A Phase 2 Study of Ixazomib and Rituximab in Bruton Tyrosine Kinase Inhibitor Resistant Mantle Cell Lymphoma
Phase: PHASE2
Conditions: Recurrent Mantle Cell Lymphoma, Refractory Mantle Cell Lymphoma
Sponsor: M.D. Anderson Cancer Center

CLINICAL STUDY PROTOCOL  
2018-1090 
 A Phase 2 Study of Ixazomib and Rituximab in Bruton’s 
Tyrosine Kinase Inhibitor Resistant Mantle Cell Lymphoma 
 
 
 
 
 
Indication: 
Bruton’s Tyrosine Kinase Inhibitor Resistant Mantle Cell 
Lymphoma 
Phase: 
Phase II 
 
 
 
Protocol History 
Original 
Revision 1 
Revision 2 
Revision 3 
Revision 4 
 
21 February 2019 
22 April 2019 
13 May 2019 
30 May 2019 
29 July 2019 
 
 
 
Investigator and Study Center: 
Hun Ju Lee  
M.D. Anderson Cancer Center  
Department of Lymphoma & Myeloma 
1515 Holcombe Blvd., Houston, TX 77030 
713-794-1829 
 
 
 
 
 
 
The principal investigator Hun Ju Lee MD (who may also be referred to as the sponsor-
investigator), is conducting the study and acting as the sponsor.  Therefore, the legal/ethical 
obligations of the principal investigator include both those of a sponsor and those of an 
investigator. 
 
 

<MD Anderson Cancer Center> 
 
MLN9708 
Clinical Study Protocol #2018-1090 
 
TABLE OF CONTENTS 
 
CLINICAL STUDY PROTOCOL ...........................................................................................1 
TABLE OF CONTENTS .........................................................................................................2 
LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS ..............................................4 
1. BACKGROUND AND STUDY RATIONALE ..................................................................8 
1.1 Scientific Background ....................................................................................................8 
1.1.1 Disease Under Treatment.........................................................................................8 
1.1.2 Ixazomib (MLN9708) ..............................................................................................8 
1.2 Preclinical Experience ....................................................................................................8 
1.3 Clinical Experience .........................................................................................................8 
1.4 Pharmacokinetics and Drug Metabolism ........................................................................8 
1.5 Clinical Trial Experience Using the Oral Formulation of Ixazomib ............................11 
1.6 Relapsed and/or Refractory Multiple Myeloma ...........................................................11 
1.7 Newly Diagnosed Multiple Myeloma (NDMM) ..........................................................11 
1.8 Clinical Trial Experience Using the Intravenous Formulation of Ixazomib ................11 
1.9 Study Rationale .............................................................................................................11 
1.10 Potential Risks and Benefits .......................................................................................12 
2. STUDY OBJECTIVES ......................................................................................................13 
2.1 Primary Objectives .......................................................................................................13 
2.2 Secondary Objectives ...................................................................................................13 
2.3 Tertiary/Exploratory Objectives ...................................................................................14 
3. STUDY ENDPOINTS ........................................................................................................14 
3.1 Primary Endpoints ........................................................................................................14 
3.2 Secondary Endpoints ....................................................................................................14 
3.3 Tertiary/Exploratory Endpoints ....................................................................................14 
4. STUDY DESIGN ...............................................................................................................14 
4.1 Overview of Study Design ...........................................................................................14 
4.2 Number of Patients .......................................................................................................14 
4.3 Duration of Study .........................................................................................................15 
5. STUDY POPULATION .....................................................................................................15 
5.1 Inclusion Criteria ..........................................................................................................15 
5.2 Exclusion Criteria .........................................................................................................16 
6. STUDY DRUG ...................................................................................................................18 
6.1 Description of Investigational Agents ..........................................................................18 
6.2 Study Drug Administration ..........................................................................................18 
6.3 Risk for TLS .................................................................................................................21 
6.3.1 High Risk for TLS: ................................................................................................21 
6.3.2 Medium Risk for TLS ............................................................................................21 
6.3.3 Low Risk for TLS ..................................................................................................21 
6.4 Dose-Modification Guidelines .....................................................................................22 
6.4.1 Recommended Ixazomib Criteria for Beginning or Delaying a Subsequent 
Treatment Cycle & Dose Modifications for Treatment Associated Toxicity.22 
6.4.2  Dosage in Patients with Renal Impairment...........................................................24 
 
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6.4.3 Recommended Dose Modifications for Rituximab Treatment Associated 
Toxicity ...........................................................................................................26 
6.5 Permitted Concomitant Medications and Procedures ...................................................27 
6.6 Precautions and Restrictions .........................................................................................28 
6.7 Management of Clinical Events ...................................................................................29 
6.8 Preparation, Reconstitution, and Dispensing ................................................................32 
6.9 Packaging and Labeling ................................................................................................32 
6.10 Storage, Handling, and Accountability .......................................................................32 
6.11 Study Compliance .......................................................................................................34 
6.12 Treatment Assignment (if applicable) ........................................................................34 
6.13 Termination of Treatment and/or Study Participation ................................................34 
7. STATISTICAL AND QUANTITATIVE ANALYSES .....................................................34 
7.1 Statistical Methods .......................................................................................................34 
7.1.1 Determination of Sample Size ...............................................................................35 
7.1.2 Randomization and Stratification ..........................................................................35 
7.1.3 Populations for Analysis ........................................................................................35 
7.1.4 Procedures for Handling Missing, Unused, and Spurious Data ............................35 
7.1.5 Demographic and Baseline Characteristics ...........................................................35 
7.1.6 Efficacy Analysis ...................................................................................................36 
7.1.7 Pharmacokinetics/Pharmacodynamics/Biomarkers ...............................................36 
7.1.8 Safety Analysis ......................................................................................................36 
7.1.9 Interim Analysis .....................................................................................................38 
8. ADVERSE EVENTS..........................................................................................................39 
8.1 Definitions ....................................................................................................................39 
8.1.1 Adverse Event Definition ......................................................................................39 
8.1.2 Adverse Drug Reaction ..........................................................................................41 
8.1.3 Serious Adverse Event Definition .........................................................................41 
8.2 Procedures for Reporting Serious Adverse Events .......................................................42 
8.3 Procedures for Reporting Drug Exposure During Pregnancy and Birth Events ..........44 
9. ADMINISTRATIVE REQUIREMENTS ..........................................................................45 
9.1 Data Collection .............................................................................................................45 
9.2 Data Confidentiality Plan .............................................................................................45 
9.3 Product Complaints ......................................................................................................45 
10. REFERENCES .................................................................................................................47 
11. APPENDICES ..................................................................................................................49 
11.1 Eastern Cooperative Oncology Group (ECOG) Scale for Performance Status ..........49 
11.2 Cockcroft-Gault Equation ...........................................................................................50 
11.3 SCHEDULE OF STUDY ASSESSMENTS ..............................................................51 
11.4 Lugano Criteria 2014 ..................................................................................................55 
 
 
 
 
 
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LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS 
Common abbreviations used in oncology protocols are provided below.  Program-specific or 
protocol-specific abbreviations must be added to this list, and unnecessary abbreviations 
removed, as applicable.  Abbreviations that are retained should not be changed.  
Abbreviation 
Term 
5-HT3 
5-hydroxytryptamine 3 serotonin receptor 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
API 
active pharmaceutical ingredient 
ASCO 
American Society of Clinical Oncology 
AST 
aspartate aminotransferase 
AUC 
area under the plasma concentration versus time curve 
AUC24 hr 
area under the plasma concentration versus time curve from zero to 24 hours 
AUCinf 
area under the plasma concentration versus time curve from zero to infinity 
AUCτ 
area under the plasma concentration versus time curve from zero to next dose 
BCRP 
breast cancer resistance protein 
βhCG 
beta-human chorionic gonadotropin 
BID 
bis in die; twice a day 
BM 
bone marrow 
BSA 
body surface area 
BTK 
Bruton’s tyrosine kinase 
BUN 
blood urea nitrogen 
CBC 
complete blood count 
CFR 
Code of Federal Regulations 
CL 
clearance, IV dosing 
CLP 
plasma clearance 
CLTotal 
total clearance 
Cmax 
single-dose maximum (peak) concentration   
CNS 
central nervous system 
CO2 
carbon dioxide 
CR 
complete remission  
CRM 
continual reassessment method 
CRP 
C-reactive protein 
CSF-1R 
colony-stimulating factor 1 receptor 
 
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Abbreviation 
Term 
CT 
computed tomography 
Ctrough 
single-dose end of dosing interval (trough) concentration 
CV 
cardiovascular  
CYP 
cytochrome P450 
DDI 
drug-drug interaction 
DLT 
dose-limiting toxicity 
DME 
drug metabolizing enzymes 
DNA 
deoxyribonucleic acid 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EDC 
electronic data capture 
ELISA 
enzyme-linked immunosorbent assay 
EOS 
End of Study (visit) 
EOT 
End of Treatment (visit) 
EU 
European Union 
FDA 
United States Food and Drug Administration 
GCP 
Good Clinical Practice 
G-CSF 
granulocyte colony stimulating factor 
GGT 
gamma glutamyl transferase 
GI 
Gastrointestinal 
GLP 
Good Laboratory Practices 
GM-CSF 
granulocyte macrophage-colony stimulating factor 
GMP 
Good Manufacturing Practice 
Hb 
Hemoglobin 
Hct 
Hematocrit 
HDPE 
high-density polyethylene 
hERG 
human ether-à-go-go related gene 
HIV 
human immunodeficiency virus 
HNSTD 
highest nonseverely toxic dose 
IB 
Investigator’s Brochure 
IC50 
concentration producing 50% inhibition 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
 
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Abbreviation 
Term 
IEC 
independent ethics committee 
IRB 
institutional review board 
ITT 
intent-to-treat 
IV 
intravenous; intravenously 
IVRS 
interactive voice response system 
Ki 
inhibition constant 
KPS 
Karnofsky Performance Status 
LDH 
lactate dehydrogenase 
LFT 
liver function test(s) 
MedDRA 
Medical Dictionary for Regulatory Activities 
Millennium 
Millennium Pharmaceuticals, Inc., and its affiliates 
MRI 
magnetic resonance imaging 
MRP2 
Multidrug resistance-associated protein 2 
MRU 
medical resource utilization 
MTD 
maximum tolerated dose 
MUGA 
multiple gated acquisition (scan) 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NPO 
nothing by mouth 
NYHA 
New York Heart Association 
OATP 
organic-anion-transporting polypeptide 
PBMC 
peripheral blood mononuclear cell 
PCR 
polymerase chain reaction 
Pgp 
P-glycoprotein 
PK 
pharmacokinetic(s) 
PO 
per os; by mouth (orally) 
PR 
partial response 
PRO 
patient-reported outcome 
PSA 
prostate-specific antigen 
QD 
quaque die; each day; once daily 
QID 
quater in die; 4 times a day 
QOD 
quaque altera die; every other day 
QOL 
quality of life 
 
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Abbreviation 
Term 
QTc 
rate-corrected QT interval (millisec) of electrocardiograph 
RBC 
red blood cell 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
serious adverse event 
SC 
Subcutaneous 
SD 
stable disease 
SmPC 
Summary of Product Characteristics 
t1/2 
terminal disposition half-life 
TGI 
tumor growth inhibition 
TLS 
Tumor lysis syndrome 
Tmax 
single-dose time to reach maximum (peak) concentration 
UK 
United Kingdom 
ULN 
upper limit of the normal range 
US 
United States 
Vz 
volume of distribution in the terminal phase 
WBC 
white blood cell 
WHO 
World Health Organization 
 
 
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1.    
BACKGROUND AND STUDY RATIONALE 
1.1    Scientific Background 
1.1.1    Disease Under Treatment 
Mantle Cell Lymphoma 
1.1.2         Ixazomib (MLN9708)  
1.2    Preclinical Experience 
Please refer to the current ixazomib Investigator’s Brochure (IB). 
1.3    Clinical Experience 
Our group published the bortezomib in combination with rituximab and cyclophosphamide in 
heavily pretreated high risk MCL patient population. We had ORR of 74% with CR rates of 
42%, we showed that no grade 3-4 neuropathy was noted in this population showing that 
proteasome inhibition plus anti CD20 antibody represents a reasonable regimen for MCL failing 
frontline therapy.18 In  another similar phase II study of rituximab, cyclophosphamide, 
bortezomib and dexamethasone in relapsed refractory MCL patients, Sonbol and colleagues at 
Mayo Clinic demonstrated robust overall response rate of 62% and complete remission rate of 
19%, with acceptable safety profile.19    
 
1.4   Pharmacokinetics and Drug Metabolism 
After oral dosing, absorption of ixazomib is rapid with a median first time to maximum 
observed plasma concentration (Tmax) of approximately 1 hour post dose. The plasma exposure 
(AUC) of ixazomib increases in a dose-proportional manner over a dose range of 0.2 to 10.6 mg 
based on population PK analysis. The absolute oral bioavailability (F) of ixazomib is estimated 
to be 58% based on population PK analysis.  A high-fat meal reduced ixazomib Cmax by 69% 
and AUC0-216 by 28%.  This indicates that a high-fat meal decreases both the rate and extent of 
absorption of ixazomib. Therefore, ixazomib should be dosed at least 2 hours after food or 
1 hour before food. 
The steady-state volume of distribution of ixazomib is large and is estimated to be 543 L based 
on a population PK model. Based on in vitro plasma protein binding measurements on samples 
from clinical studies (Studies C16015 and C16018), ixazomib is highly bound to plasma 
proteins (99%). Ixazomib concentrations are higher in whole blood than in plasma, indicating 
 
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extensive partitioning of ixazomib into red blood cells, which are known to contain high 
concentrations of the 20S proteasome. 
Metabolism appears to be the major route of elimination for ixazomib. In vitro studies indicate 
that ixazomib is metabolized by multiple cytochrome P450 (CYP) and non-CYP proteins. At 
concentrations exceeding those observed clinically (10 µM), ixazomib was metabolized by 
multiple CYP isoforms with estimated relative contributions of 3A4 (42.3%), 1A2 (26.1%), 2B6 
(16.0%), 2C8 (6.0%), 2D6 (4.8%), 2C19 (4.8%), and 2C9 (<1%). At 0.1 and 0.5 µM substrate 
concentrations, which are closer to clinical concentrations of ixazomib following oral 
administration of 4 mg ixazomib, non-CYP mediated clearance was observed and seemed to 
play a major role in ixazomib clearance in vitro.  These data indicate that at clinically relevant 
concentrations of ixazomib, non-CYP proteins contribute to the clearance of ixazomib and no 
specific CYP isozyme predominantly contributes to the clearance of ixazomib. Therefore, at 
clinically relevant concentrations of ixazomib, minimal CYP-mediated DDIs with a selective 
CYP inhibitor would be expected. 
Ixazomib is neither a time-dependent inhibitor nor a reversible inhibitor of CYPs 1A2, 2B6, 
2C8, 2C9, 2C19, 2D6, or 3A4/5.  Ixazomib did not induce CYPs 1A2, 2B6, and 3A4/5 activity 
or corresponding immunoreactive protein levels. Thus, the potential for ixazomib to produce 
DDIs via CYP isozyme induction or inhibition is low. 
Ixazomib is not a substrate of BCRP, MRP2 and OATPs. Ixazomib is not an inhibitor of P-gp, 
BCRP, MRP2, OATP1B1, OATP1B3, OAT1, OAT3, OCT2, MATE1 and MATE2-K. 
Ixazomib is unlikely to cause or be susceptible to clinical DDIs with substrates or inhibitors of 
clinically relevant drug transporters. 
The geometric mean terminal half-life (t1/2) of ixazomib is 9.5 days based on population PK 
analysis. For both IV and oral dosing, there is an approximately average 3-fold accumulation 
(based on AUC) following the Day 11 dose for the twice-weekly schedule and a 2-fold 
accumulation (based on AUC) following the Day 15 dose for the once-weekly schedule. 
Mean plasma clearance (CL) of ixazomib is 1.86 L/hr based on the results of a population PK 
analysis. Taken together with the blood-to-plasma AUC ratio of approximately 10, it can be 
inferred that ixazomib is a low clearance drug. Using the absolute oral bioavailability (F) 
estimate of 58% (also from a population PK model), this translates to an apparent oral plasma 
clearance (CL/F) of 3.21 L/hr. The geometric mean renal clearance for ixazomib is 0.119 L/hr, 
which is 3.7% of CL/F and 6.4% of CL estimated in a population PK analysis. Therefore, renal 
 
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clearance does not meaningfully contribute to ixazomib clearance in humans. Approximately 
62% of the administered radioactivity in the ADME study (Study C16016) was recovered in the 
urine and 22% of the total radioactivity was recovered in the feces after oral administration. 
Only 3.2% of the administered ixazomib dose was recovered in the urine as unchanged 
ixazomib up to 168 hours after oral dosing, suggesting that most of the total radioactivity in 
urine was attributable to metabolites.  
The PK of ixazomib was similar with and without co-administration of clarithromycin, a strong 
CYP3A inhibitor, and hence no dose adjustment is necessary when ixazomib is administered 
with strong CYP3A inhibitors. Consistently, in a population PK analysis, co-administration of 
strong CYP1A2 inhibitors did not affect ixazomib clearance. Therefore, no dose adjustment is 
required for patients receiving strong inhibitors of CYP1A2.  Based on information from the 
clinical rifampin DDI study, ixazomib Cmax and AUC0-last were reduced in the presence of 
rifampin by approximately 54% and 74%, respectively. Therefore, the co-administration of 
strong CYP3A inducers with ixazomib is not recommended.  
Mild or moderate renal impairment (CrCL ≥ 30 mL/min) did not alter the PK of ixazomib based 
on the results from a population PK analysis. As a result, no dose adjustment is required for 
patients with mild or moderate renal impairment.  In a dedicated renal impairment study 
(C16015), unbound AUC0-last was 38% higher in patients with severe renal impairment or ESRD 
patients requiring dialysis as compared to patients with normal renal function.  Accordingly, a 
reduced starting dose of ixazomib is appropriate in patients with severe renal impairment or 
ESRD requiring dialysis.  Pre- and post-dialyzer concentrations of ixazomib measured during 
the hemodialysis session were similar, suggesting that ixazomib is not readily dialyzable, 
consistent with its high plasma protein binding (99%). 
The PK of ixazomib is similar in patients with normal hepatic function and in patients with mild 
hepatic impairment, as defined by the National Cancer Institute Organ Dysfunction Working 
Group (total bilirubin <1.5 times the upper limit of normal [ULN]), based on the results from a 
population PK analysis. Consequently, no dose adjustment is required for patients with mild 
hepatic impairment. In a dedicated PK study in patients with moderate (total bilirubin >1.5 to 
3 times the ULN) or severe (total bilirubin >3 times the ULN) hepatic impairment (Study 
C16018), unbound dose-normalized AUC0-last was 27% higher in patients with moderate or 
severe hepatic impairment as compared to patients with normal hepatic function. Therefore, a 
reduced starting dose of ixazomib is appropriate in patients with moderate or severe hepatic 
impairment.  
 
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There was no statistically significant effect of age (23-91 years), sex, body surface area 
(1.2-2.7 m2), or race on the clearance of ixazomib based on the results from a population PK 
analysis. 
 
 
Further details on these studies are provided in the IB. 
 
1.5    Clinical Trial Experience Using the Oral Formulation of Ixazomib 
Please refer to the current ixazomib Investigator’s Brochure (IB). 
  
1.6    Relapsed and/or Refractory Multiple Myeloma 
Please refer to the current ixazomib Investigator’s Brochure (IB). 
  
1.7    Newly Diagnosed Multiple Myeloma (NDMM) 
Please refer to the current ixazomib Investigator’s Brochure (IB). 
 
1.8      Clinical Trial Experience Using the Intravenous Formulation of Ixazomib 
See the IB for descriptions of the 2 studies that investigated IV ixazomib in advanced solid 
tumors and advanced lymphoma (Studies C16001 and C16002, respectively). 
1.9 
Study Rationale 
Therapy for Mantle cell lymphoma has evolved rapidly over the past decade.  Ibrutinib, a 
Bruton’s tyrosine kinase (BTK) inhibitor has set a new standard for relapsed MCL, with many 
ongoing studies for frontline utilization.  However, patients who are refractory of ibrutinib face 
a difficult therapeutic challenge and poor survival outcome. One pathway believed to have 
significant role in ibrutinib refractoriness is over activation of the NFKB pathway.  Proteasome 
inhibition has been a successful therapeutic intervention in relapsed MCL.  However, the 
delivery logistics and side effects of proteasome inhibition have been difficult to manage and 
hence been underutilized. Therefore, ixazomib with its oral delivery system and milder side 
 
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effect profile would represent an improved modality for single and combination studies in this 
ibrutinib refractory MCL population. 
Rituximab is a genetically engineered chimeric murine/human monoclonal antibody directed 
against the CD20 antigen expressed on the surface of normal and malignant B lymphocytes. 
Rituximab is approved by the US Food and Drug Administration (FDA) for the treatment of 
patients with low grade CD20+ B-cell NHL. Rituximab kills NHL cells by multiple  
mechanisms, including direct induction of apoptosis, and by stimulating antibody-dependent 
cellular cytotoxicity (ADCC) and complement-mediated cytotoxicity. 
 
A retrospective analysis was performed to delineate the role of rituximab in the treatment of 
mantle cell lymphoma. Patients with newly-diagnosed MCL (n=37) and previously-treated 
MCL (n=50) received single-agent rituximab in the context of two multicenter clinical studies in 
1996 and 1997. The overall response rate was 37% (30 of 81 evaluable patients). The complete 
response rate was 14%. There was no difference in response rates between newly-diagnosed and 
previously-treated patients. At a median follow-up of 1.4 years, the median time to disease 
progression was 7 months. The median duration of response was one year, and was significantly 
longer for patients achieving CR vs. PR (p=0.04). 
 
1.10    
Potential Risks and Benefits 
Please refer to the current ixazomib IB. 
The clinical benefit of ixazomib continues to be studied in a comprehensive and global 
development plan that involves studies sponsored by Millennium.  Ixazomib appears to show 
early signs of anti-tumor activity as evidenced by at least 50% reduction in disease burden in 
some patients, including patients that have been heavily pretreated as well as those with newly 
diagnosed MM, and prolongs stabilization of the underlying disease in other patients across all 
ongoing trials.  The preliminary findings are favorable when considering historical and currently 
available therapies for the patient populations evaluated.  Though additional data are needed to 
characterize the clinical benefit of this drug, the emerging data supports expanded development 
of ixazomib for the treatment of patients with advanced malignancy. 
Proteasome inhibitor in combination with rituximab has been studied mantle cell lymphoma and 
other NHL without.  The combination studies of proteasome inhibitor and rituximab did not 
accentuate toxicity. 
 
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This study will be conducted in compliance with the protocol, good clinical practice (GCP), 
applicable regulatory requirements, and International Conference on Harmonisation (ICH) 
guidelines. 
2.    
STUDY OBJECTIVES 
2.1    Primary Objectives 
• To evaluate the complete remission rate of BTK inhibitor refractory MCL patients with 
ixazomib and rituximab at 16 weeks of therapy. 
 
2.2    Secondary Objectives 
1. To evaluate overall response rate (ORR) assessed by Lugano Criteria (2014). ORR is the 
summation of partial remission + complete remission rates. 
• To evaluate progression free survival (PFS) and overall survival (OS). Progression free 
survival time is the time interval from the start date of treatment to the date of 
progression or death due to any cause whichever happened first.  Overall survival time is 
the time interval from the start date of treatment to death date.  Patients will be censored 
at the last follow-up date if progression or death didn’t occur. 
• To evaluate the safety and tolerability  
 
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2.3    Tertiary/Exploratory Objectives  
To evaluate biomarkers of response to treatment and mechanisms of resistance with 
pretreatment and post-treatment bone marrow and blood samples with DNA and RNA 
sequencing and immune profiling by flow cytometry 
3.    
STUDY ENDPOINTS 
3.1    Primary Endpoints  
Complete remission rate of BTK inhibitor refractory MCL patients with ixazomib and rituximab 
at 16 weeks of therapy. 
3.2    Secondary Endpoints 
ORR as assessed by Lugano criteria (2014) at 16 weeks, TTR, PFS and OS 
Safety and tolerability at completion at weeks 8, 16, 28, 42 and 56 weeks.  Toxicities will/ be 
measured using CTCAE v4.0. 
3.3    Tertiary/Exploratory Endpoints  
Biomarkers of response to treatment and mechanisms of resistance with pretreatment and post-
treatment bone marrow and blood samples with DNA and RNA sequencing and immune 
profiling by flow cytometry. 
4.    
STUDY DESIGN  
4.1    Overview of Study Design 
Open label, single center, single –arm, phase II testing the combination of ixazomib and 
rituximab in the treatment of subjects with relapsed or refractory MCL.  The study will enroll 24 
patients. The treatment plan starts with oral ixazomib at the US approved dose of 4 mg.  All 
subjects will have disease restaging at 8 weeks.  Rituximab IV will be given once weekly for the 
first 4 weeks.  Rituximab IV will restart at cycle 3, and continue monthly until cycle 12.   
4.2    Number of Patients 
Twenty four subjects will be anticipated. 
 
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4.3    Duration of Study 
The study will recruit patients at a rate of 2 patients per month.  Anticipate 2 year recruitment 
unless futility endpoint is met and the study will terminate if futility conditions are met.  We 
will have approximately one year follow up from the last patient enrolled.  Anticipate 3 years 
duration of study. 
5.    
STUDY POPULATION 
5.1    Inclusion Criteria 
Each patient must meet all of the following inclusion criteria to be enrolled in the study: 
1. 
Male or female patients 18 years or older.  
2. 
Patients must have histologically confirmed diagnosis of Mantle Cell Lymphoma.  
3. 
Patients must have measurable disease, as defined by at least one of the following: 
• Lymph node or mass 2 cm or greater, splenomegaly > 13 cm 
• Bone marrow only disease as per morphology or flow cytometry 
4. 
Patients must have relapsed and/or refractory disease to at least 2 lines of therapy 
including either an anthracyline- or bendamustine- based regimen and a BTK inhibitor. 
5. 
Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status 
and/or other performance status 0, 1, or 2. 
6. 
Patients must have normal organ and marrow function as defined below: 
a. Absolute neutrophil count (ANC) ≥ 1,000/mm3 
b. Platelets ≥ 50,000/mm3 
c. Total bilirubin < 1.5 × institutional upper limit of normal (ULN).  In patients with 
documented Gilbert’s syndrome, total bilirubin ≤ 2.5 × ULN. 
d. AST (SGOT)/ALT(SGPT) ≤ 3 × ULN 
e. Creatinine clearance ≥ 30 mL/min (See Appendix 11.2) 
7. 
Patients must be willing to give written consent before performance of any study related 
procedures not part of standard medical care, with the understanding that consent may be 
withdrawn by the patient at any time without prejudice to future medical care. 
8. 
Female patients who:  
 
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• Are postmenopausal for at least 1 year before the screening visit, OR 
• Are surgically sterile, OR 
• If they are of childbearing potential, agree to practice 2 effective methods of 
contraception, at the same time, from the time of signing the informed consent 
form through 90 days after the last dose of study drug OR, 
• Agree to practice true abstinence when this is in line with the preferred and 
usual lifestyle of the patient.  (Periodic abstinence [e.g., calendar, ovulation, 
symptothermal, post-ovulation methods] and withdrawal are not acceptable 
methods of contraception.) 
 
9. 
Male patients, even if surgically sterilized (i.e., status post-vasectomy), must agree to 
one of the following: 
• Agree to practice effective barrier contraception during the entire study 
treatment period and through 90 days after the last dose of study drug OR, 
• Agree to practice true abstinence when this is in line with the preferred and 
usual lifestyle of the patient.  (Periodic abstinence [e.g., calendar, ovulation, 
symptothermal, post-ovulation methods] and withdrawal are not acceptable 
methods of contraception.) 
 
5.2    Exclusion Criteria 
Patients meeting any of the following exclusion criteria are not to be enrolled in the study: 
1. 
Female patients who are lactating or have a positive serum pregnancy test during the 
screening period.  
2. 
Failure to have fully recovered (i.e., ≤ Grade 1 toxicity) from the reversible effects of 
prior chemotherapy. 
3. 
Major surgery within 14 days before enrollment. 
 
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4. 
Radiotherapy within 14 days before enrollment. If the involved field is small, 7 days will 
be considered a sufficient interval between treatment and administration of the ixazomib. 
5. 
Central nervous system involvement. 
6. 
Infection requiring systemic antibiotic therapy or other serious infection within 14 days 
before study enrollment. Patient may be eligible, if infectious disease specialist approves 
start of therapy AND subject has completed course of antibiotic therapy. 
7. 
Evidence of current uncontrolled cardiovascular conditions, including uncontrolled 
hypertension, uncontrolled cardiac arrhythmias, symptomatic congestive heart failure, 
unstable angina, or myocardial infarction within the past 6 months. 
8. 
Systemic treatment, within 14 days before the first dose of ixazomib, with strong 
CYP3A inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, 
phenobarbital), or use of St. John’s wort. 
9. 
Ongoing or active systemic infection, active (DNA PCR positivity) hepatitis B or C 
virus infection, or known human immunodeficiency virus (HIV) positive. 
10. Any serious medical or psychiatric illness that could, in the investigator’s opinion, 
potentially interfere with the completion of treatment according to this protocol. 
11. Known allergy to any of the study medications, their analogues, or excipients in the 
various formulations of any agent. 
12. Known GI disease or GI procedure that could interfere with the oral absorption or 
tolerance of ixazomib including difficulty swallowing. 
13. Diagnosed or treated for another malignancy within 2 years before study enrollment or 
previously diagnosed with another malignancy and have any evidence of residual 
disease.  Patients with nonmelanoma skin cancer or carcinoma in situ of any type are not 
excluded if they have undergone complete resection. 
14. Patient has ≥ Grade 3 peripheral neuropathy, or Grade 2 with pain on clinical 
examination during the screening period. 
 
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15. Participation in other clinical trials, including those with other investigational agents not 
included in this trial, within 30 days of the start of this trial and throughout the duration 
of this trial. 
16.  Patients that have previously been treated with proteasome inhibitors, or participated in 
a study with proteasome inhibitors whether treated with proteasome inhibitors or not. 
6.    
STUDY DRUG 
6.1  
Description of Investigational Agents 
Ixazomib Capsules 
The ixazomib drug product is provided in strengths of 4.0-, 3.0-, and 2.3-mg capsules as the 
active boronic acid. The different dose strengths are differentiated by both capsule size and 
color as described below: 
 
Dose Strength 
Capsule Size 
Capsule Color 
4.0 mg 
Size 4 
Ivory 
3.0 mg 
Size 3 
Light gray 
2.3 mg 
Size 2 
Light pink 
 
 
 
For additional details, please see the ixazomib IB. 
 
6.2    Study Drug Administration 
Cycles 1-12 (28-day cycle) 
 
• Ixazomib 4 mg PO on Days 1, 8, and 15 (3 mg if CrCl < 30 mL/min) 
• Rituximab 375mg/m2 IV weekly for the first 4 weeks  in cycle 1, and starting cycle 3, 
Rituximab 375mg/m2 IV will be given on Day 1 of each cycle. Total of 12 cycles will be 
given. 
Patients benefiting from the clinical trial will continue with Ixazomib indefinitely until patient 
withdraws consent, disease progression or unacceptable toxicity. 
Ixazomib Administration 
All protocol-specific criteria for administration of study drug must be met and documented 
before drug administration.  Study drug will be administered or dispensed only to eligible 
patients under the supervision of the investigator or identified subinvestigator(s).  Patients 
should be monitored for toxicity, as necessary, and doses of ixazomib should be modified as 
 
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needed to accommodate patient tolerance to treatment; this may include symptomatic treatment, 
dose interruptions, and adjustments of ixazomib dose (see Section 6.3). 
Capsules of ixazomib will also be referred to as study drug.  Study drug will be supplied by 
Millennium as capsules of 2.3-, 3.0- and 4.0 mg ixazomib.  
The prescribed administration of ixazomib doses in this study is 4 mg ixazomib in a 28 day 
cycle.  
Patients should be instructed to swallow ixazomib capsules whole, with water, and not to break, 
chew, or open the capsules.  Ixazomib should be taken on an empty stomach (no food or drink) 
at least 1 hour before or at least 2 hours after food.  Each capsule should be swallowed 
separately with a sip of water.  A total of approximately 8 ounces (240 mL) of water should be 
taken with the capsules.   
Missed doses can be taken as soon as the patient remembers if the next scheduled dose is 
72 hours or more away.  A double dose should not be taken to make up for a missed dose.  If the 
patient vomits after taking a dose, the patient should not repeat the dose but should resume 
dosing at the time of the next scheduled dose. 
Ixazomib Destruction 
Investigational ixazomib (expired or end of study) should be destroyed on site according to the 
institution’s standard operating procedure.  Be sure to document removal and destruction on 
drug accountability logs. 
Rituximab Administration 
Pre-medication consisting of acetaminophen and diphenhydramine should be considered before 
each infusion of rituximab to attenuate potential infusion reactions. Since transient hypotension 
may occur during rituximab infusion, consideration should be given to withholding 
antihypertensive medications 12 hours prior to rituximab infusion.  
 
Rituximab First Infusion*: The Rituximab solution for infusion should be administered 
intravenously at an initial rate of 50 mg/hr. Rituximab should not be mixed or diluted with other 
drugs. If hypersensitivity or infusion related events do not occur, the infusion can be escalated to 
50 mg/hr increments every 30 minutes, to a maximum of 400 mg/hr. If hypersensitivity or an 
 
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infusion- related event develops, the infusion should be temporarily slowed or interrupted. The 
infusion can continue at one-half the previous rate upon improvement of patient symptoms.  
Subsequent Rituximab Infusions: Subsequent Rituximab infusions can be administered at an 
initial rate of 100 mg/hr, and increased by 100 mg/hr increments at 30 minute intervals, to a 
maximum of 400 mg/hr as tolerated. 
*Patients with peripheral blood involvement (leukemic presentation) as defined for this purpose 
as > 20,000 lymphocytes per mm3 as determined by flow cytometry studies, rituximab will 
NOT be initiated on Day 1. In this case, ixazomib will be started alone. Rituximab may be 
initiated on the next cycle if the lymphocyte count drops to < 20,000/mm3 in peripheral blood. 
For such patients, or for those with high tumor burden, despite lymphocyte count < 20,000 
cells/mm3 (as determined by the principal investigator), infusion of rituximab may be 
abbreviated as outlined below. If the patient progresses despite one cycle of ixazomib, the 
patient will be taken off protocol.  
 
Day 1 – Rituximab 50 mg/m2  
 
Day 2 – If no cytokine release phenomenon is noted on Day 1 and the peripheral blood white 
cell counts have decreased to < 20,000 cells/mm3 or < 25% of base line WBC counts, then the 
dose of rituximab can be increased to 325 mg/m2 on Day 2 at PI discretion.  
A similar 2-day split dose approach may be taken for rituximab infusion on Days 8, 15 and 22 in 
patients with high tumor burden or high peripheral blood WBC counts as determined by the PI 
prior to each infusion of rituximab. If initiation of rituximab is delayed until Cycle 2, it will be 
followed by rituximab on day one of every cycle starting in Cycles 4 – 8.  
Please refer to rituximab package insert for details concerning drug storage, preparation and 
administration guidelines.  
All rituximab infusions will be administered at MD Anderson. 
 
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6.3    Risk for TLS 
6.3.1 High Risk for TLS: 
High risk for TLS – Subjects with high tumor burden (at least one lesion >10 cm; or at least 
one lesion >5 cm and lymphocyte count >25,000 cells/mm3) and/or with baseline creatinine 
clearance (CrCl) <80 mL/min. 
o Subjects at high risk for TLS will be hospitalized for a minimum of 24 hours (and up to 48 
hours at the discretion of the investigator) after the first dose of ixazomib for monitoring 
and prophylaxis of TLS. 
o During hospitalization of the first dose for high risk pts, Blood Chemistries should be 
analyzed at baseline, between 4-8 hours, 12-24 hours after administration of the drug for 
signs of electrolyte changes. The 24 blood chemistries should be analyzed for signs of TLS 
prior to administering next dose of ixazomib. 
o Patients should receive oral hydration of 1.5 – 2 liters of fluid and 150 – 200 m/hr as 
tolerated. Start allopurinol or xanthine oxidase inhibitor 2 to 3 days prior to initiation of 
therapy and rasburicase if baseline uric acid is elevated. 
o Pre-dose blood chemistries at each step up dose of ixazomib and correct any blood 
chemistry abnormalities. 
o For high-risk patients, outpatient monitoring should occur at next dose pre-dose, 6-8 hour 
and 24 hours. The next dose should not be administrated until the 24 hour labs are examined 
for signs of TLS 
6.3.2 Medium Risk for TLS 
Any lymph node 5 cm to <10 cm OR lymphocyte count ≥ 25 x109/L 
o Patients should receive oral hydration of 1.5 – 2 liters of fluid and start allopurinol or 
xanthine oxidase inhibitor 2 to 3 days prior to initiation of therapy and consider additional 
intravenous fluids. 
o Pre-dose blood chemistries at each step up dose of ixazomib and correct any blood 
chemistry abnormalities. 
o Medium risk patients should have outpatient monitoring of blood chemistries for the 1st 
dose of ixazomib. Monitoring should occur at baseline, 6-8 hours and 24 hours. The next 
dose should not be administered until the 24 hour lab results are examined for signs of TLS. 
Subsequent doses require a pre-dose blood chemistry assessment. 
 
6.3.3 Low Risk for TLS 
All others not meeting the criteria for high risk for TLS. 
o Patients should receive oral hydration of 1.5 – 2 liters of fluid and start allopurinol or 
xanthine oxidase inhibitor 2 to 3 days prior to initiation of therapy if uric acid levels are 
 
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above normal reference range. 
o Pre-dose blood chemistries at each dose of ixazomib and correct any blood chemistry 
abnormalities. 
o Low risk pts should have outpatient monitoring of blood chemistries for the 1st dose of 
ixazomib. Monitoring should occur at baseline.  If abnormal renal function (Cr > 1.4) or 
above normal randge on uric acid.  Should repeat complete metabolic panel (CMP) in 24 
hours to make sure no biochemical evidence of tumor lysis. 
 
6.4    Dose-Modification Guidelines  
 
6.4.1 Recommended Ixazomib Criteria for Beginning or Delaying a Subsequent 
Treatment Cycle & Dose Modifications for Treatment Associated Toxicity 
Treatment with ixazomib will use a cycle length of 28 days. For a new cycle of treatment to 
begin, the patient must meet the following criteria: 
 
• ANC must be ≥ 1,000/mm3. 
• Platelet count must be ≥ 50,000/mm3. 
• All other nonhematologic toxicity (except for alopecia) must have resolved to ≤ Grade 1 
or to the patient’s baseline condition 
 
If the patient fails to meet the above-cited criteria for initiation of the next cycle of treatment, 
dosing should be delayed for 1 week. At the end of that time, the patient should be re-evaluated 
to determine whether the criteria have been met. If the patient continues to fail to meet the 
above-cited criteria, delay therapy and continue to reevaluate. The maximum delay before 
treatment should be discontinued will be 3 weeks or at the discretion of the Principal 
Investigator. 
 
For dosing recommendations upon recovery, refer to Table 6-2 and Table 6-3. 
 
 
Table 6-1 MLN908 Dose Adjustments 
 
Dose Level 
Dose (mg) 
Starting Dose 
4.0 mg 
-1 
3.0 mg 
 
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-2 
2.3 mg 
-3 
Discontinue 
 
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6.4.2 Dosage in Patients with Renal Impairment  
Reduce the starting dose of Ixazomib (MLN908) to 3 mg in patients with severe renal 
impairment (creatinine clearance less than 30 mL/min) or end-stage renal disease (ESRD) 
requiring dialysis. Ixazomib is not dialyzable and therefore can be administered without 
regard to the timing of dialysis 
Dosage adjustments for hematologic toxicity are outlined in Table 6-2. 
Table 6-2    
Ixazomib Dose Adjustments for Hematologic Toxicities 
Criteria 
Action 
Within-Cycle Dose Modifications 
 
• 
If platelet count ≤ 30 × 109/L or ANC ≤ 0.50 × 
109/L on a ixazomib dosing day (other than Day 
1) 
• 
Ixazomib dose should be withheld.   
• 
Complete blood count (CBC) with differential 
should be repeated at least every other day until 
the ANC and/or platelet counts have exceeded 
the prespecified values (see Section 6.3.1) on at 
least 2 occasions.   
• 
Upon recovery, ixazomib may be reinitiated with 
1 dose level reduction.  
Dose Modifications for Subsequent Treatment Cycles 
 
• 
Delay of > 2 weeks in the start of a subsequent 
cycle due to lack of toxicity recovery as 
defined in Section 6.3.1. 
• 
ANC < 1.0 × 109/L, platelet count < 50 × 109/L 
• 
Hold ixazomib until resolution as per criteria 
Section 6.3.1. 
• 
Upon recovery, reduce ixazomib 1 dose level. 
• 
The maximum delay before treatment should be 
discontinued will be 3 weeks or at the discretion 
of the PI. 
Dose Modifications for Subsequent Treatment Cycles 
 
• 
All hematologic toxicities 
• 
For hematologic toxicity that occurs during a 
cycle but recover in time for the start of the 
next cycle,: 
o 
 If dose was reduced within the 
cycle, start the next cycle at that 
same dose. 
o 
If due to toxicity timing, i.e., after 
Day 15 dosing thus a dose 
reduction was not required at that 
point in the cycle, reduce ixazomib 
by 1 dose level at the start of that 
cycle. 
o 
Do not reduce the dose both within 
a cycle and at the start of the cycle 
for the same most severe toxicity. 
 
 
 
 
 
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Treatment modifications due to ixazomib-related AEs are outlined in Table 6-3. 
Table 6-3    
Ixazomib Treatment Modification (Delays, Reductions, and 
Discontinuations) Due to Adverse Events (Non-Hematologic Toxicities) 
Adverse Event (Severity) 
Action on Study Drug 
Further Considerations 
Peripheral Neuropathy: 
Grade 1 peripheral neuropathy 
 
• No action 
 
Grade 1 signs and symptoms:  
asymptomatic; without pain or loss 
of function; clinical or diagnostic 
observations only [14] 
 
 
New or worsening Grade 1 
peripheral neuropathy with pain or 
Grade 2 
• Hold study drug until 
resolution to Grade ≤ 1 or 
baseline 
Grade 2 signs and symptoms:  
Moderate symptoms; limiting 
instrumental activities of daily 
living (ADL) [14] 
 
 
New or worsening Grade 2 
peripheral neuropathy with pain or 
Grade 3 
• Hold study drug until 
resolution to Grade ≤ 1 or 
baseline 
• Reduce study drug to next 
lower dose upon recovery 
 
Grade 3 signs and symptoms:  
severe symptoms; limiting self-
care ADL; assistive device 
indicated [14] 
New or worsening Grade 4 
peripheral neuropathy 
• Discontinue study drug 
 
 
 
Grade 2 Rash 
• 
Symptomatic 
recommendations as per 
section 6.7 
The investigator and project 
clinician may discuss 
considerations for dose 
modifications and symptom 
management. 
 
Grade 3 nonhematologic toxicity 
judged to be related to study drug 
 
• Hold study drug until 
resolution to Grade < 1 or 
baseline 
 
Symptomatic recommendations 
noted in Section 6.7 
 
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Table 6-3    
Ixazomib Treatment Modification (Delays, Reductions, and 
Discontinuations) Due to Adverse Events (Non-Hematologic Toxicities) 
Adverse Event (Severity) 
Action on Study Drug 
Further Considerations 
If not recovered to 
< Grade 1 or baseline 
within 4 weeks 
 
• Reduce study drug 1 to next 
lower dose upon return to 
< Grade 1 or baseline 
 
Subsequent recurrence 
Grade 3 that does not 
recover to < Grade 1 or 
baseline within 4 weeks 
• Hold study drug until 
resolution to Grade < 1 or 
baseline 
• Reduce study drug to next 
lower dose  
Monitor closely, take appropriate 
medical precautions, and provide 
appropriate symptomatic care 
 
Grade 4 nonhematologic toxicities 
judged to be related to study drug 
 
• Consider permanently 
discontinuing study drug 
 
Exceptions are cases in which the 
investigator determines the patient 
is obtaining a clinical benefit  
 
Once ixazomib is reduced for any toxicity, the dose may not be re-escalated. 
Rituximab and Ixazomib individually are FDA approved for NHL and multiple myeloma, 
respectively.  The combination of a proteasome inhibitor plus anti-CD20 antibody has been 
studied previously.   
Mechanistically, rituximab and Ixazomib does not have over lapping mechanism of action. We 
have in place Hepatitis screening at baseline. Rituximab does not have overlapping non-
hematologic toxicity with Ixazomib.  However, they will both cause cytotoxicity to 
hematopoietic cells, cytopenias and related increased risk for infection.  We are mainly 
concerned for non-hematologic toxicities.  Therefore, we would like to monitor peripheral 
neuropathy toxicities.  We will stop the current dose level and consider treating patients at a 
lower dose level for Ixazomib if we observe at anytime that the rate of any grade of peripheral 
neuropathy toxicity is > 40% or the rate of grade 3 or higher peripheral neuropathy toxicity is 
>10%. 
6.4.3 Recommended Dose Modifications for Rituximab Treatment Associated 
Toxicity  
There will be no dose reductions for rituximab. However, the rate of infusion may be reduced for 
patients experiencing hypersensitivity reaction. 
 
 
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Excluded Concomitant Medications and Procedures 
The following medications and procedures are prohibited during the study. 
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 (Rationale:  If there 
were to be a drug-drug interaction with an inducer, ixazomib exposure would be decreased): 
• Strong CYP3A inducers:  rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, and 
phenobarbital 
The following medicinal products and procedures are prohibited during the study. 
• Excluded foods and dietary supplements include St. John’s wort.  
• Any antineoplastic treatment with activity against MCL, other than study drugs 
• Radiation therapy (note that, in general, the requirement for local radiation therapy 
indicates disease progression) 
• Platelet transfusions to help patients meet eligibility criteria are not allowed within 
3 days prior to study drug dosing for any dosing day 
6.5    Permitted Concomitant Medications and Procedures  
The following medications and procedures are permitted during the study: 
• Antiemetics, including 5-HT3 serotonin receptor antagonists, may be used at the 
discretion of the investigator. 
• Loperamide or other antidiarrheal should be used for symptomatic diarrhea at discretion 
of the investigator. The dose and regimen will be according to institutional guidelines. 
IVF should be given to prevent volume depletion. 
• Growth factors (e.g., granulocyte colony stimulating factor [G-CSF], granulocyte 
macrophage-colony stimulating factor [GM-CSF], recombinant erythropoietin) are 
permitted. Their use should follow published guidelines and/or institutional practice; 
however, alternative usage may be reviewed with the Millennium Clinical or Medical 
Representative . Erythropoietin will be allowed in this study. Their use should follow 
published guidelines and/or institutional practice. 
 
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• Patients should be transfused with red cells and platelets as clinically indicated and 
according to institutional guidelines. 
• Antiviral therapy such as acyclovir may be administered if medically appropriate. 
• Concomitant treatment with bisphosphonates will be permitted, as appropriate. 
• Patients who experience worsening neuropathy from baseline may be observed for 
recovery, and have dose reductions/delays as indicated in the protocol, and any 
supportive therapy or intervention may be initiated as appropriate at the discretion of the 
investigator. 
• Supportive measures consistent with optimal patient care may be given throughout the 
study. 
6.6    Precautions and Restrictions  
• Fluid deficit should be corrected before initiation of treatment and during treatment. 
• Nonsteroidal anti-inflammatory drugs (NSAIDs) should be avoided with impaired renal 
function given reported NSAID-induced renal failure in patients with decreased renal 
function. 
Pregnancy 
It is not known what effects ixazomib has on human pregnancy or development of the embryo 
or fetus.  Therefore, female patients participating in this study should avoid becoming pregnant, 
and male patients should avoid impregnating a female partner.  Nonsterilized female patients of 
reproductive age group and male patients should use effective methods of contraception through 
defined periods during and after study treatment as specified below. 
Female patients must meet 1 of the following:  
• Postmenopausal for at least 1 year before the screening visit, or 
• Surgically sterile, or 
• If they are of childbearing potential, agree to practice 2 effective methods of 
contraception from the time of signing of the informed consent form through 90 days 
after the last dose of study drug, or  
 
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• Agree to practice true abstinence, when this is in line with the preferred and usual 
lifestyle of the subject.  (Periodic abstinence [e.g., calendar, ovulation, symptothermal, 
postovulation methods] and withdrawal are not acceptable methods of contraception.) 
Male patients, even if surgically sterilized (i.e., status postvasectomy) must agree to 1 of the 
following: 
• Practice effective barrier contraception during the entire study treatment period and 
through 90 days after the last dose of study drug, or 
• Agree to practice true abstinence, when this is in line with the preferred and usual 
lifestyle of the subject.  (Periodic abstinence [e.g., calendar, ovulation, symptothermal, 
postovulation methods for the female partner] and withdrawal are not acceptable 
methods of contraception.) 
 
6.7  
 Management of Clinical Events  
Adverse drug reactions such as thrombocytopenia, diarrhea, fatigue, nausea, vomiting, and rash 
have been associated with ixazomib treatment.  Management guidelines regarding these events 
are outlined below.  Further details of management of ixazomib AEs are described in Section 6 
of the ixazomib IB.   
Prophylaxis Against Risk of Reactivation of Herpes Infection 
Patients may be at an increased risk of infection including reactivation of herpes zoster and 
herpes simplex viruses.  Antiviral therapy such as acyclovir, valacyclovir, or other antivirals 
may be initiated as clinically indicated.  Other antivirals are also acceptable. 
Nausea and/or Vomiting 
Standard anti-emetics including 5-hydroxytryptamine 3 serotonin receptor antagonists are 
recommended for emesis if it occurs once treatment is initiated; prophylactic anti-emetics may 
also be considered at the physician’s discretion. Dexamethasone should not be administered as 
an anti-emetic. Fluid deficit should be corrected before initiation of study drug and during 
treatment. 
Diarrhea 
Prophylactic antidiarrheals will not be used in this protocol. However, diarrhea should be 
managed according to clinical practice, including the administration of antidiarrheals once 
 
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infectious causes are excluded. Fluid intake should be maintained to avoid dehydration. Fluid 
deficit should be corrected before initiation of treatment and during treatment. 
Erythematous Rash With or Without Pruritus 
As with bortezomib, rash with or without pruritus has been reported with ixazomib, primarily at 
the higher doses tested and when given with agents where rash is an overlapping toxicity.  The 
rash may range from limited erythematous areas, macular and/or small papular bumps that may 
or may not be pruritic over a few areas of the body, to a more generalized eruption that is 
predominately on the trunk or extremities.  Rash has been most commonly characterized as 
maculopapular or macular.  To date, when it does occur, rash is most commonly reported within 
the first 3 cycles of therapy.  The rash is often transient, self-limiting, and is typically Grade 1 to 
2 in severity.  
Symptomatic measures such as antihistamines or corticosteroids (oral or topical) have been 
successfully used to manage rash and have been used prophylactically in subsequent cycles.  
The use of a topical, IV, or oral steroid (e.g., prednisone ≤ 10 mg per day or equivalent) is 
permitted.  Management of a Grade 3 rash may require intravenous antihistamines or 
corticosteroids.  Administration of ixazomib (and/or other causative agent if given in 
combination) should be modified per protocol and re-initiated at a reduced level from where 
rash was noted (also, per protocol).   
In line with clinical practice, dermatology consult and biopsy of Grade 3 or higher rash or any 
SAE involving rash is recommended.  Prophylactic measures should also be considered if a 
patient has previously developed a rash (e.g., using a thick, alcohol-free emollient cream on dry 
areas of the body or oral or topical antihistamines).  A rare risk is Stevens-Johnson Syndrome, a 
severe and potentially life-threatening rash with skin peeling and mouth sores, which should be 
managed symptomatically according to standard medical practice.  Punch biopsies for 
histopathological analysis are encouraged at the discretion of the investigator. 
Thrombocytopenia 
Blood counts should be monitored regularly as outlined in the protocol with additional testing 
obtained according to standard clinical practice. Thrombocytopenia may be severe but has been 
manageable with platelet transfusions according to standard clinical practice. Ixazomib 
administration should be modified as noted as per dose modification recommendations in the 
protocol when thrombocytopenia occurs (see Table 6-2). Therapy can be reinitiated at a reduced 
level upon recovery of platelet counts. A rare risk is thrombotic thrombocytopenic purpura 
(TTP), a rare blood disorder where blood clots form in small blood vessels throughout the body 
 
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characterized by thrombocytopenia, petechiae, fever, or possibly more serious signs and 
symptoms. TTP should be managed symptomatically according to standard medical practice. 
Neutropenia 
Blood counts should be monitored regularly as outlined in the protocol with additional testing 
obtained according to standard clinical practice.  Neutropenia may be severe but has been 
manageable.  Growth factor support is not required but may be considered according to standard 
clinical practice.  Ixazomib administration should be modified as noted as per dose modification 
recommendations in the protocol when neutropenia occurs (see Table 6-2).  Therapy can be 
reinitiated at a reduced level upon recovery of ANCs. 
Fluid Deficit 
Dehydration should be avoided since ixazomib may cause vomiting, diarrhea, and dehydration.  
Acute renal failure has been reported in patients treated with ixazomib, commonly in the setting 
of the previously noted gastrointestinal toxicities and dehydration. 
Fluid deficit should be corrected before initiation of study drug and as needed during treatment 
to avoid dehydration. 
Hypotension 
Symptomatic hypotension and orthostatic hypotension with or without syncope have been 
reported with ixazomib.  Blood pressure should be closely monitored while the patient is on 
study treatment and fluid deficit should be corrected as needed, especially in the setting of 
concomitant symptoms such as nausea, vomiting, diarrhea, or anorexia.  Patients taking 
medications and/or diuretics to manage their blood pressure (for either hypo- or hypertension) 
should be managed according to standard clinical practice, including considerations for dose 
adjustments of their concomitant medications during the course of the trial.  Fluid deficit should 
be corrected before initiation of study drug and as needed during treatment to avoid dehydration. 
Posterior Reversible Encephalopathy Syndrome 
One case of posterior reversible encephalopathy syndrome, which ultimately resolved, has been 
reported with ixazomib.  This condition is characterized by headache, seizures and visual loss, 
as well as abrupt increase in blood pressure.  Diagnosis may be confirmed by magnetic 
resonance imaging (MRI).  If the syndrome is diagnosed or suspected, symptom-directed 
treatment should be maintained until the condition is reversed by control of hypertension or 
other instigating factors. 
 
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Transverse Myelitis 
Transverse myelitis has also been reported with ixazomib. It is not known if ixazomib causes 
transverse myelitis; however, because it happened to a patient receiving ixazomib, the 
possibility that ixazomib may have contributed to transverse myelitis cannot be excluded. 
 
6.8  
Preparation, Reconstitution, and Dispensing 
Ixazomib is an anticancer drug and as with other potentially toxic compounds caution should be 
exercised when handling ixazomib capsules. 
Rituximab 
Use appropriate aseptic technique. Parenteral drug products should be inspected visually for 
particulate matter and discoloration prior to administration. Rituximab should be a clear, 
colorless liquid. Do not use vial if particulates or discoloration is present. Administration 
Withdraw the necessary amount of rituximab and dilute to a final concentration of 1 mg/mL to 4 
mg/mL in an infusion bag containing either 0.9% Sodium Chloride, USP, or 5% Dextrose in 
Water, USP. Gently invert the bag to mix the solution. Do not mix or dilute with other drugs. 
Discard any unused portion left in the vial. Storage rituximab solutions for infusion may be 
stored at 2°C−8°C (36°F−46°F) for 24 hours. rituximab solutions for infusion have been shown 
to be stable for an additional 24 hours at room temperature. However, since rituximab solutions 
do not contain a preservative, diluted solutions should be stored refrigerated (2°C−8°C). No 
incompatibilities between rituximab and polyvinylchloride or polyethylene bags have been 
observed. 
6.9  
Packaging and Labeling 
The study drug ixazomib capsules will be provided by Millennium.  The study drug will be 
labeled and handled as open-label material, and packaging labels will fulfill all requirements 
specified by governing regulations.   
The capsules are individually packaged using cold-form foil-foil blisters that are in a child-
resistant carton.  There are 3 capsules in each wallet/carton.  
6.10  
Storage, Handling, and Accountability 
Upon receipt at the investigative site, ixazomib should remain in the blister and carton provided 
until use or until drug is dispensed. The container should be stored at the investigative site as per 
 
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labeled instructions (do not store above 30oC or 86°F, do not freeze). Ensure that the drug is 
used before the retest expiry date provided by Millennium. Expiry extensions will be 
communicated accordingly with updated documentation to support the extended shelf life. 
In countries where local regulations permit, ixazomib capsules dispensed to the patient for take-
home dosing should remain in the blister packaging and stored per labeled instructions as noted 
above until the point of use. The investigative site is responsible for providing the medication to 
the patient in the correct daily dose configurations. Comprehensive instructions should be 
provided to the patient in order to ensure compliance with dosing procedures. Patients who are 
receiving take-home medication should be given only 1 cycle of medication at a time. Patients 
should be instructed to store the medication per labeled instructions (not store above 30oC or 
86°F, do not freeze) for the duration of each cycle. Patients should be instructed to return their 
empty blister packs to the investigative site, rather than discarding them. Reconciliation will 
occur accordingly when the patient returns for their next cycle of take-home medication. Any 
extreme in temperature should be reported as an excursion and should be dealt with on a case-
by-case basis. 
Ixazomib should be handled with due care. Patients should be instructed not to chew, break, or 
open capsules. In case of contact with broken capsules, raising dust should be avoided during 
the clean-up operation. The product may be harmful by inhalation, ingestion, or skin absorption. 
Gloves and protective clothing should be worn during cleanup and return of broken capsules 
and powder to minimize skin contact. 
The area should be ventilated and the site washed with soap and water after material pick-up is 
complete. The material should be disposed of as hazardous medical waste in compliance with 
federal, state, and local regulations. 
In case of contact with the powder (e.g., from a broken capsule), skin should be washed 
immediately with soap and copious amounts of water for at least 15 minutes. In case of contact 
with the eyes, copious amounts of water should be used to flush the eyes for at least 15 minutes. 
Medical personnel should be notified. Patients are to be instructed on proper storage, 
accountability, and administration of ixazomib, including that ixazomib is to be taken as intact 
capsules. 
 
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6.11      Study Compliance 
Study drug will be administered or dispensed only to eligible patients under the supervision of 
the investigator or identified sub-investigator(s).  The appropriate study personnel will maintain 
records of study drug receipt and dispensing. 
6.12   
Treatment Assignment (if applicable) 
Open labeled single armed study, all subjects will receive study medications of ixazomib and 
rituximab dispensed from MD Anderson Institutional pharmacy. 
6.13   
Termination of Treatment and/or Study Participation 
Patients will be informed that they have the right to withdraw from the study at any time for any 
reason, without prejudice to their medical care.  The investigator also has the right to withdraw 
patients from the study for any of the following reasons: 
• Adverse event 
• Protocol violation 
• Lost to follow-up 
• Progressive disease 
• Study terminated  
At the time of withdrawal, all study procedures outlined for the End of Study visit should be 
completed. The primary reason for patient’s withdrawal from the study should be recorded in 
the source documents and CRF. 
7.    
STATISTICAL AND QUANTITATIVE ANALYSES 
7.1    Statistical Methods 
Primary endpoint: complete response rate at 16 weeks measured using Lugano (2014) 
Patient populations 
All endpoints will be measured on patients that received at least one dose of the study drug. 
 
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7.1.1     Determination of Sample Size 
We plan to enroll 24 patients.   When the true complete response rate at 4 months (week 16) is 
30%, a cohort size of 24 subjects will provide a 95% confidence interval with a lower bound of 
0.12 which is higher than the CR rate of 10% observed historically for Rituximab monotherapy. 
7.1.2    Randomization and Stratification   
No patient will be randomized. 
 
7.1.3    Populations for Analysis 
Primary endpoint:  
1.  Complete remission rate of BTK inhibitor refractory MCL patients with ixazomib and 
rituximab at 16 weeks of therapy. 
Secondary endpoints:  
1. ORR using Lugano Criterion at 16 weeks. ORR is the summation of partial remission + 
complete remission rates. 
2. PFS and OS is defined as the time from commencement of treatment to the date of 
progression and death from any cause, respectively. Progression free survival time is the 
time interval from the start date of treatment to the date of progression or death due to 
any cause whichever happened first.  Overall survival time is the time interval from the 
start date of treatment to death date.  Patients will be censored at the last follow-up date 
if progression or death didn’t occur. 
3. Tolerability:  completion at weeks 8, 16, 28, 42 and 56.  Toxicity measured using 
CTCAE V4.0. 
 
7.1.4    Procedures for Handling Missing, Unused, and Spurious Data 
There will be no missing, unused or spurious data.   
 
7.1.5    Demographic and Baseline Characteristics 
Clinical and laboratory characteristics, age, sex, stage, MIPI scores etc., will be scored and 
presented in tabular or percentage form. 
 
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7.1.6    Efficacy Analysis 
Overall response and complete response at each of the pre-specified time points will be 
described as percentage with exact ninety-five percent (95%) confidence interval based on 
binomial distribution. PFS and OS curves will be described using Kaplan-Meier methods. The 
curves will be presented with 95% confidence intervals. Patients who are still on follow-up 
without experiencing the relevant event by the closeout date will be censored. The maximum 
grade of each toxicity will be described in tabular form as count and percentages. 
 
7.1.7    Pharmacokinetics/Pharmacodynamics/Biomarkers  
 
Patient immunity and MCL profile:  Alterations in patient immune parameters and MCL profile 
during various (screening, end of cycle 4, end of cycle 8, end of cycle 15, and end of study) time 
points during therapy will be assessed by 8 colored flow cytometry, evaluating populations of T 
cell, regulatory T cells, PD-1 and PDL1 expressions to generate hypothesis for future studies in 
combination with checkpoint inhibitors or Bispecific antibody therapies. Blood and bone 
marrow samples will be collected under protocol LAB11-0342 (Collection and use of samples 
from patients with lymphoma, multiple myeloma, and other plasma cell dyscrasias for 
translational research, PI: Liang Zhang) and transported to specified laboratory.  Participants 
will sign a separate consent for their samples to be collected under LAB11-0342. 
 
Minimal residual disease (MRD) measurement by Flow Cytometry:  a four color assay as per 
institutional pathology flow cytometry analysis, CD3, CD4, CD5, CD8, CD10, CD19, CDCD20 
CD22, CD34, CD38, CD43, CD45 CD56, CD200 and Lambda and Kappa.  Blood and bone 
marrow samples will be collected under protocol LAB11-0342 (Collection and use of samples 
from patients with lymphoma, multiple myeloma, and other plasma cell dyscrasias for 
translational research, PI: Liang Zhang) and transported to specified laboratory.  Participants 
will sign a separate consent for their samples to be collected under LAB11-0342. 
 
7.1.8    Safety Analysis 
Adverse event monitoring, vital signs, physical examination, 12-lead ECG, and laboratory 
assessments will be evaluated. Guidelines for the management for TLS are provided below in 
 
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Section 7.1.8.1. A safety analysis will be performed for all subjects participating in the study 
who took at least 1 dose of study drug. 
 
For patient safety, the event of grade 3 or higher peripheral neuropathy toxicity within the first two 
cycles will be monitored.  A rate of higher than 20% is considered excessive.   
The prior probability of grade 3 or higher peripheral neuropathy toxicity is modelled by beta 
distribution (Beta (0.2, 0.8)).  Denoting the probability of toxicity by p (TOX), the following 
decision criterion will be applied: We will stop the current dose level and consider treating patients 
at a lower dose level for Ixazomib if Prob{p(TOX) > 20% | data} > 0.90 
 
Patients will be monitored in a cohort of 6 according to the following stopping boundaries for grade 
3 or higher peripheral neuropathy toxicity.   
Number of patients 
evaluated 
Recommend stopping if ≥ toxicities 
observed 
6 
3-6 
12 
5-12 
18 
7-18 
24 
Always stop with this many patients 
 
The operating characteristics are summarized in the following table (based on simulations from 
10,000 trials). 
True Toxicity Rate 
Prob(stop the dose 
early) 
Average number of patients treated 
0.05 
0.0023 
23.96 
0.10 
0.0182 
23.69 
0.15 
0.0616 
23.00 
0.20 
0.1439 
21.76 
 
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0.25 
0.2677 
19.97 
0.30 
0.4214 
17.77 
0.35 
0.5831 
15.39 
 
7.1.8.1 Recommendation for Management of Tumor Lysis Syndrome (TLS) 
Event 
Occurrence 
Action 
Tumor Lysis Syndrome 
Blood chemistry 
changes or symptoms 
suggestive of TLS 
Any 
Withhold the next dose. If resolved within 24 
to 48 hours of last dose, resume at 
the same dose. 
For any blood chemistry changes requiring 
more than 48 hours to resolve, resume at a 
reduced dose by one dose level. 
For any events of clinical TLS, resume at a 
reduced dose following resolution. 
 
7.1.9    Interim Analysis  
If early progression occurs in 2 or more of the first 5 patients, or 4 or more of the first 10 
patientsprior to the first restaging at week 16, the study will be closed for future enrollment.  
Using this rule, the probability of stopping the study early is 81.3% after 5 patients and 89.6% 
after 10 patients when the true rate of early progression is 50%. Early progression is defined as 
greater than 50% increase in the sum of bidirectional tumor measurement or new lesion prior to 
the first restaging at week 16. 
 
 
 
 
 
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8.    
ADVERSE EVENTS   
8.1    Definitions 
8.1.1       Adverse Event Definition 
Adverse event (AE) means any untoward medical occurrence in a patient or subject 
administered a pharmaceutical product; the untoward medical occurrence does not necessarily 
have a causal relationship with this treatment.  An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal (investigational) product whether or not it is related to the 
medicinal product.  This includes any newly occurring event, or a previous condition that has 
increased in severity or frequency since the administration of study drug. 
An abnormal laboratory value will not be assessed as an AE unless that value leads to 
discontinuation or delay in treatment, dose modification, therapeutic intervention, or is 
considered by the investigator to be a clinically significant change from baseline.  
The investigator (or physician designee) is responsible for verifying and providing source 
documentation for all adverse events and assigning the attribution for all adverse events for 
subjects enrolled. 
For the purposes of this clinical study, AEs include events which are either new or represent 
detectable exacerbations of pre-existing conditions. 
The term “disease progression” should not be reported as an adverse event term; instead, signs 
and symptoms of clinical sequelae resulting from disease progression/lack of efficacy will be 
reported if they fulfill the serious adverse event definition. As an example, "worsening of 
underlying disease" or the clinical diagnosis that is associated with disease progression should 
be reported. 
Adverse events may include, but are not limited to: 
• Subjective or objective symptoms provided by the patient and/or observed by the 
Investigator or study staff including laboratory abnormalities of clinical significance. 
• Any AEs experienced by the patient from the time of informed consent through the 
completion of final study procedures (approximately 30 days following the last dose of 
study drug). 
• AEs not previously observed in the patient that emerge during the protocol-specified AE 
reporting period, including signs or symptoms associated with the underlying disease that 
were not present before the AE reporting period 
 
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• Complications that occur as a result of protocol-mandated interventions (e.g., invasive 
procedures such as biopsies). 
The following are NOT considered AEs: 
• Pre-existing condition: A pre-existing condition (documented on the medical history CRF) 
is not considered an AE unless the severity, frequency, or character of the event worsens 
during the study period. 
• Pre-planned or elective hospitalization: A hospitalization planned before signing the 
informed consent form is not considered an SAE, but rather a therapeutic intervention. 
However, if during the pre-planned hospitalization an event occurs, which prolongs the 
hospitalization or meets any other SAE criteria, the event will be considered an SAE. 
Surgeries or interventions that were under consideration, but not performed before 
enrollment in the study, will not be considered serious if they are performed after enrollment 
in the study for a condition that has not changed from its baseline level. Elective 
hospitalizations for social reasons, solely for the administration of chemotherapy, or due to 
long travel distances are also not SAEs. 
• Diagnostic testing and procedures: Testing and procedures should not to be reported as AEs 
or SAEs, but rather the cause for the test or procedure should be reported. 
• Asymptomatic treatment related lymphocytosis: This event should also not be considered 
an AE. Patients with treatment-related lymphocytosis should remain on study treatment and 
continue with all study-related procedures. 
 
Recommended Adverse Event Recording Guidelines 
 
Attribution 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Unrelated 
Phase I 
Phase I 
Phase I 
Phase II   
 
Phase I 
Phase II   
Phase III 
Phase I  
Phase II   
Phase III 
Unlikely 
Phase I 
Phase I 
Phase I  
Phase II   
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Possible 
Phase I 
Phase II   
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Probable 
Phase I 
Phase II  
 
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Definitive 
Phase I 
Phase II  
  
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Phase I 
Phase II  
Phase III  
Phase I 
Phase II   
Phase III 
 
 
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8.1.2       Adverse Drug Reaction 
 
An adverse drug reaction (ADR) is a response to a medicinal product which is noxious and 
unintended. Response in this context means that a causal relationship between a medicinal 
product and an adverse event is at least a reasonable possibility. This includes adverse reactions 
which arise from: use of a medicinal product within the terms of the marketing authorization; 
use outside the terms of the marketing authorization, including overdose, misuse, abuse and 
medication errors; and occupational exposure*. 
 
* This corresponds to the exposure to a medicinal product for human use as a result of one’s 
occupation, such as nurses who may handle products routinely in their occupational setting. 
  
8.1.3    Serious Adverse Event Definition 
 
An adverse event or suspected adverse reaction is considered “serious” if, in the view of either the 
investigator or the sponsor, it results in any of the following outcomes: 
 
• Death 
• A life-threatening adverse drug experience – any adverse experience that places the patient, in the 
view of the initial reporter, at immediate risk of death from the adverse experience as it occurred. 
It does not include an adverse experience that, had it occurred in a more severe form, might have 
caused death. 
• Inpatient hospitalization or prolongation of existing hospitalization 
• A persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions. 
• A congenital anomaly/birth defect. 
 
Important medical events that may not result in death, be life-threatening, or require hospitalization 
may be considered a serious adverse drug experience when, based upon appropriate medical 
judgment, they may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. Examples of such medical 
events include allergic bronchospasm requiring intensive treatment in an emergency room or at 
home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse (21 CFR 312.32). 
  
It is the responsibility of the PI and the research team to ensure serious adverse events are reported 
according to the Code of Federal Regulations, Good Clinical Practices, the protocol guidelines, the 
sponsor’s guidelines, and Institutional Review Board policy. 
 
 
 
 
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8.2    Procedures for Reporting Serious Adverse Events 
AEs may be spontaneously reported by the patient and/or in response to an open question from 
study personnel or revealed by observation, physical examination, or other diagnostic 
procedures.  Any clinically relevant deterioration in laboratory assessments or other clinical 
finding is considered an AE.  When possible, signs and symptoms indicating a common 
underlying pathology should be noted as one comprehensive event.  For serious AEs, the 
investigator must determine both the intensity of the event and the relationship of the event to 
study drug administration.  
AEs which are serious must be reported to Millennium Pharmacovigilance (or designee) from 
the 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 Millennium Pharmacovigilance (or designee).  In addition, 
new primary malignancies that occur during the follow-up periods must be reported, regardless 
of causality to study regimen, for a minimum of three years after the last dose of the 
investigational product, starting from the first dose of study drug. All new cases of primary 
malignancy must be reported to Millennium Pharmacovigilance (or designee).  Active follow up 
for detection of second primary malignancies beyond the planned study is not required; 
however, if the sponsor-investigator learns about the occurrence of a second primary 
malignancy in one of the study patients within 3 years after the last study drug administration he 
must report the event to Millennium Pharmacovigilance (or designee).  
Planned hospital admissions or surgical procedures for an illness or disease that existed before 
the patient was enrolled in the trial are not to be considered AEs unless the condition 
deteriorated in an unexpected manner during the trial (e.g., surgery was performed earlier or 
later than planned).  All SAEs should be monitored until they are resolved or are clearly 
determined to be due to a patient’s stable or chronic condition or intercurrent illness(es). 
The principal investigator, Hun Ju Lee 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 Millennium 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 
 
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sponsor-investigator’s observation or awareness of the event 
 
See below for contact information for the reporting of SAEs to Millennium Pharmacovigilance.   
The sponsor-investigator must fax or email the SAE Form per the timelines above.  A sample of 
an SAE Form will be provided.   
The SAE report must include at minimum: 
• Event term(s) 
• Serious criteria 
• Intensity of the event(s): Sponsor-investigator’s or sub-investigator’s 
determination.  Intensity for each SAE, including any lab abnormalities, will be 
determined by using the NCI CTCAE version specified in the protocol, as a 
guideline, whenever possible.  The criteria are available online at 
http://ctep.cancer.gov/reporting/ctc.html. 
• Causality of the event(s): Sponsor-investigator’s or sub-investigator’s 
determination of the relationship of the event(s) to study drug administration.  
Follow-up information on the SAE may be requested by Millennium.   
Intensity for each SAE, including any lab abnormalities, will be determined by using the NCI 
CTCAE version used at your institution, as a guideline, whenever possible.  The criteria are 
available online at http://ctep.cancer.gov/reporting/ctc.html. 
In the event that this is a multisite study, the sponsor-investigator is responsible to ensure that 
the SAE reports are sent to Millennium Pharmacovigilance (or designee) from all sites 
participating in the study.  Sub-investigators must report all SAEs to the sponsor-investigator so 
that the sponsor-investigator can meet his/her foregoing reporting obligations to the required 
regulatory agencies and to Millennium Pharmacovigilance, unless otherwise agreed between the 
sponsor-investigator and sub-investigator(s).   
Relationship to all study drugs for each SAE will be determined by the investigator or sub-
investigator by responding yes or no to the question: Is there a reasonable possibility that the AE 
is associated with the study drug(s)? 
 
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Sponsor-investigator must also provide Millennium Pharmacovigilance with a copy of all 
communications with applicable regulatory authorities related to the study product(s), as soon as 
possible but no later than 4 calendar days of such communication. 
 
 
SAE and Pregnancy Reporting Contact Information 
 
US & Canada 
Fax Number: 1-800-963-6290 
Email: TakedaOncoCases@cognizant.com 
 
Suggested Reporting Form:   
• 
SAE Report Form (provided by Millennium) 
• 
US FDA MedWatch 3500A:  
http://www.fda.gov/Safety/MedWatch/HowToReport/DownloadForms/default.htm 
• 
Any other form deemed appropriate by the sponsor-investigator 
8.3    Procedures for Reporting Drug Exposure During Pregnancy and Birth Events 
If a woman becomes pregnant or suspects that she is pregnant while participating in this study 
or within 90 days after the last dose, she must inform the investigator immediately and 
permanently discontinue study drug.  The sponsor-investigator must immediately fax a 
completed Pregnancy Form to the Millennium Department of Pharmacovigilance or designee 
(see Section 8.2).  The pregnancy must be followed for the final pregnancy outcome. 
If a female partner of a male patient becomes pregnant during the male patient’s participation in 
this study, the sponsor-investigator must also immediately fax a completed Pregnancy Form to 
the Millennium Department of Pharmacovigilance or designee (see Section 8.2).  Every effort 
should be made to follow the pregnancy for the final pregnancy outcome. 
Suggested Pregnancy Reporting Form: 
• Pregnancy Report Form (provided by Millennium)   
 
 
 
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9.    
ADMINISTRATIVE REQUIREMENTS  
9.1 Data Collection 
Data for the study will be collected and entered in RedCap database and in CORe.   
 
9.2 Data Confidentiality Plan 
To maintain patient confidentiality, all information will be de-identified and only labeled with a 
sponsor provided deidentifed random number key. A confidential list will be created that links the 
code to the subject's name.  However, patient confidentiality will be strictly maintained at all 
times.  Only authorized people (PI, delegated research staff) will have access to the list of names. 
The data and the confidential list of coded names will be kept securely at MD Anderson /  Red 
Cap database and password protected behind the institutional firewall. This information is 
expected to lead to publication and confidentiality will be maintained throughout the analysis. No 
individual patient will be identified in any published or presented data, only summary data will be 
used. All paper files containing data will be destroyed per MDACC policy on medical records 
retention and destruction within 5 years after study publication.  Electronic data will not be 
destroyed after 5 years as electronic data on MDACC servers is stored indefinitely.  
 
 
9.3    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 Millennium (see 
below) and report the event.  Whenever possible, the associated product should be maintained in 
accordance with the label instructions pending further guidance from a Millennium Quality 
representative. 
A medication error is a preventable event that involves an identifiable patient and that leads to 
inappropriate medication use, which may result in patient harm.  While overdoses and underdoses 
constitute medication errors, doses missed inadvertently by a patient do not.  Investigators must 
record all medication errors (including overdose) on the appropriate CRF form. Individuals who 
identify a potential medication error situation should immediately contact Takeda (see below) and 
report the event.  
 
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For Product Complaints, or Medication Errors (Including Overdose), contact Takeda 
Pharmacovigilance 
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 Millennium Pharmacovigilance (refer to Section 
8.2). 
 
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10.    REFERENCES    
1. Cheson, B., et al., Recommendations for Initial Evaluation, Staging, and Response Assessment of 
Hodgkin and Non-Hodgkin Lymphoma: The Lugano Classification. Journal of Clinical Oncology 
2014 32:27, 3059-3067 
2. 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. 
3. 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 
4. 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 
5. 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. 
6. 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 Meeting. 2012. Chicago, Illinois. 
7. 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.. 
8. 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. 
9. 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. 
10. 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. 
11. 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. 
12. 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. 
 
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13. 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. 
14. 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. 
15. 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. 
16. 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 
17. Common Terminology Criteria for Adverse Events (CTCAE). 2010. 
18. Lee HJ, Romaguera JE, Feng L, Desai AP, Zhang L, Fanale M, et al. Phase II Study of Bortezomib in 
Combination with Cyclophosphamide and Rituximab for Relapsed or Refractory Mantle Cell 
Lymphoma. Oncologist. 2017 May;22(5):549-553. doi: 10.1634/theoncologist.2016-0328. Epub 
2017 Apr 13. 
19. Sonbol MB, Hilal T, Dueck AC, Rosenthal AC, Conley CR, Kosiorek HE, et al. A phase 2 study of 
rituximab, cyclophosphamide, bortezomib and dexamethasone (R-CyBorD) in relapsed low 
grade and mantle cell lymphoma, Leukemia & Lymphoma, 59:9, 2128-
2134, DOI: 10.1080/10428194.2017.1416368 
 
 
 
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11.    APPENDICES 
11.1    
Eastern Cooperative Oncology Group (ECOG) Scale for Performance Status 
Grade 
Description 
0 
Normal activity.  Fully active, able to carry on all predisease performance without restriction 
1 
Symptoms but ambulatory.  Restricted in physically strenuous activity, but ambulatory and 
able to carry out work of a light or sedentary nature (e.g., light housework, office work) 
2 
In bed < 50% of the time.  Ambulatory and capable of all self-care, but unable to carry out 
any work activities.  Up and about more than 50% of waking hours. 
3 
In bed > 50% of the time.  Capable of only limited self-care, confined to bed or chair more 
than 50% of waking hours. 
4 
100% bedridden.  Completely disabled.  Cannot carry on any self-care.  Totally confined to 
bed or chair 
5 
Dead 
Source:  Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET et al. Toxicity and 
response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982; 5 (6):649-55.  
 
 
 
 
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11.2   
Cockcroft-Gault Equation 
For males: 
Creatinine Clearance = (140-age[years]) × weight [kg] 
OR 
(140–age[years]) × weight [kg] 
72 × (serum creatinine[mg/dL])  
0.81 × (serum creatinine[µmol/L]) 
 
For females: 
Creatinine Clearance = 0.85 (140-age[years]) × weight [kg] OR  0.85 (140-age[years]) × weight [kg] 
72 × (serum creatinine[mg/dL])  
0.81 × (serum creatinine[µmol/L]) 
 
Source:  Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 
1976;16(1):31-41. 
==
 
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11.3 SCHEDULE OF STUDY ASSESSMENTS 
Days (+/-3d) 
ScreeningA C1D1 
C2D1 
C3D1 
C4D1 
C5D1 
C6D1 
C7D1 
C8D1 
C9D1 
C10D1 
C11D1 
C12D1 
C13D1 
C14D1 
C15D1+ 
EOS 
(+/- 7 
days) 
Informed 
consent, review 
inclusion 
/exclusion, 
general medical 
historyB 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs, 
weight and 
height 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECOG and B 
symptomsC 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical ExamD 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12 lead ECG and 
ECHOE 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PET/CT or CT 
scanF 
X 
 
 
 
XF 
 
 
 
XF 
 
 
 
XF 
 
 
XF 
XF 
Bone marrow 
biopsy/aspirateG 
X 
 
 
 
XG 
 
 
 
XG 
 
 
 
 
 
 
XG 
X 
MRD 
assessmentH 
X 
 
 
 
XH 
 
 
 
XH 
 
 
 
 
 
 
XH 
X 
Tumor biopsy 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
CBC, CMP, and 
Hepatitis Testing 
i, j  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
XJ 
 
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Footnotes Table of Assessments 
 
A.  Perform within 28 days prior to cycle 1 day 1.  Asssessments performed as standard of care may be used for screening.  BIOPSY TISSUES obtained up 
to 8 weeks prior to start of C1D1 can be used as long as we have enough tissue for analysis. 
B. Written informed consent form(s) must be signed by the patient before any study specific procedures are performed. 
C. B symptoms: Unexplained weight loss>10% over previous 6 months, fever (>38C) and/or drenching night sweats. 
D. Complete physical exam at screening, including cardiovascular, respiratory, abdominal, lymph node, skin ENT, extremties and endocrinological 
examination.  Targeted physical exams at subsequent visits, limited to systems of clinical relevance, (i.e., cardiovascular, respiratory, lymph nodes, 
liver, and spleen), and dose systems associated with clinical signs/symptoms. 
E. Single 12-lead ECG and Echo is required at screening. If clinically significant abnormality is noted by the attending physician, a referral to cardiology 
will be made. 
F.  CT scans must include neck, chest, abdomen, pelvis and include oral and IV contrast.  PET/CT performed at screening, at the end of Cycle 4, at the end 
of cycle 8, at the end of Cycle 15, and at the End of Study visit if not performed within the last 2 months. After Cycle 15, CT scans will be performed 
every 4 months.  If  PET/CT is performed and includes a CT scan of sufficient diagnostic quality and provides bidimensional nodal and liver and spleen 
measurements, an additional dedicated CT is not required at the time point. MRI may be used in place of CT at investigator's discretion.   
G.  Bone marrow biopsies/aspirates at specified time points are mandatory (Screening, at the end of cycle 4, at the end of cycle 8, at the end of Cycle 15, 
and at the End of Study visit ) unless shown to be clear on previous examination by multi flow cytometry minimum sensitivity 10-4.  * If patient has 
progression on the study, we do require Bone marrow biopsy/aspiration at progression.  For example, if week 9 imaging study shows clear progression 
beyond a reasonable doubt, we would like to perform a bone marrow biopsy/aspiration for end of study. 
H.  Minimal residual disease assessment by ASO PCR in mantle cell lymphoma patients and flow cytometry.  Peripheral blood will be collected from all 
patients as well as bone marrow aspirates in those patients required to undergo bone marrow aspirate and biopsy will be collected at Screening, at the 
end of cycle 4, at the end of cycle 8, at the end of cycle 15, and at the End of Study visit. Collect 20 mL's of blood in EDTA and 5 mL of a bone marrow 
aspirate in EDTA.  Transport within 4 hours at room temperature to appropriate laboratory.   
Days (+/-3d) 
ScreeningA C1D1 C2D1 C3D1 C4D1 C5D1 C6D1 C7D1 C8D1 C9D1 C10D1 C11D1 C12D1 C13D1 C14D1 C15D1 
 
Quantitative 
Immunoglobulins 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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I. 
Blood chemistry: Sodium, potassium, chloride, BUN, creatinine, glucose, calcium, total protein, albumin, AST, ALT, alkaline phosphatase, total 
bilirubin, LDH, phosphate, uric acid, magnesium and bicarbonate. 
J. 
Hepatitis C antibody, hepatitis B surface antigen and hepatitis B core antibody will be evaluated. If hepatitis B core antibody or hepatitis B surface 
antigen or Hepatitis C antibody is positive, then PCR to quantitate hepatitis B DNA or hepatitis C RNA must be performed. DNA PCR needs to be 
confirmed negative (<29 U) prior to enrollment in subjects who are hepatitis B core antibody or hepatitis B surface antigen positive. For subjects who 
are hepatitis C antibody positive, hepatitis C PCR needs to be confirmed negative prior to enrollment. Hepatitis testing does not need to be repeated at 
the End of Study visit. 
 
Special Attention 
 
Patients who wish to continue with ixazomib after completion of week 56 can continue on with therapy with ixazomib single agent.  Rituximab will not be 
continued post week 56. 
End of study biopsy and MRD testing is required. 
 
Medications 
C1D1 
 C1D8 
C1D15 
C1D21 
C2 and Beyond 
Rituximab 
X 
X 
X 
X 
Rituxan to continue 
C3D1, with each 
cycle D1 
Ixazomib 
X 
X 
X 
 
Continue days 1, 8 
and 15 of each 
cycle. 
TLS AssessmentA 
X 
X 
X 
X 
Continue days 1, 8 
and 15 of each 
cycle. 
Physical Exam 
 
X 
 
 
 
 
CBC 
 
X 
X 
X 
X 
 
CMP 
 
X 
X 
X 
X 
 
 
 
 
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A.  Patients should be assessed for risk and should receive appropriate prophylaxis for TLS, including hydration and anti-
hyperuricemics. Monitor blood chemistries and manage abnormalities promptly. Interrupt dosing if needed. Employ more 
intensive measures (intravenous hydration, frequent monitoring, hospitalization) as overall risk increases 
 
 
 
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11.4 Lugano Criteria 2014 
 
 
 
 
 
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Source: Recommendations for Initial Evaluation, Staging, and Response Assessment of Hodgkin and Non-Hodgkin 
Lymphoma: The Lugano Classification 
Bruce D. Cheson, Richard I. Fisher, Sally F. Barrington, Franco Cavalli, Lawrence H. Schwartz, Emanuele Zucca, 
and T. Andrew Lister 
Journal of Clinical Oncology 2014 32:27, 3059-3067  
 
 
 
 
 
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