
15 
 
 
Day 
22 
 
 
Day 
1 
4 weeks after 
last study drug 
intake 
 
 
Q 3 months X 2 
years 
Window  
 
±3 days 
±7 days 
±7 days 
Informed Consent 
X 
 
 
 
 
 
 
 
 
Complete medical history1 
 
X 
X 
 
 
 
 
 
 
Physical exam, vital signs 
Wt, PS 
 
X 
X 
 
 
 
X 
X 
X 
Pregnancy test2 
 
X 
 
 
 
 
 
 
 
Hematology group 
CBC w/diff 
 
X 
X 
X 
X 
X 
X 
X 
X 
Chemistry group 
Sodium 
Chloride 
Potassium 
Magnesium 
Phosphate 
Uric acid 
BUN 
Glucose 
ALT/AST 
Alkaline phosphatase 
Total protein 
Total Bilirubin 
Direct Bilirubin 
Albumin 
Serum creatinine 
Creatinine clearance 
calcium 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 

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Version Date: 07May2021 
 
 
 
 
 
 
 
 
 
Tests and procedures 
 
 
 
 
≤ 28 days 
prior to 
registration 
 
 
 
≤ 14 days 
prior to 
registration 
 
Cycle 1 
Cycles 2-24 
(During course of 
treatment)12 
(End of 
treatment) 
 
Clinical 
Follow-up 
 
 
Day 
1 
 
 
Day 
8 
 
 
Day 
15 
 
 
Day 
22 
 
 
Day 
1 
4 weeks after 
last study drug 
intake 
 
 
Q 3 months X 2 
years 
Bone marrow aspirate and 
biopsy3 
X 
 
 
 
 
 
X 
X 
X 
Electrophoresis of serum and 
urine (SPEP/UPEP) 
 
X9 
 
 
 
 
X9 
X9 
X9 
Affected immunoglobulins4 
 
X 
 
 
 
 
X 
X 
X 
Immunofixation serum and 
urine (IF) 
 
X 
 
 
 
 
X 
X 
X 
Immunoglobulin free light 
chains (FLC) 
 
X 
 
 
 
 
X 
X 
X 
Serum beta-2-microglobulin, 
LDH, serum viscosity 
 
X 
 
 
 
 
X 
X 
X 
Tumor measurement5 
 
X 
 
 
 
 
X 
X 
X 
EKG or ECHO or MUGA6 
 
X 
 
 
 
 
X 
X 
X 
Adverse event monitoring 
 
X 
X 
X 
X 
X 
X 
X 
X 
Patient Medication Diary 
(Appendix II)7 
 
 
X 
 
 
 
X 
X 
 
Research Bone Marrow 
Aspirate SampleR (see Section 
14.0) 
 
X10 
 
 
 
 
X11 
X11 
 
Mandatory Research blood 
specimens (see Section 
14.0)8,R 
 
X10 
 
 
 
 
 
X 
 
X 
 
Cycle = 28 days (except at treatment completion where cycle length will be the number of treatment days in that cycle + 28 days) 
1. Does not need to be repeated on cycle 1, day 1 if completed within 5 days. A complete physical exam, including height (screening only) and 
weight, neurologic assessment and assessment for lymphadenopathy/organomegaly will be conducted at screening, day one of each cycle, end 

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Version Date: 07May2021 
 
 
 
of treatment visit. A symptom directed physical examination will be conducted as needed during a cycle. Weight to be measured on day one of 
each cycle. Objective assessment of peripheral neuropathy as per CTCAE v 4.0 should be documented on Day 1 of every cycle of treatment. 
2. Negative pregnancy test done at screening and ≤3 days (72 hours) prior to registration, for women of childbearing potential. 
3. Standard of care procedure ≤28 days prior to registration, as clinically indicated after cycle 1, and to document CR or PD while on treatment. 
4. Serum immunoglobulins to include IgA, IgG, IgM in all cases and IgD, IgE as clinically indicated. 
5. Tumor measure will be done by physical examination and or biochemical testing of the blood (such as M spike, IgM levels). In addition, 
radiological evaluation can be used if clinically needed. The modality of radiological testing such as PET scan, or CT scan or MRI scan of 
the specific part of the body (i.e. chest or abdomen or pelvis) will be selected based upon the clinical needs or clinical scenario (i.e. site 
where extranodal / extramedullary disease was observed) of the patient and at the discretion of the treating physician. None of these scans is 
mandatory and will only be utilized to best assess patient disease consistent with standard clinical practice guidelines. It is recommended to 
use same measurement technique throughout the study to be consistent with assessing accurately the response to treatment. If imaging is the 
predominant method of assessing disease burden (such as in cases of extramedullary, or extranodal disease or hypo-secretory patient) then it 
is recommended to be done every 2 cycles or as clinically necessary to accurately and timely assess response (or lack of) to the treatment 
give. Every 2 months radiological testing is not mandatory for all patients. Note:  PET scan is not mandatory in this study. If baseline PET 
scan is done as per clinical practice guidelines than it is recommended that a post end of treatment scan be done to assess response, however 
given the re-imbursement challenges of PET scan – this is not mandatory and will be done as part of standard of care and consistent with 
the best clinical practice.  
6. To be performed at screening and as clinically indicated throughout the study. Check EKG at any time if the patient’s vital signs suggest an 
issue or if the patient has complaints that could be related to atrial fibrillation as per the physician’s assessment. 
7. The diary must begin the day the patient starts taking the medication and must be completed per protocol and returned to the treating 
institution OR compliance must be documented in the medical record by any member of the care team. 
8. Blood specimens will be collected and submitted as specified in Section 14.0. Kits are required. 
9.   UPEP testing required at baseline only. Subsequent testing will be as needed per physician discretion. 
10. Collected at registration but prior to treatment 
11. After Cycle 1, Additional samples to be drawn if a bone marrow is done for confirmation of response or as otherwise clinically indicated. 
12. Patient return visit requirements:  Day 1 of cycles 1, 2, 3 and 4. After cycle 4, the patient may be allowed to come every other cycle (to 
coincide with cycle 6, 8, 10, 12, 14, 16, 18, 20, 22, 24) if considered appropriate by the treating physician. (See section 7.3)  
R Research funded (see Section 19.0) 
 
4.2 
Survival Follow-up 
 
 
 
Survival Follow-up1 
 
Every 3 months until 
disease progression or 
subsequent treatment 
At disease progression 
or initiation of 
subsequent therapy 
Every 6 months after disease 
progression or initiation of 
subsequent therapy 
At death 
Event Monitoring 
X 
X 
X 
X 
1. If a patient is still alive 5 years after registration, no further follow-up is required. 

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5.0 
Stratification Factors OR Grouping Factor: 
None. 
6.0 
Registration/Randomization Procedures 
6.1 
Registering a patient 
To register a patient, access the Mayo Clinic Cancer Center (MCCC) web page 
and enter the registration/randomization application. The registration/ 
randomization application is available 24 hours a day, 7 days a week. Back up 
and/or system support contact information is available on the website. If unable 
to access the website, call the MCCC Registration Office at (507) 284-2753 
between the hours of 8 a.m. and 5:00 p.m. Central Time (Monday through 
Friday). 
The instructions for the registration/randomization application are available on 
the MCCC web page (http://ccswww/training/index.html) and detail the 
process for completing and confirming patient registration. Prior to initiation of 
protocol treatment, this process must be completed in its entirety and an MCCC 
subject ID number must be available as noted in the instructions. It is the 
responsibility of the individual and institution registering the patient to confirm 
the process has been successfully completed prior to release of the study agent. 
Patient registration via the registration/randomization application can be 
confirmed in any of the following ways: 
• 
Contact the MCCC Registration Office (507) 284-2753. If the patient 
was fully registered, the MCCC Registration Office staff can access 
the information from the centralized database and confirm the 
registration. 
• 
Refer to “Instructions for Remote Registration” in section 
“Finding/Displaying Information about A Registered Subject.” 
6.2 
Verification of information 
Prior to accepting the registration, the registration/randomization application will 
verify the following: 
• 
IRB approval at the registering institution 
• 
Patient registration eligibility 
• 
Existence of a signed consent form 
• 
Existence of a signed authorization for use and disclosure of protected health 
information. 
 
6.3 
Documentation of IRB approval 
Documentation of IRB approval must be on file in the Registration Office before 
an investigator may register any patients. 
In addition to submitting initial IRB approval documents, ongoing IRB approval 
documentation must be on file (no less than annually) at the Registration Office 
(fax: 507-284-0885). If the necessary documentation is not submitted in advance 
of attempting patient registration, the registration will not be accepted and the 
patient may not be enrolled in the protocol until the situation is resolved. 
When the study has been permanently closed to patient enrollment, submission of 
annual IRB approvals to the Registration Office is no longer necessary. 

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6.4 
Correlative Research 
6.41 A mandatory correlative research component is part of this study, the patient 
will be automatically registered onto this component (see Sections 3.18, 14.1). 
6.5 
Treatment on protocol 
Treatment on this protocol must commence at Mayo Clinic Rochester or 
Mayo Clinic Florida under the supervision of a medical 
oncologist/hematologist. 
6.6 
Treatment start 
Treatment cannot begin prior to registration and must begin ≤ 28 days after 
registration. 
6.7 
Pretreatment 
Pretreatment tests/procedures (see Section 4.0) must be completed within the 
guidelines specified on the test schedule. 
6.8 
Baseline symptoms 
All required baseline symptoms (see Section 10.6) must be documented and 
graded. 
6.9 a 
Study drug 
Study drug is available on site. 
6.9b 
Blood draw kits 
Blood draw kit is available on site. 
6.9c 
Study Conduct 
The clinical trial will be conducted in compliance with regulations (21 CFR 312, 
50, and 56), guidelines for Good Clinical Practice (ICH Guidance E6), and in 
accordance with general ethical principles outlined in the Declaration of 
Helsinki; informed consent will be obtained from all participating patients; the 
protocol and any amendments will be subject to approval by the designated IRB 
prior to implementation, in accordance with 21 CFR 56.103(a); and subject 
records will be stored in a secure location and subject confidentiality will be 
maintained. The investigator will be thoroughly familiar with the appropriate use 
of the study drug as described in the protocol and Investigator’s Brochure. 
Essential clinical documents will be maintained to demonstrate the validity of the 
study and the integrity of the data collected. Master files should be established at 
the beginning of the study, maintained for the duration of the study and retained 
according to the appropriate regulations. 

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7.0 
Protocol Treatment 
Both the study drugs are to be self-administered by the patients. Ibrutunib is administered daily as 
3 tablets and ixazomib is to be taken as per the schedule below. Ixazomib may be administered by 
the patient within ±1 day of the scheduled dose. 
7.1 
Treatment Schedule 
Table 7.1a 
 
 
*All Cycles = 28 days each (except at treatment completion where cycle length 
will be the number of treatment days in that cycle + 28 days) 
Any dose adjustments will be made as per guidelines in section 8. 
Use actual weight or estimated dry weight if fluid retention 
 
Treatment Schedule (in case of dose de-escalation required after safety analysis of first 6 
patients as per Section 16.215) 
 
Table 7.1b 
Agent 
Dose 
Route 
Day 
Cycles* 
Ixazomib 
3 mg 
PO 
1, 8, 15 
Cycle 1-24 
Ibrutinib 
420 mg 
PO 
1-28 
Cycle 1-24 
*All Cycles = 28 days each (except at treatment completion where cycle length 
will be the number of treatment days in that cycle + 28 days) 
Any dose adjustments will be made as per guidelines in section 8. 
Use actual weight or estimated dry weight if fluid retention 
 
7.2 
Treatment by local medical doctor (LMD) 
Treatment by a local medical doctor (LMD) is not allowed. 
7.3 
Return to treating institution 
For this protocol, the patient must return to the consenting institution for evaluation and 
drug administration at least every 28 days during treatment for the first 4 cycles.  After cycle 
4, patients may elect to return every other cycle per treating MD’s discretion as long as there 
are no active ongoing toxicities that have not returned to baseline. Clinical evaluation and 
blood tests can be obtained per test schedule and mailed/faxed to the consenting institution 
and patient can return at least every other cycle for follow up to the consenting institution. 
The cycle length will remain at 28 days and data collection forms will be due at the end of 
each cycle. Adverse events and adherence to study treatment will be collected at the end of 
each cycle by telephone for cycles where the patient does not return to the clinic. The 
patient should retain the pill diaries and medication bottles (even if unopened or empty) 
along with any unused pills for each cycle and bring them to their next visit so that dosing 
can be recorded on the evaluation/treatment forms for each cycle. 
8.0 
Dosage Modification Based on Adverse Events 
A dose of ixazomib and ibrutinib (as per attribution by the treating physician) is held if a patient 
experiences any of the following considered at least possibly related to ixazomib and/or ibrutinib at the 
beginning of a new cycle of treatment: 
 
• 
ANC <1,000/mm3 (grade 2) 
• 
Platelet <75,000/mm3 (grade 1) 
• 
Any other nonhematologic toxicity (except for alopecia or fatigue) ≥ grade 3 with the 
Agent 
Dose 
Route 
Day 
Cycles* 
Ixazomib 
4 mg 
PO 
1, 8, 15 
Cycle 1-24 
Ibrutinib 
420 mg 
PO 
1-28 
Cycle 1-24 

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following considerations: 
o Grade 3 nausea, vomiting or diarrhea will be considered significant if they occur 
despite appropriate maximal anti-emetic and/or antidiarrheal therapy. 
o Grade 3 hyperglycemia will be a considered significant if the patient is symptomatic 
or glucose level is >300 mg/ml despite appropriate administration of insulin and/or oral 
antidiabetic agents. 
 
→ ALERT: 
ADR reporting may be required for some adverse events (See Section 10.0) ← 
8.1 
Dose Levels (Based on Adverse Events in Tables 8.2 and 8.3) 
Dose Level 
Ixazomib 
Ibrutinib 
Starting Dose 
4.0 mg 
420 mg 
-1 
3.0 mg 
280 mg 
-2 
2.3 mg 
140 mg 
-3 
Discontinue 
Current dose 

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NOTE: If ixazomib is discontinued, the patient can continue on single-agent ibrutinib at the dose the 
patient is on when ixazomib is discontinued. 
  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) current version 4.0* unless 
otherwise specified  
* 
Located at http:/ctep.cancer.gov/protocolDevelopment/electronic_applications.ctc.htm 
8.2 
Ixazomib dose modifications 
 
CTCAE 
System/Organ/Class 
(SOC) 
 
 
ADVERSE EVENT 
 
 
AGENT 
 
 
ACTION** 
 
 
 
 
Investigations 
 
 
 
Neutrophil count 
decreased 
Grade 4 
 
 
 
 
 
 
 
 
 
 
 
 
Ixazomib 
*Omit dose until AE has resolved to 
Grade 2 or better 
• Follow CBC weekly 
* If neutropenia has resolved to ≤Grade 2, 
resume dose at one level lower 
*If, after ixazomib has been omitted, and 
the AE does not return to ≤Grade 2within 
4 weeks, then the patient may continue on 
single-agent ibrutinib till the completion 
of treatment and then proceed to survival 
follow-up 
 
Blood and lymphatic 
system disorders 
Febrile neutropenia 
≥Grade 3 
• Omit dose and follow CBC weekly 
• If neutropenia has resolved to ≤Grade 2, 
resume dose at same level with GCSF 
support (See Section 9.2) 
 
 
 
 
 
Investigations 
 
 
 
 
 
Platelet count decreased 
Grade 4 
*Omit dose until AE has resolved to 
Grade 1 or better 
• Follow CBC weekly 
• If thrombocytopenia <25,000/mm3 
recurs, reduce dose by one dose level and 
continue therapy when platelet count 
≥75,000/mm3 
If, after ixazomib has been omitted, and 
the AE does not return to ≤Grade 1 within 
4 weeks, then the patient may continue on 
single-agent ibrutinib till the completion 
of treatment and then proceed to survival 
follow-up 

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CTCAE 
System/Organ/Class 
(SOC) 
 
 
ADVERSE EVENT 
 
 
AGENT 
 
 
ACTION** 
 
 
Nervous System 
Disorders 
 
Peripheral Motor 
Neuropathy and 
Peripheral Sensory 
Neuropathy.Grade 2 or 
Grade 1 with pain 
 
Omit ixazomib until resolution to Grade ≤ 
1 without pain or baseline. 
*If, after ixazomib has been omitted, and 
the AE does not return to ≤Grade 1 within 
4 weeks, then the patient may continue on 
single-agent ibrutinib till the completion 
of treatment and then proceed to survival 
follow-up 
 
 
 
New or worsening 
Grade 2 peripheral 
motor neuropathy and 
peripheral sensory 
neuropathy with pain or 
Grade 3 
Omit ixazomib until resolution to Grade ≤ 
1 without pain or baseline and then reduce 
ixazomib to next lower dose upon 
recovery. 
*If, after ixazomib has been omitted, and 
the AE does not return to ≤Grade 1 within 
4 weeks, then the patient may continue on 
single-agent ibrutinib till the completion 
of treatment and then proceed to survival 
follow-up. 
 
New or worsening 
Grade 4 peripheral 
neuropathy 
Discontinue ixazomib. The patient may 
continue on single-agent ibrutinib till the 
completion of treatment and then proceed 
to survival follow-up. 
** Use the following to describe actions in the Action column: 
 Omit = The current dose(s) for the specified drug(s) during a cycle is skipped. The 
patient does not make up the omitted dose(s) at a later time. 
 Hold/Delay = The current dose(s) of all drugs during a cycle is delayed. The patient 
does make up the delayed dose(s) when the patient meets the protocol criteria to restart 
drugs. 
 Discontinue = The specified drug(s) are totally stopped. 
Additional Adverse Events: 
Grade ≥3 non-hematological toxicity (other than peripheral neuropathy) considered at least probably 
related to ixazomib: 
• 
Omit ixazomib until resolution to Grade ≤ 1 or baseline, then restart at the same dose. 
• 
If not recovered to ≤ Grade 1 or baseline despite adequate supportive care within 4 weeks, then 
the patient may continue on single-agent ibrutinib till the completion of treatment and then 
proceed to survival follow-up. 
• 
For reoccurrence of ≥3 non-hematological toxicity (other than peripheral neuropathy) omit 
ixazomib until resolution to Grade ≤ 1 or baseline, then restart at one lower dose level. 
• 
For ≥3 nausea, vomiting or diarrhea: Once the ixazomib is omitted and the toxicity recovers to 
Grade ≤ 1 or baseline within 4 weeks of holding ixazomib, it should be restarted at one lower 
dose level. 
• 
Once ixazomib is reduced for any toxicity, the dose may not be re-escalated. If it is ultimately 
determined that therapy with ixazomib is no longer safe, the patient may continue on ibrutinib until 
completion of treatment and then proceed to survival follow. 

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• 
If multiple AEs are seen, administer the dose based on the greatest reduction required by any single AE 
observed. Dose modifications are for AEs attributed to study treatment only. Dose modifications are not 
required for AEs if they are deemed unlikely or unrelated to study treatment. 

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8.3 
Ibrutinib dose modifications 
 
 
CTCAE 
System/Organ/Class 
(SOC) 
 
 
ADVERSE EVENT 
 
 
AGENT 
 
 
ACTION** 
 
 
Investigations 
 
Neutrophil count 
decreased 
Grade 4 
 
 
 
 
 
Ibrutinib 
If the AE does not return to ≤Grade 2 after 
reduction of ixazomib to 2.3 mg, then 
reduce ibrutinib dose as per table 8.1. 
If no recovery on the 140 mg dose level, 
then discontinue study therapy and then 
proceed to survival follow-up. 
 
 
Investigations 
 
 
Platelet count decreased 
Grade 4 
If the AE does not return to ≤Grade 1 after 
reduction of ixazomib to 2.3 mg, then 
reduce ibrutinib dose as per table 8.1. 
If no recovery on the 140 mg dose level, 
then discontinue study therapy and then 
proceed to survival follow-up. 
** Use the following to describe actions in the Action column: 
 Omit = The current dose(s) for the specified drug(s) during a cycle is skipped. The 
patient does not make up the omitted dose(s) at a later time. 
 Hold/Delay = The current dose(s) of all drugs during a cycle is delayed. The patient 
does make up the delayed dose(s) when the patient meets the protocol criteria to restart 
drugs. 
 Discontinue = The specified drug(s) are totally stopped. 
Additional Adverse Events: 
 
• 
The dose of ibrutinib will be omitted in case a patient experiences any of the following considered at 
least possibly related to ibrutinib: 
Any Grade ≥3 or greater non-hematological toxicities (other than alopecia or fatigue) with the 
following considerations: 
o Grade 3 nausea, vomiting or diarrhea will be considered significant if they occur despite 
appropriate maximal anti-emetic and/or antidiarrheal therapy. 
o Grade 3 hyperglycemia will be a considered significant if the patient is symptomatic or 
glucose level is >300 mg/ml despite appropriate administration of insulin and/or oral 
antidiabetic agents. 
• 
Ibrutinib will be omitted until the non-hematologic AE recovers to Grade ≤1 or baseline and may be 
restarted at the original dose for the first occurrence. 
• 
Upon each subsequent occurrence, ibrutinib is restarted at the next lower dose (as per Table 8.1) after 
recovery to Grade ≤1 or baseline. 
• 
If Grade ≥3 non-hematological AE or Grade 4 neutropenia and thrombocytopenia occurs at  the lowest 
dose, discontinue ibrutinib treatment. The treatment with ibrutinib should also be discontinued 
entirely if ibrutinib is omitted for 4 consecutive weeks or at the discretion of the Principal 
Investigator for patient safety. Patients may then continue with ixazomib monotherapy. 
• 
Patient will discontinue ibrutinib and enter survival follow-up if AE is grade > 3 bleeding (other 
than bruising) that is probably or definitely attributed to ibrutinib. 
• 
Patients who require a dose reduction during a given cycle will remain at that dose for at least 2 
additional cycles. At the investigator discretion, the dose of ibrutinib may be re-escalated after 2 
cycles of a dose reduction in the absence of a recurrence of the toxicity that led to this reduction. 

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This is particularly reasonable based upon the long-term safety data now available in Ibrutinib treated 
patients that show that most of the hematological or non-hematological AEs either decreased or 
remained stable. 
If multiple AEs are seen, administer the dose based on the greatest reduction required by any 
single AE observed. Dose modifications are for AEs attributed to study treatment only. Dose 
modifications are not required for AEs if they are deemed unlikely or unrelated to study 
treatment. 

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9.0 
Ancillary Treatment/Supportive Care 
9.1 
Full supportive care 
Patients should receive full supportive care while on this study. This includes blood 
product support, antibiotic treatment, and treatment of other newly diagnosed or 
concurrent medical conditions. All blood products and concomitant medications such as 
antidiarrheals, analgesics, and/or antiemetics received from the first day of study 
treatment administration until 30 days after the final dose will be recorded in the medical 
records. 
9.2 
Blood products and growth factors 
Blood products and growth factors should be utilized as clinically warranted and 
following institutional policies and recommendations. The use of growth factors should 
follow published guidelines of the Journal of Clinical Oncology, Volume 33, No 28 
(October 1), 2015: pp. 3199-3212 (WBC growth factors) AND Journal of Clinical 
Oncology, Volume 28, No 33 (November 20), 2010: pp. 4955-5010 
(darbepoetin/epoetin). 
9.3 
Antiemetics 
Antiemetics may be used at the discretion of the attending physician. 
9.4 
Diarrhea 
Diarrhea could be managed conservatively with loperamide. The recommended dose of 
loperamide is 4 mg at first onset, followed by 2 mg every 2-4 hours until diarrhea free 
(maximum 16 mg/day). 
In the event of Grade 3 or 4 diarrhea, the following supportive measures are allowed: 
hydration, octreotide, and antidiarrheals. 
If diarrhea is severe (requiring intravenous rehydration) and/or associated with fever or 
severe neutropenia (Grade 3 or 4), broad-spectrum antibiotics must be prescribed. 
Patients with severe diarrhea or any diarrhea associated with severe nausea or vomiting 
should be hospitalized for intravenous hydration and correction of electrolyte 
imbalances. 
9.5 
Prior or Concomitant treatment: 
• 
Ancillary treatments will be given as medically indicated; they should be recorded in 
the patient’s medical chart and on the appropriate Case Report Form (CRF). 
• 
Radiotherapy may be given concomitantly for control of bone pain BUT NOT for 
lesions considered due to disease progression. If possible, not all evaluable lesions 
should be included in the irradiated field. If this cannot be realized, the patient will be 
removed from the study and will not be evaluable for response from that moment on. 
Any lesion within the irradiated area cannot be used as a parameter for response 
assessment. The area should therefore be as small as possible. 
• 
Patients will not receive other anticancer treatments or other investigational agents 
from start of study treatment until last study treatment. (Hormonal therapy for prior 
history of prostate or breast cancer are allowed). 
• 
Due to potential of increased risk of viral infections, patients must be treated with 
antiviral prophylaxis starting Day 1 of treatment (e.g., acyclovir, valacyclovir or other). 
• 
For Ibrutinib: Avoid co-administration with strong or moderate CYP3A inhibitors 
and consider alternative agents with less CYP3A inhibition. Concomitant use of strong 
CYP3A inhibitors which would be taken chronically (e.g., ritonavir, indinavir, 

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nelfinavir, saquinavir, boceprevir, telaprevir, nefazodone) is not recommended. For 
short-term use (treatment for 7 days or less) of strong CYP3A inhibitors (e.g., 
antifungals and antibiotics) consider interrupting ibrutinib therapy until the CYP3A 
inhibitor is no longer needed. Reduce ibrutinib dose to 140 mg if a moderate CYP3A 
inhibitor must be used (e.g., fluconazole, darunavir, erythromycin, diltiazem, 
atazanavir, aprepitant, amprenavir, fosamprevir, crizotinib, imatinib, verapamil, and 
ciprofloxacin). Patients taking concomitant strong or moderate CYP3A inhibitors 
should be monitored more closely for signs of ibrutinib toxicity. Any strong CYP3A 
inducers 
should 
be 
avoided 
concomitantly 
with 
ibrutinib 
(http://medicine.iupui.edu/clinpharm/ddis/main-table/). Avoid grapefruit and 
Seville oranges during ibrutinib treatment, as these contain moderate inhibitors of 
CYP3A. No dose adjustment is required in combination with mild inhibitors. 
• 
For Ixazomib: 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: Strong CYP3A inducers (rifampin, rifapentine, rifabutin, 
carbamazepine, phenytoin, phenobarbital, and St. John’s Wort). 
• 
Antiplatelet agents and anticoagulants: Warfarin or vitamin K antagonist 
administration should be avoided concomitantly with ibrutinib. Supplements such as 
fish oil and vitamin E preparations should be avoided. Use ibrutinib with caution in 
subjects requiring other anticoagulants or medications that inhibit platelet function. 
Subjects requiring the initiation of therapeutic anticoagulation therapy (e.g., atrial 
fibrillation), consider the risks and benefits of continuing ibrutinib treatment. If 
therapeutic anticoagulation is clinically indicated, treatment with ibrutinib should be 
held and not be restarted until the subject is clinically stable and has no signs of 
bleeding. Subjects should be observed closely for signs and symptoms of bleeding. No 
dose reduction is required when study drug is restarted. 

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10.0 
Adverse Event (AE) Monitoring and Reporting 
The site principal investigator is responsible for reporting any/all serious adverse events to the 
sponsor as described within the protocol, regardless of attribution to study agent or treatment 
procedure. 
The sponsor/sponsor-investigator is responsible for notifying FDA and all participating 
investigators in a written safety report of any of the following: 
• 
Any suspected adverse reaction that is both serious and unexpected. 
• 
Any findings from laboratory animal or in vitro testing that suggest a significant risk for 
human subjects, including reports of mutagenicity, teratogenicity, or carcinogenicity. 
• 
Any findings from epidemiological studies, pooled analysis of multiple studies, or 
clinical studies, whether or not conducted under an IND and whether or not conducted by 
the sponsor, that suggest a significant risk in humans exposed to the drug 
• 
Any clinically important increase in the rate of a serious suspected adverse reaction over 
the rate stated in the protocol or Investigator’s Brochure (IB). 
Summary of SAE Reporting for this study 
(please read entire section for specific instructions): 
WHO: 
WHAT form: 
WHERE to send: 
 
 
 
 
 
 
All sites 
 
 
 
 
 
Pregnancy Reporting 
http://ctep.cancer.gov/protocolDevelopment/electronic_a 
pplications/docs/PregnancyReportFormUpdated.pdf 
Mayo Sites – attach to MCCC 
Electronic SAE Reporting Form 
http://livecycle2.mayo.edu/worksp 
ace/?startEndpoint=MC4158- 
56/Processes/MC4158-56- 
Process.MC4158-56 
Will automatically be sent to 
CANCERCROSAFETYIN@mayo 
.edu and  
RSTP2CSAES@mayo.edu 
Non Mayo sites – complete and 
forward to 
RSTP2CSAES@mayo.edu 
 
 
 
Mayo Clinic 
Sites 
Mayo Clinic Cancer Center SAE Reporting 
Form:http://livecycle2.mayo.edu/workspace/?startEnd 
point=MC4158-56/Processes/MC4158-56- 
Process.MC4158-56 
AND attach 
MedWatch 3500A: 
http://www.fda.gov/downloads/AboutFDA/ReportsMa 
nualsForms/Forms/UCM048334.pdf 
 
 
Will automatically be sent to 
CANCERCROSAFETYIN@mayo 
.edu and  
RSTP2CSAES@mayo.edu 

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Definitions 
Adverse Event 
Any untoward medical occurrence associated with the use of a drug in humans, whether or 
not considered drug related. 
Suspected Adverse Reaction 
Any adverse event for which there is a reasonable possibility that the drug caused the adverse 
event. 
Expedited Reporting 
Events reported to sponsor within 24 hours, 5 days or 10 days of study team becoming aware 
of the event. 
Routine Reporting 
Events reported to sponsor via case report forms 
Events of Interest 
Events that would not typically be considered to meet the criteria for expedited reporting, but 
that for a specific protocol are being reported via expedited means in order to facilitate the 
review of safety data (may be requested by the FDA or the sponsor). 
10.1 
Adverse Event Characteristics 
CTCAE term (AE description) and grade: The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0 will be utilized for AE reporting. All appropriate treatment areas should have access 
to a copy of the CTCAE version 4.0. A copy of the CTCAE version 4.0 can be 
downloaded from the CTEP web site: 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm) 
a. Identify the grade and severity of the event using the CTCAE version 4.0. 
b. Determine whether the event is expected or unexpected (see Section 10.2). 
c. Determine if the adverse event is related to the study intervention (agent, treatment or 
procedure) (see Section 10.3). 
d. Determine whether the event must be reported as an expedited report. If yes, 
determine the timeframe/mechanism (see Section 10.4). 
e. Determine if other reporting is required (see Section 10.5). 
f. Note: All AEs reported via expedited mechanisms must also be reported via the 
routine data reporting mechanisms defined by the protocol (see Sections 10.6 and 
18.0). 
NOTE: A severe AE is NOT the same as a serious AE, which is defined in Section 10.4. 
10.2 
Expected vs. Unexpected Events 
Expected events - are those described within the Section 15.0 of the protocol, the study 
specific consent form, package insert (if applicable), and/or the investigator brochure, (if 
an investigator brochure is not required, otherwise described in the general 
investigational plan). 
Unexpected adverse events or suspected adverse reactions are those not listed in Section 
15.0 of the protocol, the study specific consent form, package insert (if applicable), or in 
the investigator brochure (or are not listed at the specificity or severity that has been 
observed); if an investigator brochure is not required or available, is not consistent with 
the risk information described in the general investigational plan. 

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Unexpected also refers to adverse events or suspected adverse reactions that are 
mentioned in the investigator brochure as occurring with a class of drugs but have not 
been observed with the drug under investigation. 
An investigational agent/intervention might exacerbate the expected AEs associated with a 
commercial agent. Therefore, if an expected AE (for the commercial agent) occurs with a 
higher degree of severity or specificity, expedited reporting is required. 
NOTE: *The consent form may contain study specific information at the discretion of the 
Principal Investigator; it is possible that this information may NOT be included in the 
protocol or the investigator brochure. Refer to protocol or IB for reporting needs. 
10.3 
Attribution to agent(s) or procedure 
When assessing whether an adverse event (AE) is related to a medical agent(s) medical or 
procedure, the following attribution categories are utilized: 
Definite - The AE is clearly related to the agent(s)/procedure. 
Probable - The AE is likely related to the agent(s)/procedure. 
Possible - The AE may be related to the agent(s)/procedure. 
Unlikely - The AE is doubtfully related to the agent(s)/procedure. 
Unrelated - The AE is clearly NOT related to the agent(s)/procedure. 
 
10.31 AEs Experienced Utilizing Investigational Agents and Commercial Agent(s) on the  
SAME (Combination) Arm 
NOTE: When a commercial agent(s) is (are) used on the same treatment arm as 
the investigational agent/intervention (also, investigational drug, biologic, 
cellular product, or other investigational therapy under an IND), the entire 
combination (arm) is then considered an investigational intervention for 
reporting. 
• An AE that occurs on a combination study must be assessed in accordance with the 
guidelines for investigational agents/interventions. 
• An AE that occurs prior to administration of the investigational agent/intervention 
must be assessed as specified in the protocol. In general, only Grade 4 and 5 AEs 
that are unexpected with at least possible attribution to the commercial agent require 
an expedited report, unless hospitalization is required. Refer to Section 10.4 for 
specific AE reporting requirements or exceptions. 
An investigational agent/intervention might exacerbate the expected AEs associated 
with a commercial agent. Therefore, if an expected AE (for the commercial agent) 
occurs with a higher degree of severity or specificity, expedited reporting is 
required. 
• An increased incidence of an expected adverse event (AE) is based on the 
patients treated for this study at their site. A list of known/expected AEs is 
reported in the package insert or the literature, including AEs resulting from a 
drug overdose. 
• Commercial agent expedited reports must be submitted to the FDA via MedWatch 
3500A for Health Professionals (complete all three pages of the form). 
http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM0 
48334.pdf 
10.32 EXPECTED Serious Adverse Events: Protocol Specific Exceptions to Expedited 
Reporting 

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For this protocol only, the following Adverse Events/Grades are expected to occur 
within this population and do not require Expedited Reporting. These events must still 
be reported via Routine Reporting (see Section 10.6).* 
*Report any clinically important increase in the rate of a serious suspected 
adverse reaction (at your study site) over that which is listed in the protocol or 
investigator brochure as an expedited event. 
*Report an expected event that is greater in severity or specificity than expected 
as an expedited event. 
*Specific protocol exceptions to expedited reporting should be reported 
expeditiously by investigators ONLY if they exceed the expected grade of the 
event. 
 
 
 
System Organ Class (SOC) 
 
 
Adverse event/ Symptoms 
CTCAE Grade at which the 
event will not be reported in 
an expedited manner1 
Blood and lymphatic system 
disorders 
Anemia 
≤Grade 4 
Gastrointestinal 
Vomiting 
≤Grade 3 
Nausea 
≤Grade 3 
Diarrhea 
≤Grade 3 
General disorders and 
administrations site conditions 
Fatigue 
≤Grade 3 
Investigations 
Lymphocyte count decreased 
≤Grade 4 
Neutrophil count decreased 
≤Grade 4 
Platelet count decreased 
≤Grade 4 
White blood cell count decreased 
≤Grade 4 
1 These exceptions only apply if the adverse event does not result in hospitalization. If the adverse 
event results in hospitalization, then the standard expedited adverse events reporting 
requirements must be followed. 
The following hospitalizations are not considered to be SAEs because there is no “adverse event” 
(i.e., there is no untoward medical occurrence) associated with the hospitalization: 
● Hospitalizations for respite care 
● Planned hospitalizations required by the protocol 
● Hospitalization planned before informed consent (where the condition requiring the hospitalization 
has not changed post study drug administration) 
● Hospitalization for elective procedures unrelated to the current disease and/or treatment on this trial 
● Hospitalization for administration of study drug or insertion of access for administration of study 
drug 
● Hospitalization for routine maintenance of a device (e.g., battery replacement) that was in place 
before study entry 
● Hospitalization, or other serious outcomes for signs and symptoms of progression of the cancer. 
 
10.4 
Expedited Reporting Requirements for IND Agents 
10.41 Phase 1 and Early Phase 2 Studies: Expedited Reporting Requirements for 
Adverse Events that Occur on Studies under an IND within 30 Days of the 
Last Administration of the Investigational Agent/Intervention 1, 2 

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FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE: Investigators MUST immediately report to the sponsor ANY Serious Adverse Events, whether or not they 
are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes: 
1) 
Death 
2) 
A life-threatening adverse event 
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 
hours 
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions 
5) 
A congenital anomaly/birth defect. 
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization 
may be considered serious when, based upon medical judgment, they may jeopardize the patient or subject 
and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. (FDA, 
21 CFR 312.32; ICH E2A and ICH E6). 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the sponsor within 
the timeframes detailed in the table below. 
Hospitalization 
Grade 1 and Grade 2 Timeframes 
Grade 3-5 
Timeframes 
Resulting in 
Hospitalization 
≥24 hrs 
 
7 Calendar Days 
 
 
24-Hour 3 Calendar 
Days 
Not resulting in 
Hospitalization 
≥24 hrs 
 
Not required 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 3 Calendar Days” - The AE must initially be reported within 24 hours of learning of the AE, 
followed by a complete expedited report within 3 calendar days of the initial 24-hour report. 
o “7 Calendar Days” - A complete expedited report on the AE must be submitted within 7 calendar days 
of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows: 
Expedited 24-hour notification followed by complete report within 3 calendar days for: 
• All Grade 3, 4, and Grade 5 AEs 
Expedited 7 calendar day reports for: 
• Grade 2 AEs resulting in hospitalization or prolongation of hospitalization 
2 For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, 
rounded UP to the nearest whole day, after the agent/intervention was last administered. Footnote “1” above 
applies after this reporting period. 
Effective Date: May 5, 2011 
 
10.42 General reporting instructions 
The Mayo IND and/or MCCC Compliance will assist the sponsor-investigator in 
the processing of expedited adverse events and forwarding of suspected 
unexpected serious adverse reactions (SUSARs) to the FDA and IRB. 
Use Mayo Expedited Event Report form 
http://livecycle2.mayo.edu/workspace/?startEndpoint=MC4158- 
56/Processes/MC4158-56-Process.MC4158-56 and US FDA MedWatch form 
http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM0 
48334.pdf for investigational agents or commercial/investigational agents on the 
same arm.

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Site CRA to Contact (Takeda): 
SAE and Pregnancy Reporting Contact Information 
Fax Number: 1-800-963-6290 
Email: TakedaOncoCases@cognizant.com 
Suggested Reporting Form: 
• 
SAE Report Form (provided by Takeda) 
• 
US FDA MedWatch 3500A: 
http://www.fda.gov/Safety/MedWatch/HowToReport/DownloadForms/defau 
lt.htm 
• 
Any other form deemed appropriate by the sponsor-investigator 
 
 
10.43 Reporting of re-occurring SAEs 
ALL SERIOUS adverse events that meet the criteria outlined in table10.41 
MUST be immediately reported to the sponsor within the timeframes detailed in 
the corresponding table. This reporting includes, but is not limited to SAEs that 
re-occur again after resolution. 
10.5 
Other Required Reporting 
10.51 Unanticipated Problems Involving Risks to Subjects or Others (UPIRTSOS) 
Unanticipated Problems Involving Risks to Subjects or Others (UPIRTSOS) in 
general, include any incident, experience, or outcome that meets all of the 
following criteria: 
1. Unexpected (in terms of nature, severity, or frequency) given (a) the research 
procedures that are described in the protocol-related documents, such as the 
IRB-approved research protocol and informed consent document; and (b) the 
characteristics of the subject population being studied; 
2. Related or possibly related to participation in the research (in this guidance 
document, possibly related means there is a reasonable possibility that the 
incident, experience, or outcome may have been caused by the procedures 
involved in the research); and 
3. Suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was 
previously known or recognized. 
Some unanticipated problems involve social or economic harm instead of the 
physical or psychological harm associated with adverse events. In other cases, 
unanticipated problems place subjects or others at increased risk of harm, but no 
harm occurs. 
Note: If there is no language in the protocol indicating that pregnancy is not 
considered an adverse experience for this trial, and if the consent form does not 
indicate that subjects should not get pregnant/impregnate others, then any 
pregnancy in a subject/patient or a male patient’s partner (spontaneously 
reported) which occurs during the study or within 120 days of completing the 
study should be reported as a UPIRTSO. 

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Mayo Clinic Cancer Center (MCCC) Institutions: 
If the event meets the criteria for IRB submission as a Reportable 
Event/UPIRTSO, provide the appropriate documentation and use the Mayo 
Clinic Cancer Center Expedited Event Report form 
http://livecycle2.mayo.edu/workspace/?startEndpoint=MC4158- 
56/Processes/MC4158-56-Process.MC4158-56, to submit to 
CANCERCROSAFETYIN@mayo.edu. The Mayo Clinic Compliance Unit will 
review and process the submission to the Mayo Clinic IRB and work with the 
IND Coordinator for submission to FDA. 
10.52 Death 
Note: A death on study requires both routine and expedited reporting 
regardless of causality, unless as noted below. Attribution to treatment or other 
cause must be provided. 
Any death occurring within 30 days of the last dose, regardless of attribution to 
an agent/intervention under an IND requires expedited reporting within 24- 
hours. 
Any death occurring greater than 30 days with an attribution of possible, 
probable, or definite to an agent/intervention under an IND requires expedited 
reporting within 24-hours. 
Reportable categories of Death 
• 
Death attributable to a CTCAE term. 
• 
Death Neonatal: A disorder characterized by cessation of life during the 
first 28 days of life. 
• 
Death NOS: A cessation of life that cannot be attributed to a CTCAE term 
associated with Grade 5. 
• 
Sudden death NOS: A sudden (defined as instant or within one hour of the 
onset of symptoms) or an unobserved cessation of life that cannot be 
attributed to a CTCAE term associated with Grade 5. 
• 
Death due to progressive disease should be reported as Grade 5 
“Neoplasms benign, malignant and unspecified (including cysts and 
polyps) – Other (Progressive Disease)” under the system organ class 
(SOC) of the same name. Evidence that the death was a manifestation of 
underlying disease (e.g., radiological changes suggesting tumor growth or 
progression: clinical deterioration associated with a  disease  process) 
should be submitted. 
10.53 Secondary Malignancy 
• 
A secondary malignancy is a cancer caused by treatment for a previous 
malignancy (e.g., treatment with investigational agent/intervention, radiation 
or chemotherapy). A secondary malignancy is not considered a metastasis of 
the initial neoplasm. 
• 
All secondary malignancies that occur following treatment with an agent under 
an IND will be reported. Three options are available to describe the event: 
o Leukemia secondary to oncology chemotherapy (e.g., Acute Myeloctyic 
Leukemia [AML]) 
o Myelodysplastic syndrome (MDS) 

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o Treatment-related secondary malignancy 
• 
Any malignancy possibly related to cancer treatment (including AML/MDS) 
should also be reported via the routine reporting mechanisms outlined in each 
protocol. 
10.54 Second Malignancy 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is 
NOT a metastasis from the initial malignancy). Second malignancies require ONLY 
routine reporting unless otherwise specified. 
10.55 Pregnancy, Fetal Death, and Death Neonatal 
If a female 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 
Takeda Department of Pharmacovigilance or designee. 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 Takeda Department of Pharmacovigilance or 
designee (see Section 8.2). Every effort should be made to follow the pregnancy 
for the final pregnancy outcome. 
Prior to obtaining private information about a pregnant woman and her infant, the 
investigator must obtain consent from the pregnant woman and the newborn 
infant’s parent or legal guardian before any data collection can occur. A consent 
form will need to be submitted to the IRB for these patients if a pregnancy 
occurs. If informed consent is not obtained, no information may be collected. 
In cases of fetal death, miscarriage or abortion, the mother is the patient. In cases 
where the child/fetus experiences an SAE other than fetal death, the child/fetus is 
the patient. 
Suggested Pregnancy Reporting Form: 
Pregnancy Report Form (provided by Takeda) 
NOTE: When submitting Mayo Expedited Adverse Event Report reports for 
“Pregnancy”, “Pregnancy loss”, or “Neonatal loss”, the potential risk of exposure 
of the fetus to the investigational agent(s) or chemotherapy agent(s) should be 
documented in the “Description of Event” section. Include any available medical 
documentation. Include this form: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/Pregna 
ncyReportFormUpdated.pdf 
10.551 
Pregnancy 
Pregnancy should be reported in an expedited manner as Grade 3 
“Pregnancy, puerperium and perinatal conditions - Other 
(pregnancy)” under the Pregnancy, puerperium and perinatal 
conditions SOC. Pregnancy should be followed until the outcome is 
known. 
10.552 
Fetal Death 
Fetal death is defined in CTCAE as “A disorder characterized by death 
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respiration, heartbeat, or definite movement of a voluntary muscle after 
expulsion from the uterus, without possibility of resuscitation.” 
Any fetal death should be reported expeditiously, as Grade 4 
“Pregnancy, puerperium and perinatal conditions - Other 
(pregnancy loss)” under the Pregnancy, puerperium and perinatal 
conditions SOC. 
10.553 
Death Neonatal 
Neonatal death, defined in CTCAE as “A disorder characterized by 
cessation of life occurring during the first 28 days of life” that is felt by 
the investigator to be at least possibly due to the investigational 
agent/intervention, should be reported expeditiously. 
A neonatal death should be reported expeditiously as Grade 4 
“General disorders and administration - Other (neonatal loss)” 
under the General disorders and administration SOC. 
10.6 
Required Routine Reporting 
10.61 Baseline and Adverse Events Evaluations 
Pretreatment symptoms/conditions to be graded at baseline and AEs to be graded 
at each evaluation. 
 
Grading is per CTCAE v4.0 unless alternate grading is indicated in the table below: 
 
 
System Organ Class 
 
Adverse event/Symptoms 
 
Baseline 
Each 
evaluation 
Blood and lymphatic 
system disorders 
Anemia 
X 
X 
 
Gastrointestinal disorders 
# of stools 
X 
 
Diarrhea 
 
X 
Nausea 
 
X 
Vomiting 
 
X 
General disorders and 
administration site 
conditions 
 
Fatigue 
 
X 
 
X 
Investigations 
Neutrophil count decreased 
X 
X 
Platelet count decreased 
X 
X 
Nervous system disorders 
Peripheral motor neuropathy 
X 
X 
Peripheral sensory neuropathy 
X 
X 
10.62 Submit via appropriate MCCC Case Report Forms (i.e., paper or electronic, as 
applicable) the following AEs experienced by a patient: 
- 
Grade 2 AEs deemed possibly, probably, or definitely related to the study 
treatment or procedure. 
- 
Grade 3 and 4 AEs regardless of attribution to the study treatment or procedure. 
- 
Grade 5 AEs (Deaths) 
- 
Any death within 30 days of the patient’s last study treatment or procedure 
regardless of attribution to the study treatment or procedure. 
- 
Any death more than 30 days after the patient’s last study treatment or procedure 
that is felt to be at least possibly treatment related must also be submitted as a 
Grade 5 AE, with a CTCAE type and attribution assigned. 

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10.7 
Late Occurring Adverse Events 
Refer to the instructions in the Forms Packet (or electronic data entry screens, as 
applicable) regarding the submission of late occurring AEs following completion of the 
Active Monitoring Phase (i.e., compliance with Test Schedule in Section 4.0). 
10.8 
Takeda Additional Event Reporting Instructions 
10.81 Special reporting requirements for Takeda (Pharmaceutical Sponsor) 
Serious Adverse Event Definition 
 
Serious AE (SAE) means any untoward medical occurrence that at any dose: 
 
 Results in death. 
 Is life-threatening (refers to an AE in which the patient was at risk of death at the 
time of the event. It does not refer to an event which hypothetically might have 
caused death if it were more severe). 
 Requires inpatient hospitalization or prolongation of an existing hospitalization (see 
clarification in the paragraph below on planned hospitalizations). 
• 
Results in persistent or significant disability or incapacity. (Disability is defined as a 
substantial disruption of a person’s ability to conduct normal life functions). 
 Is a congenital anomaly/birth defect. 
 Is a medically important event. This refers to an AE that may not result in death, be 
immediately life threatening, or require hospitalization, but may be considered 
serious when, based on appropriate medical judgment, may jeopardize the patient, 
require medical or surgical intervention to prevent 1 of the outcomes listed above, or 
involves suspected transmission via a medicinal product of an infectious agent. 
Examples of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or convulsions that do 
not result in inpatient hospitalization, or the development of drug dependency or drug 
abuse; any organism, virus, or infectious particle (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. 

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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. 
 
AEs which are serious must be reported to Takeda Pharmacovigilance (or designee) from 
the first dose of study drug through 30 days after administration of the last dose 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 Takeda 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 Takeda 
Pharmacovigilance (or designee). 
 
Planned hospital admissions or surgical procedures for an illness or disease that existed 
before the patient was enrolled in the trial are not to be considered AEs unless the 
condition deteriorated in an unexpected manner during the trial (e.g., surgery was 
performed earlier or later than planned). All SAEs should be monitored until they are 
resolved or are clearly determined to be due to a patient’s stable or chronic condition or 
intercurrent illness(es). 
 
Since this is an investigator-initiated study, the principal investigator, Asher Chanan- 
Khan, 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 in English to Takeda Pharmacovigilance (or designee): 
 
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 Takeda 
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 

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• 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 Takeda. 
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 Takeda 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 Takeda 
Pharmacovigilance, unless otherwise agreed between the sponsor-investigator and sub- 
investigator(s). 
Relationship to all study drugs for each SAE will be determined by the 
investigator or sub-investigator by responding yes or no to the question: Is there a 
reasonable possibility that the AE is associated with the study drug(s)? 
Sponsor-investigator must also provide Takeda 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. 
 
10.82 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 Takeda and report the event. Whenever possible, the 
associated product should be maintained in accordance with the label instructions 
pending further guidance from a Takeda Quality representative. 
 
For Product Complaints 
• 
Phone: 1-844-N1-POINT (1-844-617-6468) 
• 
E-mail: GlobalOncologyMedinfo@takeda.com  
• 
FAX: 1-800-881-6092 
• 
Hours: Mon-Fri, 9 a.m. – 7 p.m. ET 
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 Takeda 
Pharmacovigilance 
 
 
11.0 
Treatment Evaluation/Measurement of Effect 
11.1 
Terms and definitions 
 
• 
M-protein: synonyms include M-spike, monoclonal protein and myeloma protein, 
paraprotein, M-component. 

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Serum M-protein level is quantitated using densitometry on SPEP except in cases where 
the SPEP is felt to be unreliable. 
• M-proteins migrating in the β-region (usually IgA M-proteins) 
• Cases in which the M-protein is so large and narrow on agarose (some 
specimens >4 g/dL) that they underestimate the actual immunoglobulin level 
(by greater than 1500 mg/dL) due to technical staining properties of the 
agarose gel. 
• Cases in which there are multiple peaks of same M-protein (aggregates or 
dimers). 
 
If SPEP is not available or felt to be unreliable (above examples) for routine M-protein 
quantitation, then quantitative immunoglobulin levels derived from nephelometry or 
turbidometry can be accepted, with the exception that quantitative IgG may not be used. 
However, this must be explicitly reported at baseline, and only nephelometry can be used 
for that patient to assess response. SPEP derived M-protein values and quantitative 
nephelometric immunoglobulin values cannot be used interchangeably. 
 
Urine M-protein measurement is estimated using 24-h UPEP only. Random or 24 h urine 
tests measuring kappa and lambda light chain levels are not reliable and are not 
recommended. 
 
• 
FLC estimation is currently carried out using the serum FLC assay (Freelite, The 
Binding Site Limited, UK). Patients with kappa/lambda FLC ratio <0.26 are defined as 
having monoclonal lambda FLC and those with ratios >1.65 as having a monoclonal 
kappa FLC. The monoclonal light chain isotype is considered the involved FLC isotype, 
and the opposite light chain type as the uninvolved FLC type. 
 
Response terms: The following response terms will be used: complete response (CR), Very 
Good Partial Response (VGPR), Partial Response (PR), Minor Response (MR), Stable Disease 
(SD), and Progressive Disease (PD). (APPENDIX III) 
 
An objective status of CR is defined as (See Appendix III): 
• 
Absence of serum monoclonal IgM protein by immunofixation 
• 
Normal serum IgM level 
• 
Complete resolution of extramedullary disease, i.e. lymphadenopathy and splenomegaly 
if present at baseline 
• 
Morphologically normal bone marrow aspirate and trephine biopsy (ref: Owen 2013) 
• 
No signs or symptoms attributable to WM 
 
12.0 
Descriptive Factors 
12.1 
Prior ibrutinib treatment at the time of registration: yes vs. no. 
 
13.0 
Treatment/Follow–up Decision at Evaluation of Patient 
 
 
Reason Off Treatment (from the Off Treatment Form) 
Go to CFU, SFU, or end 
folder rollout 
1 = Treatment (Intervention) Completed Per Protocol Criteria 
CFU 

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2 = Patient Withdrawal/Refusal After Beginning Protocol Therapy 
(Intervention) 
SFU 
3 = Adverse Events/Side Effects/Complications 
SFU 
4 = Disease Progression, Relapse During Active Treatment (Intervention) 
SFU 
5 = Alternative Therapy 
SFU 
6 = Patient Off-Treatment (Intervention) For Other Complicating Disease 
SFU 
7 = Death On Study 
No follow-up 
8 = Other 
SFU 
10 = Disease Progression Before Active Treatment (Intervention) 
No follow-up 
24 = Patient Withdrawal/Refusal Prior To Beginning Protocol Therapy 
(Intervention) 
No follow-up 
13.1 
Continuation of treatment 
Patients who are CR, VGPR, PR, MR, or SD will continue treatment per protocol. 
13.2 
Progressive disease (PD) 
Treatment may continue as per treatment schema until disease progression as long as the 
patient continues to respond and does not have any unacceptable toxicity. Patients who 
develop PD while receiving therapy will go to the survival follow-up phase. 
13.3 
Off protocol treatment 
Patients who go off protocol treatment for the following reasons will go to the survival 
follow-up phase per Section 4.2: 
 
Progressive Waldenstrom's macroglobulinemia at any time on the clinical trial 
 
Patient requests to discontinue study treatment 
 
Patient develops an intercurrent illness that precludes further participation, or 
requires a prohibited concomitant treatment 
 
The Investigator withdraws the patient in the patient’s best interests 
 
Administrative reasons (e.g., the patient is transferred to hospice care) 
 
An adverse event, which in the opinion of the Investigator, precludes further trial 
participation 
 
A dose omission of more than 28 days beyond the scheduled date of retreatment 
for ixazomib and ibrutinib 
 
All attempts should be made to complete the End of Treatment procedures if a patient 
goes off treatment early. 
13.4 
Clinical follow-up 
If the patient has achieved CR, VGPR, PR, MR, or SD after the completion of 24 cycles 
of study treatment, the patient will be observed every 3 months for 2 years. After the 
completion of clinical follow-up, the patient will go to survival follow-up per Section 4.2 
of the protocol. If the patient has progressive disease or receives subsequent treatment 
for Waldenstrom macroglobulinemia at any time while in clinical follow-up, the patient 
will go directly to survival follow-up. 
13.5 
Ineligibles 
A patient is deemed ineligible if after registration, it is determined that at the time of 
registration, the patient did not satisfy each and every eligibility criteria for study entry. 
The patient may continue treatment off-protocol at the discretion of the physician as long 
as there are no safety concerns, and the patient was properly registered. The patient will 
go directly to the event-monitoring phase of the study (or off study, if applicable). 
• 
If the patient received treatment, all data up until the point of confirmation of 

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ineligibility must be submitted. Survival follow-up will be required per the protocol. 
• 
If the patient never received treatment, on-study material and the End of Active 
Treatment/Cancel Notification Form must be submitted. No further data submission 
is necessary. 
13.6 
Major violation 
A patient is deemed a major violation, if protocol requirements regarding treatment in 
cycle 1 of the initial therapy are severely violated that evaluability for primary end point 
is questionable. All data up until the point of confirmation of a major violation must be 
submitted. The patient will go directly to the survival follow-up phase of the study. The 
patient may continue treatment off-protocol at the discretion of the physician as long as 
there are no safety concerns, and the patient was properly registered. Survival follow-up 
will be required per Section 4.2 of the protocol. 
13.7 
Cancel 
A patient is deemed a cancel if he/she is removed from the study for any reason before 
any study treatment is given. On-study material and the End of Active Treatment/Cancel 
Notification Form must be submitted. No further data submission is necessary. 

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14.0 
Body Fluid Biospecimens 
14.1 
Summary Table of Research Blood and Body Fluid Specimens to be collected for this Protocol 
 
 
 
Research (Section 
for more 
information) 
 
 
Specimen Purpose 
(check all that 
apply) 
 
 
Mandatory 
or Optional 
 
 
Blood or Body 
Fluid being 
Collected 
 
Type of 
Collection 
Tube (color 
of tube top) 
Volume to 
collect per 
tube (# of 
tubes to be 
collected) 
 
 
 
Baseline 
 
 
During 
course of 
treatment 
 
 
End of 
Treatment 
 
Process 
at site? 
(Yes or 
No) 
 
Temperature 
Conditions 
for Storage 
/Shipping 
 
 
BTK Signalosome 
☒ Correlative 
☐ Eligibility 
Confirmation 
☐ Banking 
☐ Other (specify) 
 
 
Mandatory 
 
 
Bone marrow 
aspirate 
 
 
Green Top 
tube 
 
 
5 mL (2) 
 
Baseline/ after 
registration but 
prior to 
treatment 
After 
cycle 1 
and then 
as    
clinically 
indicated* 
 
Confirmed 
disease 
progression 
 
 
No 
 
 
Refrigerate 
 
Effect of treatment 
on          
microenvironment 
☒ Correlative 
☐ Eligibility 
Confirmation 
☐ Banking 
☐ Other (specify) 
 
 
Mandatory 
 
 
Bone marrow 
aspirate 
 
 
Green Top 
tube 
 
 
5 mL (1) 
 
Baseline/after 
registration but 
prior to 
treatment 
After 
cycle 1 
and then 
as 
clinically 
indicated* 
 
Confirmed 
disease 
progression 
 
 
No 
 
 
Refrigerate 
 
 
Effect of treatment 
on          
microenvironment 
 
 
☒ Correlative 
☐ Eligibility 
Confirmation 
☐ Banking 
☐ Other (specify) 
 
 
 
 
Mandatory 
 
 
 
Peripheral 
Blood 
 
 
 
Green Top 
tube 
 
 
 
5 mL (2) 
 
 
Baseline/ 
after registration 
but prior to 
treatment 
End of 
every 3 
cycles 
while 
patient 
continues 
on   
treatment* 
* 
 
 
 
Confirmed 
disease 
progression 
 
 
 
No 
 
 
 
Refrigerate 
 
* Additional samples to be drawn if a bone marrow is done for confirmation of response or as otherwise clinically indicated. 
**Additional samples to be drawn in-between every 3 cycles in case there is confirmed disease progression 

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14.2 
Shipping and Handling 
14.21 Kits will be used for this study. 
14.211 Kits will be supplied by the Biospecimen Accessioning and Processing 
(BAP). 
Mayo Biorepositories 
BAP/PRC FLA 4500 San Pablo Rd 
Campus Support Center 150 
Jacksonville, FL 32224 
14.212 The kit contains supplies and instructions for collecting, processing and 
shipping specimens. 
14.213 Participating institutions may obtain kits by using the Supply Order Form 
and sending it to the email on the form. Because we are charged for all 
outgoing kits, a small, but sufficient, supply of the specimen collection 
kits should be ordered prior to patient entry. Supply Order Forms must 
be filled in completely and legibly for quick processing. 
14.214 Kits will be sent via FedEx® Ground at no additional cost to the 
participating institutions. Allow at least two weeks to receive the kits. 
14.215 Kits will not be sent via rush delivery service unless the participating 
institution provides their own Fed Ex® account number or alternate 
billing number for express mail. Cost for rush delivery of kits will not 
be covered by the study. 
14.216 All specimens must be collected and shipped Monday – Thursday 
ONLY. 
14.41 Shipping Specimens 
1. Biological samples (ie, plasma) should be shipped refrigerate. Samples should 
be shipped only on Monday, Tuesday, or Wednesday, and at least 2 days prior to 
a national holiday, in order to minimize the possibility of samples in transit over 
a weekend or holiday. If duplicate samples are to be shipped, send SET 1 
samples and await confirmation of arrival before shipping the duplicate SET 2 
samples. 
 
2. Before shipping, make sure the sample tubes are tightly sealed. Separate each 
subject’s samples as follows: 
 
3. Separate the duplicate SET 2 samples from the SET 1 samples. 
 
4. Place SET 1 samples for each subject into self-sealing bag (eg, Ziploc®) 
containing additional absorbent material. 
 
5. Using a permanent marker, write the 4-digit randomization sequence number, 
sample matrix (ie, plasma), analyte (Ixazomib), number of samples, and “SET 1” 
on each self-sealing bag. 
 
6. Place the bags of individual subject’s samples into a larger plastic bag so that 
samples are double bagged. Duplicate SET 2 samples should be returned to the 
refrigerator for storage. Repeat steps 3 through 6 above when preparing duplicate 
samples for shipment, except self-sealing bags should be marked “SET 2.” 
 

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An inventory of individual samples should accompany each shipment and 
should include the Sponsor’s name, study drug (ixazomib), protocol number 
(MC178B), investigator’s name, sample type (ie, plasma), randomization 
sequence number, cycle, profile day and scheduled time point, and intended 
sample storage conditions. When duplicate SET 2 samples are being shipped, 
make a copy of the original SET 1 sample inventory and mark as “SET 2.” 
Place the inventory paperwork into a large self-sealing bag. SET 1 samples will 
be shipped refrigerate, followed by shipment of duplicate SET 2 samples after 
SET 1 samples have been received by the analytical laboratory. 
 
7. For sample packing, utilize refrigerate packs appropriately. Use wypall or 
other material to insulate the double-bagged samples from direct contact with the 
cool pack. Place the sample bundles into a cardboard box (or other suitable 
container) and fill the excess space with packing materials. 
 
8. Place the inventory paperwork (in a large self-sealing bag) on top of the 
refrigerate pack in the styrofoam container. Place the lid on the styrofoam 
container and seal completely with strapping tape. Place the styrofoam container 
in a cardboard shipping carton and seal securely with strapping tape. 
 
9. Mark the outside of shipping carton(s) with a tally number (eg, 1 of 5, 2 of 5). 
 
10. Affix the appropriate address label to each shipping carton and ship to  
Chanan-Khan laboratory 
Attn: Aneel Paulus, M.D. 
Griffin Building 164 
4500 San Pablo Rd. 
Jacksonville, FL 32224 
14.3 
Background and Methodology 
14.22 To determine the role of members of the BTK signalosome in achievement or 
lack thereof of response to ibrutinib and ixazomib: The variability in extent of 
response to a therapeutic agent may suggest underlying adaptability of the WM 
clone through components of the BTK signalosome. Patients with B-cell 
malignancies treated with ibrutinib demonstrate upregulation of p-Akt and p- 
Erk (downstream mediators of BTK) in some (but not all) cases, suggesting that 
these pathways may contribute to survival of the malignant clone. It was also 
concluded in this work that these cells might not be dependent upon the 
proximal BTK pathways mediated apoptosis and thus, resistant to killing by 
ibrutinib. To address this question we will establish the profile of BTK 
signalosome for each patient through determination of the mRNA (RT- 
PCR/nanostring assay; whole exome sequencing (WES), transcriptome 
analysis) and protein expression (western blot analysis) of members of the BTK 
signaling pathway and look for associations between this and eventual response 
(or lack thereof) to the treatment. The said tests will be done analyzing the 
lymphoplasmacytic cells enriched from the bone marrow samples collected at 
baseline, and then at the time of disease progression. This will help explore 
mechanisms of acquired resistance to ibrutinib when used with ixazomib. We 
will also look for pAKT, pS6 and pERK as indirect pharmacodynamic 
biomarkers analyzed in patient’s PBMC collected as a peripheral blood sample. 

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14.23 To explore biologic effects of Ibrutinib and Ixazomib on microenvironment in 
WM and correlate with response to treatment: In cancer redirection of host 
immunity from a predominant Th2 to Th1 response can deliver antitumor 
response. Ibrutinib can bind to ITK, a member of the TEC-kinase family, which 
mediates TCR signaling through PLCg, NFAT, NF-kappaB and MAPK. This 
results in activation and proliferation of CD8+ cells. Our hypothesis is that 
ibrutinib with ixazomib alters the Th2:Th1 balance in the blood and bone marrow 
microenvironment, skewing towards a more Th1 profile and this may translate 
into clinical efficacy. We further hypothesize that the robustness of the Th1 
response will direct this combination’s depth of response. We will assess this in 
bone marrow samples comparing the baseline sample to one collected after 1 
cycle of treatment with ibrutinib and ixazomib using the MultiOmyx Tumor 
Infiltrating Lymphocytes panel for T helper (CD4+), Treg (FOXP3+), T 
cytotoxic (CD8+), B cells (CD20+), macrophage (CD68+), NK cells (CD56+), 
immunosuppression (PD-L1), CD138+, CD38+, ITK and BTK. Furthermore, 
BTK/ITK occupancy by Ibrutinib has been associated with response rates in other 
B-cell malignancies where this is an effective agent (CLL) but this has never been 
tested in WM. This assay will be performed to assess target coverage in bone 
marrow samples obtained from patients at the end of 1 cycle of treatment with 
Ibrutinib and Ixazomib. In addition, PBMC samples (2 ml of whole blood with 
heparin) from baseline and after 1 cycle of treatment will be assessed for: 
• 
Th1 cells (live+, CD19-, CD3+, CD4+, CD8-, IFNg+) 
• 
Th2 cells (live+, CD19-, CD3+, CD4+, CD8-, IL4+) 
• 
Th17 cells (live+, CD19-, CD3+, CD4+, CD8-, IL17+) 
• 
Treg cells (live+, CD19-, CD14-, CD3+, CD4+, CD25+, CD127-, 
FOXP3, CCR4+). 

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15.0 
Drug Information 
IND number (pending) 
• 
Investigator brochure and Drug order contact: 
Takeda Pharmaceuticals International Co 
Rebecca Kaganov 
Phone: (617) 679-7138 
Email address: Rebecca.Kaganov@takeda.com 
15.1 
Ixazomib (MLN9708, Ninlaro®) 
15.11 Background: Ixazomib (MLN9708) is a second-generation small molecule 
inhibitor of the 20S proteasome that is under development for the treatment of 
multiple myeloma, other plasma cell dyscrasias, nonhematologic 
malignancies, and pediatric acute lymphoblastic leukemia and lymphoma. 
Ixazomib (MLN2238) refers to the biologically active, boronic acid form of the 
drug substance, ixazomib citrate (MLN9708). The transition to MLN2238 occurs 
in any aqueos system. 
 
15.12 Formulation: The ixazomib (MLN9708) capsule drug product formulation 
consists of drug substance, microcrystalline cellulose, talc, and magnesium 
stearate. Seven different capsule strengths are manufactured: 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 ixazomib (the active boronic acid). Ixazomib (MLN9708) capsules are 
individually packaged in blisters. 
 
Matching placebo capsules have been manufactured for the 2.3, 3.0, 4.0, and 5.5 
mg ixazomib (MLN9708) capsules. The placebo capsules contain 
microcrystalline cellulose, talc, and magnesium stearate and are identical in color 
and size to the corresponding active dose. 
 
15.13 Preparation, Storage: Ixazomib capsules (0.2 mg, 0.5 mg, 
2 mg), individually packaged in blisters, can be stored at 2ºC to 8ºC 
or “Do not store above 25°C. Do not freeze." Ixazomib capsules (2.3 mg, 3 mg, 4 
mg, and 5.5 mg), individually packaged in blisters can be stored at “2°C - 8°C” 
or “Do not store above 30°C. Do not freeze." 
 
Ixazomib that is dispensed to the patient for take-home dosing should remain in 
the blister packaging until the point of use. The investigative site is responsible 
for providing the medication to the patient in units that comprise the correct daily 
dose configurations. Capsules should remain in the blisters until the point of use. 
Ixazomib capsules must be administered as intact capsules and must not be 
opened or manipulated in any way. Comprehensive instructions should be 
provided to the patient in order to ensure compliance with dosing procedures. 
Patients will be instructed to store the medication in the refrigerator until the time 
of use. Reconciliation will occur accordingly when the patient returns for their 
next cycle of therapy. Any extremes in temperature should be reported as an 
excursion and will be managed on a case by case basis. Returned unused 
capsules should be discarded in a proper biohazard container. 

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Ixazomib is an anticancer drug. As with other potentially toxic compounds, 
caution should be exercised when handling ixazomib. It is recommended to wear 
gloves and protective garments during preparation when dispensed in clinic. 
Please refer to published guidelines regarding the proper handling and disposal of 
anticancer agents. 
 
15.14 Administration: Ixazomib (MLN9708) capsules must be administered as intact 
capsules and are not intended to be opened or manipulated in any way. Capsules 
should be taken on an empty stomach with approximately 8 oz (1 cup) of water at 
least 1 hour before or at least 2 hours after food. 
 
Ixazomib should not be taken if the patient has had a serious allergic reaction to 
boron or boron containing products. 
 
Health care providers should instruct patients and caregivers that only one dose 
of ixazomib should be taken at a time, and only at the prescribed interval (e.g. 
one capsule, once a week, on Days 1,8, and 15 of a 28-day cycle). The 
importance of carefully following all dosage instructions should be discussed 
with patients starting treatment. 
 
15.15 Pharmacokinetics Information 
a) Absorption: After oral dosing, ixazomib is rapidly absorbed with a median 
Tmax of 1 hour. 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. The absolute oral bioavailability of ixazomib is ~58%.  
A high-fat meal decreased both the rate and extent of absorption. Therefore, 
ixazomib should be administered on an empty stomach. 
b) Distribution: The steady state volume of distribution is large and is estimated 
to be 543 L.. Protein binding is 99% to plasma proteins and the extent of 
binding is not altered by severe renal impairment, moderate-severe hepatic 
impairment. 
c) Metabolism: Metabolism is the primary route for elimination of ixazomib by 
both CYP and non-CYP enzymes. CYP3A4 and 1A2 comprise the major CYP 
isozymes that contribute to Ixazomib metabolism. 
d) Excretion: The mean terminal half-life is 9.5 days. Renal elimination is a 
minor clearance pathway for ixazomib. Dosing adjustment is not required in 
patients with mild and moderate renal impairment in studies. However, in a 
dedicated renal impairment study (C16015), unbound AUC0-last was 38% higher 
in patients with severe renal impairment or end-stage renal disease (ESRD) 
requiring dialysis as compared to patients with normal renal function. 
Accordingly, a reduced starting dose of ixazomib is recommended in patients 
with severe renal impairment and ESRD requiring dialysis. Ixazomib is not 
dialyzable and therefore can be administered without regard to the timing of 
dialysis.  Unbound systemic exposures of ixazomib are 27% higher in patients 
with moderate or severe hepatic impairment as compared to patients with normal 
hepatic function. A reduced starting dose of ixazomib is recommended for 
patients with moderate or severe hepatic impairment. 
 
15.16 Potential Drug Interactions 
The PK of ixazomib was similar with and without coadministration of 

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clarithromycin, a strong CYP3A inhibitor, and therefore no dose adjustment is 
necessary when ixazomib is administered with CYP3A inhibitors. In the 
population PK analysis, coadministration of strong CYP1A2 inhibitors did not 
affect ixazomib clearance. Thus, no dose adjustment is required for patients 
receiving strong CYP1A2 inhibitors. In a clinical rifampin DDI study, ixazomib 
Cmax and AUC0-last were reduced in the presence of rifampin by approximately 
54% and 74%, respectively. As a result, the coadministration of strong CYP3A 
inducers with ixazomib should be avoided. Ixazomib is neither a time-dependent 
nor reversible inhibitor of CYPs 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4/5, 

MC178B 
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therefore the potential for Ixazomib to produce DDIs via CYP isozyme inhibition 
is low. Ixazomib did not induce CYP1A2, CYP2B6, and CYP3A4/5 activity. 
The potential for ixazomib to cause DDIs with substrates or inhibitors of P-gp, 
BCRP, MRP2, MATE-1, MATE2-K, OCT2, OAT1, OAT3, and OATPs is low. 
 
Pharmacokinetic parameters for ixazomib coadministered with lenalidomide and 
dexamethasone (LenDex) are like those observed when ixazomib is 
administered as a single agent. This suggests that there is no readily apparent 
effect of coadministration of LenDex on the clinical PK of ixazomib. 
 
Ixazomib should not be taken if the patient has had a serious allergic reaction to 
boron or boron containing products. 
 
15.17 Known Potential Adverse Events 
See the current version of the Investigator’s Brochure for more complete 
information including potential risks, as well as recommendations for clinical 
monitoring and medical management of toxicity. There are no human data 
available for potential effect of ixazomib on pregnancy or development of the 
embryo or fetus; however, embryo-fetal studies in animals have 
demonstrated that ixazomib has the potential to cause lethality. 
Very common (≥10%): peripheral edema, skin rash, constipation, 
diarrhea, nausea, vomiting, neutropenia, thrombocytopenia, 
peripheral neuropathy, peripheral sensory neuropathy, back pain, 
eye disease, upper respiratory tract infection. 
Common (≥1% to <10%): Herpes zoster, hepatic insufficiency, blurred 
vision, conjunctivitis, xerophthalmia, pneumonia ,  
Uncommon ( <1%) or case reports: cholestatic hepatitis, 
hepatocellular hepatitis, hepatotoxicity, liver steatosis, peripheral 
motor neuropathy, reversible posterior leukoencephalopathy 
syndrome, Stevens-Johnson syndrome, Sweet’s syndrome, thrombotic 
thrombocytopenic purpura, transverse myelitis, tumor lysis syndrome, 
thrombotic microangiopathy 
Herpes zoster – antiviral prophylaxis should be considered in patients 
being treated with Ixazomib to decrease the risk of herpes zoster 
reactivation. 
Overdose – There is no known specific antidote for ixazomib overdose. 
Symptoms of overdose are generally consistent with the known risks of ixazomib 
and reports have been associated with serious adverse events such as nausea, 
aspiration pneumonia, multiple organ failure, and death. In the event of an 
overdose in blinded studies, study medication assignment should be unblinded 
immediately.  The clinician should consider admitting the patient to the hospital 
for IV hydration, monitoring for adverse drug reactions, monitoring of vital 
signs, and appropriate supportive care. Gastric lavage may be considered, but it 
should be kept in mind that ixazomib absorption is rapid. Ixazomib is not readily 
dialyzable. 
 
15.18 Special populations: 
• 
Geriatric Use: Of the total number of subjects in clinical studies of 
NINLARO, 55% were 65 and over, while 17% were 75 and over. No overall 
differences in safety or effectiveness were observed between these subjects 
and younger subjects, and other reported clinical experience has not 
identified differences in responses between the elderly and younger patients, 

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but greater sensitivity of some older individuals cannot be ruled out. 
• 
Renal Impairment: In patients with severe renal impairment or ESRD 
requiring dialysis, the mean AUC increased by 39% when compared to 
patients with normal renal function. Reduce the starting dose of NINLARO 

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in patients with severe renal impairment or ESRD requiring dialysis. 
NINLARO is not dialyzable and therefore can be administered without 
regard to the timing of dialysis 
• 
Hepatic Impairment: In patients with moderate or severe hepatic 
impairment, the mean AUC increased by 20% when compared to patients 
with normal hepatic function. Reduce the starting dose of NINLARO in 
patients with moderate or severe hepatic impairment 
 
15.19 Drug procurement: 
Investigational product will be supplied free of charge to trial participants by 
Millennium Pharmaceuticals, Inc. 
 
15.20 Nursing guidelines: 
15.201 Capsules must be administered intact and should not be opened or 
manipulated in any way. Additionally, capsules should remain in the 
blister packs until they are ready to be taken. It is recommended to wear 
gloves and protective garments during preparation when dispensed in 
clinic. 
 
15.202 Capsules should be taken on an empty stomach (either 1 hour before or 2 
hours after meals) with 8 oz. of water. Make sure that patients are 
instructed to take exactly as directed to avoid overdose.  
 
15.203 Cytopenias have been observed. Monitor CBC w/diff . Instruct patient to 
report any signs or symptoms of infection or bleedning to the study team. 
 
15.204 GI side effects have been seen (nausea, diarrhea, vomiting), treat 
symptomatically and monitor for effectiveness of intervention. 
 
15.205 Rash has been seen. Rarely Steven Johnson syndrome (SJS) has been 
seen with this agent. Instruct patients to report any rash to study team. 
 
15.206 Assess patients concomitant medications, including over the counter and 
supplements. Ixazomib is metabolized through both CYP and non-CYP 
enzymes, and drug to drug interactions exist. Instruct patients not to start 
any new medications or supplements without checking with the study 
team first. 
 
15.207 Fatigue has been seen. Instruct patient in energy conserving lifestyle. 
 
15.208 Insomnia can be seen. Treat symptomatically and monitor for 
effectiveness. 
 
15.209 a Patients who have had an allergic reaction to boron or boron containing 
products should not take Ixazomib. 
 
15.209b The following rare but life threatening conditions have been seen 
with agent: CHF, liver failure, TTP, TLS, renal failure, bowel 
obstruction, and RPLS, transverse myelitis, progressive multifocal 
leukoencephalopathy. Monitor labs closely, instruct patient to 

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report any new or worsening symptoms to the study team and 
provide further assessment based on symptoms. 
 
15.210 Monitor LFT’s. Rarely hepatotoxicity has been seen.  
 
15.2 
Ibrutinib for Oral Administration (Imbruvica®) 
15.21 Background: Ibrutinib is a potent and irreversible inhibitor of Bruton’s tyrosine 
kinase (BTK), an integral component of the B-cell receptor (BCR) and cytokine 
receptor pathways. Constitutive activation of B-cell receptor signaling is 
important for survival of malignant B-cells; BTK inhibition results in decreased 
malignant B-cell proliferation and survival. 
 
15.22 Formulation: Commercially available for oral administration as a capsule: 
140mg. 
 
15.23 Preparation and storage: Refer to package insert for complete dispensing 
instructions. Store capsules at room temperature between 20°C and 25°C 
(68°F and 77°F). Excursions are permitted between 15° and 30°C (59°F to 
86°F. Keep in original container. 
 
15.24 Administration: Refer to the treatment section for specific administration 
instructions. The manufacturer recommends ibrutinib should be taken with water 
at the same time every day. Swallow capsules whole; do not open, break, or chew 
the capsules. Maintain adequate hydration during treatment. Hazardous agent; 
use appropriate precautions for handling and disposal. 
 
15.25 Pharmacokinetic information: 
Distribution: ~10,000 L 
Bioavailability: Administration with food increased the maximum concentration 
by ~2 to 4-fold and the AUC 2-fold (compared with overnight fasting). 
Administration under fasting conditions resulted in exposure of ~60% compared 
to when administered either 30 minutes before or after a meal, or 2 hours after a 
high-fat meal. 
Protein binding: ~97% 
Metabolism: Hepatic via CYP3A (major) and CYP2D6 (minor) to active 
metabolite PCI-45227 
Half-life elimination: 4 to 6 hours 
Time to peak: 1 to 2 hours 
Excretion: Feces (80%; ~1% as unchanged drug); urine (<10%, as metabolites) 
 
15.26 Potential Drug Interactions: 
 
Metabolism Effects: Ibrutinib is primarily metabolized by cytochrome P450 
enzyme 3A4/5. Avoid concomitant use of ibrutinib with any of the following: 
CYP3A4 inducers (strong), CYP3A4 inhibitors (strong or moderate) and herbs 
that are CYP3A4 inducers or inhibitors. The levels of ibrutinib may be increased 
by CYP3A4 inhibitors and decreased by CYP3A4 inducers (the active metabolite 
has inhibitory activity towards Bruton’s tyrosine kinase that is approximately 15 
times lower than that of ibrutinib). 

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Transport Effects: Ibrutinib is a P-glycoprotein/ABCB1 inhibitor and may 
increase the serum concentrations of: afatinib, bosutinib, brentuximab, 
colchicine, active metabolites of dabigatran etexilate, doxorubicin, edoxaban, 
everolimus, ledipasvir, naloxegol, pazopanib, prucalopride, rifaximin, 
rivaroxaban, silodosin, topotecan and vincristine. 
 
Ibrutinib may enhance the adverse/toxic effect of clozapine, leflunomide, 
natalizumab, pimecrolimus, tofacitinib, tacrolimus, and live vaccines. It may 
also enhance the adverse/toxic effect of anticoagulants and agents with 
antiplatelet properties. Dipyrone may enhance the adverse/toxic effect of 
Ibrutinib. 
 
Grapefruit juice and Seville oranges moderately inhibit 3A4 and may increase 
ibrutinib exposure. 
 
15.27 Known potential toxicities: Consult the package insert for the most current and 
complete information. 
 
Common known potential toxicities, >10%: 
Cardiovascular: Peripheral edema, hypertension 
Central nervous system: Fatigue, dizziness, headache, anxiety, chills 
Dermatologic: Skin rash, skin infection, pruritis 
Endocrine & metabolic: Hyperuricemia, hypoalbuminemia, hypokalemia, 
dehydration 
Gastrointestinal: Diarrhea, nausea, constipation, abdominal pain, vomiting, 
decreased appetite, stomatitis, dyspepsia, gastroesophageal reflux disease, upper 
abdominal pain 
Genitourinary: Urinary tract infection 
Hematologic & oncologic: Decreased platelet count, bruise, neutropenia, 
decreased hemoglobin, petechia, malignant neoplasm (secondary) 
Infection: infection 
Neuromuscular & skeletal: Musculoskeletal pain, arthralgia, muscle spasm, 
weakness, arthropathy 
Ophthalmic: Dry eye syndrome, increased lacrimation, blurred vision, decreased 
visual acuity 
 
Respiratory: Upper respiratory tract infection, dyspnea, sinusitis, cough, 
oropharyngeal pain, pneumonia, epistaxis, bronchitis 
Miscellaneous: Fever 
 
Less common known potential toxicities, 1% - 10%: 
Cardiovascular: Atrial fibrillation, atrial flutter 
 
Renal: Increased serum creatinine 
 
Limited to important or life threatening: Abnormal platelet aggregation, 
hepatic failure, hypersensitivity (includes anaphylactic shock, angioedema, 
urticaria), interstitial pulmonary disease, onychoclasis, pneumonia due to 
Pneumocystis carinii, pneumonitis, progressive multifocal leukoencephalopathy, 
renal failure, Stevens-Johnson syndrome, tumor lysis syndrome 

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15.28 Drug procurement: Commercial supplies. Pharmacies or clinics shall obtain 
supplies from normal commercial supply chain or wholesaler. 
 
15.29 Nursing Guidelines: 
• 
There are numerous drug to drug interactions. Record all of patient’s medications 
including OTC, and herbal use. Avoid concomitant use with agents as listed in 
section 15.16. 
• 
Ibrutinib should be taken with water at approximately the same time each day 
and can be taken with or without food. Capsules should be swallowed whole. 
• 
Patients should be instructed to avoid eating grapefruit (including juice) and 
Seville oranges while on ibrutinib. 
• 
Peripheral edema is common. Instruct patients to report this to the study team. 
• 
Gastrointestinal side effects are common (diarrhea, nausea, constipation, 
abdominal pain, vomiting, etc). Treat symptomatically and monitor for 
effectiveness of intervention. 
• 
Monitor CBC w/diff. Instruct patients in energy conserving lifestyle (anemia) 
and to report any unusual bruising or bleeding and/or signs or symptoms of 
infection to study team. 
• 
Arthralgias, myalgias, and muscle spasm can be seen. Treat symptomatically and 
monitor for effectiveness. 
• 
Monitor renal function/uric acid levels, especially in patients who may be 
experiencing dehydration. 
• 
Respiratory symptoms may include, cough, SOB, and URI. Instruct patients to 
report these symptoms to the study team. 
• 
Rarely patients can experience secondary skin cancers. Instruct patients to report 
any new skin lesions to the study team. 
• 
Rash can be seen. Instruct patient to report to study team. 
• 
Cardiac arrhythmias have been seen with this agent including a-fib, atrial flutter 
and ventricular tachyarrhythmia’s, some of which have led to death. Instruct 
patients who experience any palpitations, lightheadedness, syncope, or SOB to 
see medical care immediately. This is especially important in patients who have 
pre-existing cardiac issues. 

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16.0 
Statistical Considerations and Methodology 
16.1 
Overview 
This is a Phase II, single arm, open-label, study to assess the safety, tolerability, pharmacokinetics 
and pharmacodynamics of the combination of ibrutinib and ixazomib administered to patients with 
WM. 
16.11 
Primary Endpoint: The primary endpoint of this trial is the rate of complete 
response. A complete response is defined as an objective status of CR per 
Appendix III at any time, where confirmation of the complete response status is 
required on two consecutive evaluations with a second immunofixation before 
calling the patient a CR. All patients meeting the eligibility criteria, who have 
signed a consent form and have begun treatment, will be evaluable for response, 
unless they are determined to be a major violation. 
 
16.2 
Statistical Design 
16.21 Decision Rule: The largest success proportion where the proposed treatment 
regimen would be considered ineffective in this population is 5%, and the 
smallest success proportion that would warrant subsequent studies with the 
proposed regimen in this patient population is 20%. The following one–stage 
design with an interim analysis is based on a two-stage Simon optimum design 
and requires 37 evaluable patients to test the null hypothesis that the true success 
proportion in this patient population is at most 5%. 
 
16.211 Interim Analysis: Enter 12 evaluable patients into the study. If no 
successes are observed in the first 12 evaluable patients, we will consider 
this regimen ineffective in this patient population and terminate the study. 
Otherwise, if the number of successes is at least 1, we will continue 
accrual. 
 
16.212 Final Decision Rule: Enter an additional 25 evaluable patients into the 
study. If 3 or fewer successes are observed in the first 37 evaluable 
patients, we will consider this regimen ineffective in this patient 
population and terminate this study. Otherwise, if the number of successes 
is at least 4, this will be considered evidence of promising activity and the 
treatment may be recommended for further testing in subsequent studies 
in this population. 
 
16.213 Over Accrual: If more than the target number of patients are accrued, the 
additional patients will not be used to evaluate the stopping rule or used in 
any decision making process. Analyses involving over accrued patients are 
discussed in Section 16.313. 
 
16.214 NOTE: We will not suspend accrual at the interim analysis to allow the 
first 12 patients to become evaluable, unless undue toxicity is observed. 
Given the limited overall sample size and the inclusion of an AE stopping 
rule, we feel it is ethical to not halt accrual for the interim analysis. 
However, if accrual is extremely rapid, we may temporarily suspend 
accrual in order to obtain safety data on these patients before re- opening 
accrual to further patients. 

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16.215 Dose de-escalation in safety analysis: A safety analysis will be performed 
in the first 6 evaluable patients per Section 16.4. In the case of 
unacceptable toxicity, the dose of ixazomib will be de-escalated (Table 
7.1b). If this occurs, the first 6 patients will be evaluated separately and 
will not be included in any decision making criteria. 
 
16.22 Sample Size: The one stage study design with an interim analysis to be utilized is 
fully described above. A minimum of 12 and a maximum of 37 evaluable 
patients will be accrued onto this phase II study unless undue toxicity is 
encountered. If dose de-escalation is required during the safety analysis, an 
additional 6 evaluable patients will be accrued per Section 16.4. We anticipate 
accruing an additional up to 4 patients to account for ineligibility, cancellation, 
major treatment violation, or other reasons for a total of up to 47 patients. 
 
 
16.23 Accrual Rate and Study Duration: The anticipated accrual rate is 2 evaluable 
patients per month. At this rate, it will likely take about 2 years to enroll all 
patients. The maximum study duration is expected to be approximately 7 years, 
or until the last patient accrued has been followed by 5 years. 
 
16.24 Power and Significance Level: Power and Significance Level: Assuming that the 
number of successes is binomially distributed, the significance level is .09, i.e. 
there is a 9% chance of finding the drug to be effective when it truly is not. The 
probability of declaring that this regimen warrants further study (i.e. statistical 
power) and the probability of stopping at the interim analysis under various 
success proportions can be tabulated as a function of the true success proportion 
as shown in the following table. 
 
If the true success proportion is... 
0.05 
0.10 
0.15 
0.20 
Then the probability of declaring 
that the regimen warrants further 
study is… 
 
0.09 
 
0.45 
 
0.75 
 
0.90 
And the probability of stopping at 
the interim analysis is… 
0.54 
0.28 
0.14 
0.07 
 
16.25 Other Considerations: AEs, quality/duration of response, and patterns of 
treatment failure observed in this study, as well as scientific discoveries or 
changes in standard care will be taken into account in any decision to terminate 
the study 
16.3 
Analysis Plan 
The analysis for this trial will commence at planned time points (see 16.2) and at the time 
the patients have become evaluable for the primary endpoint. The Statistician and Study 
Chair will make the decision, in accord with CCS Standard Operating Procedures, 
availability of data for secondary endpoints (e.g., laboratory correlates), and the level of 
data maturity. It is anticipated that the earliest date in which the results will be made 
available via manuscript, abstract, or presentation format is when last patient has been 
followed for at least 6 months. 

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16.31 Primary Outcome Analysis 
16.311 Definition: The primary endpoint of this trial is the complete response rate. 
A success is defined as an objective status of CR per Appendix III  at any 
time, where confirmation of the complete response status is required on 
two consecutive evaluations with a second immunofixation before calling 
the patient a CR. All patients meeting the eligibility criteria who have 
signed a consent form and have begun treatment will be evaluable for 
response, unless they are determined to be a major violation. 
 
16.312 Estimation: The proportion of successes will be estimated by the number 
of successes divided by the total number of evaluable patients. 95% 
confidence intervals for the true success proportion will be calculated 
according to the approach of Duffy and Santner. 
 
16.313 Over Accrual: If more than the target number of patients are accrued, the 
additional patients will not be used to evaluate the stopping rule or used 
in any decision making processes; however, they will be included in final 
point estimates and confidence intervals. 
 
16.32 Secondary Outcome Analysis 
 
16.321 The overall response rate will be estimated by the total number of patients 
who achieve a CR VGPR, or PR divided by the total number of evaluable 
patients. All evaluable patients will be used for this analysis. Exact 
binomial 95% confidence intervals for the true overall response rate will 
be calculated. 
 
16.322 Time to progression is defined as the time from registration to the earliest 
date of documentation of disease progression. The distribution of time to 
progression will be estimated using the method of Kaplan-Meier. 
 
16.323 Overall survival is defined as the time from registration to death due to any 
cause. The distribution of overall survival will be estimated using the 
method of Kaplan-Meier. 
 
16.324 AEs: All eligible patients that have initiated treatment will be considered 
evaluable for assessing AE rate(s). The maximum grade for each type of 
AE will be recorded for each patient, and frequency tables will be 
reviewed to determine patterns. Additionally, the relationship of the AE(s) 
to the study treatment will be taken into consideration. 
 
 
16.33 Correlative Analysis 
16.331 BTK signaling proteins (western blot and densitometric quantification) 
and gene expression (quantitative real-time PCR) will be examined in 
CD19/CD138+ WM cells collected from patients on the study. 15 
protein/genes associated with BTK-signaling will be assessed and their 
levels from baseline samples will be compared with levels from samples 
during treatment. Changes over time will be evaluated using paired 

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sample approaches (Wilcoxon signed rank test). Baseline levels will be 
correlated with response (responder vs. non-responder) using Wilcoxon 
rank sum tests. 
 
16.332 Exploration of the biologic effects of ibrutinib and ixazomib on 
microenvironment in WM will include 3 types of data: 
 
• 
Immunophenotyping of tumor infiltrating lymphocytes (TILs) using the 
Multi-Omyx TILs platform. This will identify 17 different types of TILs 
from BM samples collected at baseline and then after one cycle of 
treatment. This data is represented as % and actual cell counts. 
• 
Identification of 4 types of T-cells from the blood. This will be done from 
peripheral blood samples collected at Baseline and then after one cycle of 
treatment with Ixa+Ibr. 
• 
BTK receptor occupancy: This is a competitive-binding assay essentially 
and will be performed in CD19+/CD138+ WM cells collected at baseline 
and then after one cycle of treatment with Ixa+Ibr. Readout is % 
occupancy 
 
Values will be correlated with response (responder vs. non-responder) 
using Wilcoxon rank sum tests. 
 
16.4 
Early Safety Analysis 
7.1 An early safety analysis will be performed after the first 6 evaluable patients 
have been accrued to the study and observed for one cycle. Accrual will be 
temporarily halted while these patients are evaluated. If 2 or more of the first 6 
patients experience a significant toxicity as defined below, then the dose of 
ixazomib may be de-escalated (as per Table b). In this case, another safety analysis 
will be conducted on the first 6 evaluable patients treated at the reduced dose level. 
Toxicity will be measured per NCI-CTCAE version 4. Significant toxicity is defined as 
an adverse event occurring during the first cycle of treatment that is possibly, probably, 
or definitely related to study treatment and that meets one of the following: 
 
• 
Grade 3 diarrhea, nausea, and fatigue lasting > 3 days despite optimal supportive 
medications 
• 
Any other ≥ Grade 3 non-hematological toxicity with the exceptions of 
electrolyte abnormalities that are reversible and asymptomatic. 
• 
Febrile neutropenia 
• 
Grade 3 thrombocytopenia with clinically significant bleeding 
• 
Any ≥Grade 4 neutrophil count decreased or platelet count decreased that persists 
>7 days 
16.5 
Data & Safety Monitoring 
16.51 The principal investigator(s) and the study statistician will review the study at 
least twice a year to identify accrual, AE, and any endpoint problems that might 
be developing. The Mayo Clinic Cancer Center (MCCC) Data Safety Monitoring 
Board (DSMB) is responsible for reviewing accrual and safety data for this trial 
at least twice a year, based on reports provided by the MCCC Statistical Office. 
 
16.52 Adverse Event Stopping Rules 
The stopping rules specified below are based on the knowledge available at study 
development. We note that the AE Stopping Rule may be adjusted in the event of 

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either (1) the study re-opening to accrual or (2) at any time during the conduct of 
the trial and in consideration of newly acquired information regarding the AE 
profile of the treatment(s) under investigation. The study team may choose to 
suspend accrual because of unexpected AE profiles that have not crossed the 
specified rule below. 
 
Accrual will be temporarily suspended to this study if at any time we observe 
events considered at least possibly related to study treatment (i.e. an AE with 
attribute specified as “possible,” “probable,” or “definite”) that satisfy one of the 
following: 
• 
if 4 or more patients in the first 12 treated patients experience a grade 4 or 
higher non-hematologic AE at least possibly related to treatment. 
• 
if after the first 12 patients have been treated, 30% of all patients experience 
a grade 4 or higher non-hematologic AE at least possibly related to treatment. 
 
We note that we will review grade 4 and 5 AEs deemed “unrelated” or “unlikely 
to be related”, to verify their attribution and to monitor the emergence of a 
previously unrecognized treatment-related AE. 
 
16.6 
Results Reporting on ClinicalTrials.gov 
 
At study activation, this study will have been registered within the “ClinicalTrails.gov” 
website. The Primary and Secondary Endpoints along with other required information for 
this study will be reported on www.ClinicalTrials.gov. For purposes of timing of the 
Results Reporting, the initial estimated completion date for the Primary Endpoint of this 

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study is 4 years after the study opens to accrual. The definition of “Primary Endpoint 
Completion Date” (PECD) for this study is at the time all patients registered have 
completed 24 cycles of treatment or have discontinued treatment before the completion of 
24 cycles. 
 
16.7 
Subset Analyses for Minorities 
16.71 Study availability 
This study will be available to all eligible patients, regardless of gender, race or 
ethnic origin. 
16.72 Statistical analysis by subset 
There is no information currently available regarding differential effects of this 
regimen in subsets defined by race, gender, or ethnicity, and there is no reason to 
expect such differences to exist. Therefore, although the planned analysis will, as 
always, look for differences in treatment effect based on racial and gender 
groupings, the sample size is not increased in order to provide additional power for 
subset analyses. 
16.73 Regional population 
The geographical region served by MCCC has a population which includes 
approximately 3% minorities. Based on prior MCCC studies involving similar 
disease sites, we expect about 3-5% of patients will be classified as minorities by 
race and about 20% of patients will be women. 
 
Accrual Estimates by Gender/Ethnicity/Race 
 
Ethnic Category 
Sex/Gender 
Females 
Males 
Unknown 
Total 
Hispanic or Latino 
0 
1 
0 
1 
Not Hispanic or Latino 
9 
37 
0 
46 
Ethnic Category: Total of all patients* 
9 
38 
0 
47 
Racial Category 
American Indian or Alaskan Native 
0 
0 
0 
0 
Asian 
0 
0 
0 
0 
Black or African American 
0 
1 
0 
1 
Native Hawaiian or other Pacific Islander 
0 
0 
0 
0 
White 
9 
37 
0 
46 
Racial Category: Total of all patients* 
9 
38 
0 
47 
 
Ethnic 
Categories: 
Hispanic or Latino – a person of Cuban, Mexican, Puerto Rican, South or Central 
American, or other Spanish culture or origin, regardless of race. The term “Spanish 
origin” can also be used in addition to “Hispanic or Latino.” 
Not Hispanic or Latino 

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Racial 
Categories: 
American Indian or Alaskan Native – a person having origins in any of the original 
peoples of North, Central, or South America, and who maintains tribal affiliations or 
community attachment. 
Asian – a person having origins in any of the original peoples of the Far East, Southeast 
Asia, or the Indian subcontinent including, for example, Cambodia, China, India, Japan, 
Korea, Malaysia, Pakistan, the Philippine Islands, Thailand, and  Vietnam. (Note: 
Individuals from the Philippine Islands have been recorded as Pacific Islanders in 
previous data collection strategies.) 
Black or African American – a person having origins in any of the black racial groups 
of Africa. Terms such as “Haitian” or “Negro” can be used in addition to “Black or 
African American.” 
Native Hawaiian or other Pacific Islander – a person having origins in any of the 
original peoples of Hawaii, Guam, Samoa, or other Pacific Islands. 
White – a person having origins in any of the original peoples of Europe, the Middle 
East, or North Africa. 

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17.0 
Pathology Considerations/Tissue Biospecimens 
17.1 
None. 
 
18.0 
Records and Data Collection Procedures 
18.1 
Submission Timetable 
Data submission instructions for this study can be found in the Data Submission 
Schedule. 
18.2 
Survival Follow-up 
See Section 4.2 
18.3 
CRF completion 
This study will use Medidata Rave for remote data capture (rdc) of all study data. Data 
collection for this study will be done exclusively through the Medidata Rave clinical data 
management system. Access to the trial in Rave is granted through the iMedidata 
application to all persons with the appropriate roles assigned in Regulatory Support 
System (RSS). To access Rave via iMedidata, the site user must have an active account 
and the appropriate Rave role (Rave CRA, Read-Only, Site Investigator) on either the 
organization roster at the enrolling site. 
18.4 
Site responsibilities 
Each site will be responsible for insuring that all materials contain the patient’s initials, 
MCCC registration number, and MCCC protocol number. Patient’s name must be 
removed. 
18.5 
Supporting documentation 
This study requires supporting documentation for diagnosis, response to previous 
treatment with ibrutinib, and last date of ibrutinib treatment prior to study entry as well as 
for evidence of response to study therapy and progression after study therapy. Supporting 
documentation for diagnosis will include a pathology report and a laboratory report 
demonstrating Waldenström macroglobulinemia (including serum quantitative 
immunoglobulins, SPEP, UPEP, FLC, Serum and Urine Immunofixation, Bone Marrow 
Biopsy and Aspirate, CT/PET scan,). These reports should be uploaded into the 
Supporting Documentation: Baseline form within 14 days of registration. 
 
For response to treatment, supporting documentation may include serum quantitative 
immunoglobulins, SPEP, UPEP, FLC, Serum and Urine Immunofixation, Bone 
Marrow Biopsy and aspirate, and PET scan. These documents should be uploaded 
into the Supporting Documentation form. 
 
For patients who progress after study therapy supporting documentation may include any 
of the following: serum quantitative immunoglobulins, SPEP, UPEP, FLC, serum and 
urine immunofixation, bone marrow biopsy and aspirate, and PET/CT scan. These 
documents should be uploaded into the Supporting Documentation form 
18.6 
Labeling of materials 
Each site will be responsible for insuring that all materials contain the patient’s initials, 
MCCC registration number, and MCCC protocol number. Patient’s name must be 
removed. 
18.7 
Overdue lists 

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19.0 
Budget 
A list of overdue forms and outstanding queries will be available in Rave through the 
Rave Task Summary. In addition to this, the Overdue Materials report is available on the 
Cancer Center Systems homepage. 
19.1 
Costs charged to patient: routine clinical care, ibrutinib 
19.2 
Tests to be research funded: ixazomib is provided by Takeda (Millennium) 
Pharmaceuticals, Inc, Bone Marrow Biopsy aspirate at Cycle 2 Day 1, personnel 
effort, statistics, and research correlatives. 

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20.0 
References 
1. Assouline, S., et al. Once-weekly MLN9708, an investigational proteasome inhibitor, in patients with 
relapsed/refractory lymphoma: results of a phase 1 dose-escalation study in 17th EHA Annual 
Congress. 2012. Amsterdam, the Netherlands. 
2. Cao Y, Hunter ZR, Liu X, et al: CXCR4 WHIM-like frameshift and nonsense mutations promote 
Ibrutinib resistance but do not supplant MYD88(L265P) -directed survival signalling in Waldenström 
macroglobulinaemia cells. Br J Haematol. 168:701-7, 2015 
3. Chow, L.Q., et al. MLN9708, an investigational proteasome inhibitor, in patients with solid tumors; 
Updated phase 1 results in Head and Neck Symposium. 2012. Phoenix, AZ 
4. Common Terminology Criteria for Adverse Events (CTCAE). 2010. 
5. Dimopoulos MA, Kastritis E, Owen RG, et al: Treatment recommendations for patients with 
Waldenström macroglobulinemia (WM) and related disorders: IWWM-7 consensus. Blood 124:1404- 
11, 2014 
6. Gupta, N., et al., Clinical Pharmacokinetics of Intravenous and Oral MLN9708, An Investigational 
Proteasome Inhibitor: An Analysis of Data From Four Phase 1 Monotherapy Studies. in 52nd ASH 
Annual Meeting and Exposition, 2010. 116(21): p. abstr 1813. 
7. Gupta, N., M. Saleh, and K. Venkatakrishnan. Flat-Dosing Versus BSA-Based Dosing for MLN9708, 
An Investigational Proteasome Inhibitor: Population Pharmacokinetic (PK) Analysis of Pooled Data 
From 4 Phase-1 Studies in 53rd ASH Annual Meeting and Exposition. 2011. San Diego, CA; p. abstr 
1433 
8. Kapoor P, Ansell SM, Fonseca R, et al: Diagnosis and Management of Waldenstrom 
Macroglobulinemia: Mayo Stratification of Macroglobulinemia and Risk-Adapted Therapy (mSMART) 
Guidelines 2016. JAMA Oncol (Epub ahead of print), 2017. 
9. Kimby E, Treon SP, Anagnostopoulos A, et al: Update on recommendations for assessing response 
from the Third International Workshop on Waldenstrom's Macroglobulinemia. Clin Lymphoma 
Myeloma 6:380-383, 2006. 
10. Kumar S, Bensinger W, Reeder C, Zimmerman T, Berenson J, Liu G, et al. Weekly dosing of the 
investigational oral proteasome inhibitor MLN9708 in patients (pts) with relapsed/refractory multiple 
myeloma (MM): A phase I study. Journal of Clinical Oncology 2012 ASCO Annual Meeting 
Proceedings 2012:Abstract 8034. 
11. Kumar S, Bensinger W, Reeder C, Zimmerman T, Berenson J, Berg D, et al. Weekly Dosing of the 
Investigational Oral Proteasome Inhibitor MLN9708 in Patients with Relapsed and/or Refractory 
Multiple Myeloma: Results From a Phase 1 Dose- Escalation Study In: 53rd ASH Annual Meeting and 
Exposition; 2011 10-13 Dec; San Diego, CA; p. abstr 816. 
12. Kumar, S. et al. A Phase 1/2 Study of Weekly MLN9708, an Investigational Oral Proteasome Inhibitor, 
in Combination with Lenalidomide and Dexamethasone in Patients with Previously Untreated Multiple 
Myeloma (MM) in 54th ASH Annual Meeting and Exposition. 2012. Atlanta, Georgia. 
13. Kumar S, et al. Weekly Dosing of the Investigational Oral Proteasome Inhibitor MLN9708 in Patients 
with Relapsed and/or Refractory Multiple Myeloma: Results From a Phase 1 Dose- Escalation Study 
In 53rd ASH Annual Meeting and Exposition; 2011 10-13 Dec; San Diego, CA; p. abstr 816. 
14. Kumar S, Niesvizky R, Berdeja J, Bensinger W, Zimmerman T, Berenson J, et al. Safety and 
Pharmacokinetics of Weekly MLN9708, an Investigational Oral Proteasome Inhibitor, Alone and in 
Combination. Clinical Lymphoma Myeloma and Leukemia 2013;13(Supplement 1):S154; abstr P- 230. 
15. Lonial S, Baz R, Wang M, Talpaz M, Liu G, Berg D, et al. Phase I study of twice weekly dosing of the 
investigational oral proteasome inhibitor MLN9708 in patients (pts) with relapsed and/or refractory 
multiple myeloma (MM). J Clin Oncol (ASCO Meeting Abstracts) 2012;30(15 suppl):abstr 8017. 
16. Lonial, S., et al. Phase I study of twice-weekly dosing of the investigational oral proteasome inhibitor 
MLN9708 in patients (pts) with relapsed and/or refractory multiple myeloma (MM) in ASCO Annual 

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Meeting. 2012. Chicago, Illinois. 
17. Merlini, G., et al. MLN9708, a Novel, Investigational Oral Proteasome Inhibitor, in Patients with 
Relapsed or Refractory Light-Chain Amyloidosis (AL): Results of a Phase 1 Study in 54th ASH Annual 
Meeting and Exposition. 2012. Atlanta, Georgia. 
18. Owen RG, et al. Response assessment in Waldenström macroglobulinaemia: update from the VIth 
International Workshop. VIth International Workshop on Waldenström macroglobulinaemia. Br J 
Haematol. 2013 Jan;160(2):171-6. doi: 10.1111/bjh.12102. 
19. Richardson P, Baz R, Wang L, Jakubowiak A, Berg D, Liu G, et al. Investigational Agent MLN9708, 
An Oral Proteasome Inhibitor, in Patients (Pts) with Relapsed and/or Refractory Multiple Myeloma 
(MM): Results From the Expansion Cohorts of a Phase 1 Dose-Escalation Study In: 53rd ASH Annual 
Meeting and Exposition; 2011 10-13 Dec; San Diego, CA; p. abstr 301. 
20. Richardson, P.G., et al. MLN9708, an investigational proteasome inhibitor, in combination with 
lenalidomide and dexamethasone in previously untreated multiple myeloma patients  (pts): Evaluation 
of weekly and twice-weekly dosing in 17th EHA Annual Congress. 2012. Amsterdam, the Netherlands. 
21. Roccaro AM, Sacco A, Jimenez C, et al: C1013G/CXCR4 acts as a driver mutation of tumor 
progression and modulator of drug resistance in lymphoplasmacytic lymphoma. Blood 123:4120-31, 
2014. 
22. San Miguel, J., et al. Oral MLN9708, an an investigational proteasome inhibitor, in combination with 
melphalan and prednisone in patients with previously untreated multiple myeloma: a phase 1 study in 
17th EHA Annual Congress. 2012. Amsterdam, the Netherlands. 
23. Treon SP, Xu L, Hunter Z: MYD88 Mutations and Response to Ibrutinib in Waldenström's 
Macroglobulinemia. N Engl J Med 373:584-6, 2015 

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Appendix I 
ECOG Performance Status 
 
 
ECOG PERFORMANCE STATUS* 
Grade ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work 
activities. Up and about more than 50% of waking hours 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of 
waking hours. 
4 
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or 
chair. 
5 
Dead 
*As published in Am. J. Clin. Oncol.: 
Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, P.P.: 
Toxicity And Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649- 
655, 1982. 
 
The ECOG Performance Status is in the public domain therefore available for public use. To duplicate the 
scale, please cite the reference above and credit the Eastern Cooperative Oncology Group, Robert Comis 
M.D., Group Chair. 
 
From http://www.ecog.org/general/perf_stat.html 

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Appendix II Patient Medication Diary 
 
Name _ 
 
Study ID Number 
 
 
Please complete this diary on a daily basis. Please bring your dosing diary to your next 
scheduled appointment. Write in the amount of the dose of ixazomib and ibrutinib that you took 
in the appropriate “Day” box. On the days that you do not take any study drug, please write in 
“0”. If you forget to take your daily dose, please write in “0” and do not make up this missed 
dose. Remember to take your prescribed dose at the next regularly scheduled time. 
 
Please store the ixazomib as indicated on the bottle. Ixazomib should be taken on an empty 
stomach (either 1 hour before or 2 hours after meals) with 8 oz. of water. Swallow the capsules 
whole; do not open, break, or chew the capsules. If you experience a vomiting episode in the 
same day after taking ixazomib, do not make up this dose. Please indicate the time you took the 
drug and the time you vomited. 
 
Ibrutinib should be taken with water at approximately the same time each day and can be taken 
with or without food. Swallow the capsules whole; do not open, break, or chew the capsules. 
Please avoid grapefruit and Seville oranges during your ibrutinib treatment. Supplements such as 
fish oil and vitamin E preparations should also be avoided.   
 
If you experience any health/medical complaints or take any medication other than ixazomib and 
ibrutinib please record this information. 
 
Study Drug(s) 
Dose Study Coordinator only: 
Write in the dose assigned by the study doctor in this 
column if different than the dose listed in the previous 
column 
Ibrutinib 
420 mg 
 
Ixazomib  
4mg 
 
 
Week of: 
Study Drug 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Date 
 
 
 
 
 
 
 
Ixazomib 
 
 
 
 
 
 
 
Ibrutinib 
 
 
 
 
 
 
 
 
Week of: 
Study Drug 
Day 8 
Day 9 
Day 10 
Day 11 
Day 12 
Day 13 
Day 14 
Ixazomib 
 
 
 
 
 
 
 
Ibrutinib 
 
 
 
 
 
 
 
 
Week of: 
Study Drug 
Day 15 
Day 16 
Day 17 
Day 18 
Day 19 
Day 20 
Day 21 
Ixazomib 
 
 
 
 
 
 
 
Ibrutinib 
 
 
 
 
 
 
 
 
Week of: 
Study Drug 
Day 22 
Day 23 
Day 24 
Day 25 
Day 26 
Day 27 
Day 28 

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Ixazomib 
 
 
 
 
 
 
 
Ibrutinib 
 
 
 
 
 
 
 
 
Patient signature:   
 
 
Health or medical complaints during this time: 
 
 
 
 
 
 
 
 
 
Other medications or supplements taken during this time: 
 
 
Name of medication or 
supplement 
 
How much did you take? 
(example: Two 500mg pills) 
When did you take it 
(examples: Every day 
Or Day 19 and Day 20) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Use a separate sheet of paper if more space is needed. 
 
 
 
 
 
 
Study Coordinator Use Only 
 
Number of pills returned   
 
Number of vials returned:   
  
Discrepancy Yes  
/No  
 
Verified by   
 
Date  
 
My next scheduled visit is:   
 
If you have any questions, please call:   
 

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Appendix III Response Assessment Criteria 
 
Response 
Criteria 
Complete 
response 
• 
Absence of serum monoclonal IgM protein by immunofixation 
• 
Normal serum IgM level 
• 
Complete resolution of extramedullary disease, i.e., lymphadenopathy 
(resolution to ≤1.5 cm in longest diameter of all nodes) and 
splenomegaly/hepatomegaly if present at baseline 
• 
Morphologically normal bone marrow aspirate and trephine biopsy 
• 
No signs or symptoms attributable to WM 
 
Confirmation of the complete response status is required on two consecutive 
evaluations with a second immunofixation before reporting an objective status 
of CR 
Very good partial 
response 
• 
Monoclonal IgM protein is detectable 
• 
≥90% reduction in serum IgM level from baseline 
• 
Complete resolution of extramedullary disease, i.e., lymphadenopathy 
(resolution to ≤1.5 cm in longest diameter of all nodes) and 
splenomegaly/hepatomegaly if present at baseline 
• 
No new signs or symptoms of active disease 
Partial response 
• 
Monoclonal IgM protein is detectable 
• 
≥50% but <90% reduction in serum IgM level from baseline 
• 
≥50% reduction in extramedullary disease, i.e., ≥50% reduction in SPD from 
baseline for lymphadenopathy and ≥50% reduction from baseline in 
splenomegaly/hepatomegaly if present at baseline 
• 
No new signs or symptoms of active disease 
Minor response 
• 
Monoclonal IgM protein is detectable 
• 
≥25% but<50% reduction in serum IgM level from baseline 
• 
No new signs or symptoms of active disease 
Stable disease 
• 
Monoclonal IgM protein is detectable 
• 
<25% reduction and <25% increase in serum IgM level from baseline 
• 
No progression in extramedullary disease, 
i.e.,lymphadenopathy/splenomegaly/hepatomegaly 
• 
No new signs or symptoms of active disease 
Progressive 
disease 1 
• 
≥25% increase in serum IgM level from lowest nadir confirmed by a 
second measurement 4 weeks apart and/or progression in clinical features 
attributable the disease (i.e., anemia, thrombocytopenia, leukopenia, bulky 
adenopathy/ organomegaly)2 
or 
• 
symptoms attributable to WM (unexplained recurrent fever 38.4°C, 
drenching night sweats, 10% body weight loss, hyperviscosity, 
neuropathy, symptomatic cryoglobulinemia, or amyloidosis) 
or 
• 
Transformation to a more aggressive histology 
or 
• 
Progression criteria for lymphadenopathy: In patients who achieved PR, 
MR, or SD an increase of ≥ 25% from the nadir in the SPD of any  previous 
lymph nodes or appearance of a new lymph node (that must be > 

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1 In the case where progression is first observed, the objective status will be entered as unconfirmed 
progression (uPD) on the measurement form. Once this criterion is confirmed at least 4 weeks later, the 
objective status will be entered as PD. If confirmed, the date of first evidence of progression (date of first 
uPD) will be considered the progression date (and should be entered on the event monitoring form). 
2 If IgM alone is used to determine progression, there must be ≥ 500 mg/dL increase in IgM from the nadir. 
(Owen, 2013) 
2 cm). For patients who have achieved a VGPR or CR, progression will 
be defined as appearance of a new lymph node (that must be > 2 cm). 
• 
Progression criteria based upon splenic or hepatic enlargement: In patients 
who achieved PR, MR, or SD an increase in the size of the spleen and / or 
liver of > 25% from the nadir.  For patients who have achieved a VGPR  or 
CR, progression will be defined if there is increase in the size of spleen and 
/ or liver that is >25% the upper limit of normal measured in the longitudinal 
axis.