A Phase I-II Trial of DA-EPOCH-R Plus Ixazomib as Frontline Therapy for Patients With MYC-aberrant Lymphoid Malignancies: The DACIPHOR Regimen
Phase: PHASE1
Conditions: Adult Burkitt Lymphoma, B-Cell Lymphoma, Unclassifiable, With Features Intermediate Between Diffuse Large B-Cell Lymphoma and Burkitt Lymphoma, Diffuse Large B-Cell Lymphoma, MYC Gene Mutation, Plasmablastic Lymphoma
Sponsor: Northwestern University

NU Study Number: NU 14H09
Takeda Study Number: IISR-2013-M100150
NU_14H09-Protocol A-8 - 01.16.2020
A Phase I-II Trial of DA-EPOCH-R Plus Ixazomib as Frontline Therapy 
for Patients with MYC-aberrant Lymphoid Malignancies: The 
DACIPHOR Regimen
Principal Investigator:
Barbara Pro, MD
Division of Hematology/Oncology
Northwestern University
676 N. St. Clair, Suite 850
Chicago, IL 60611
Phone: 312-695-6180
Fax: 312.695.6189
barbara.pro@northwestern.edu 
Sub-Investigator(s):
Biostatistician:
Borko Jovanovic, PhD
borko@northwestern.edu 
Study Intervention(s):
DA-EPOCH-R and Ixazomib (MLN-9708)
IND Number:
126936
IND Holder:
Barbara Pro, MD
Funding Source: 
Takeda Pharmaceuticals
Version Date:
January 16, 2020 (Amendment 8)
Coordinating Center:
Clinical Trials Office (CTO)
Robert H. Lurie Comprehensive Cancer Center 
Northwestern University
676 N. St. Clair, Suite 1200
Chicago, IL  60611
http://cancer.northwestern.edu/research/clinical-trials-office/index.html
Leo Gordon, MD
Jane Winter, MD
Shuo Ma, MD, PhD
Reem Karmali, MD
Valerie Nelson, MD
Northwestern University 
Andreas Klein, MD
Tufts Medical Center
800 Washington St 
Boston, MA 02111 
Phone: 617-636-2694 
aklein2@tuftsmedicalcenter.org  
Deepa Jagadeesh, MD, MPH
Cleveland Clinic
9500 Euclid Ave.
Cleveland, OH 44195
Phone: 216-444-0857
Fax: 216-444-9464
jagaded@ccf.org
Mehdi Hamadani, M.D.
Froedtert & Medical College of Wisconsin
Division of Hematology and Oncology
9200 W. Wisconsin Avenue 
Milwaukee, WI 53226
Phone: 414-805-6700
Fax: 414-805-0714
mhamadani@mcw.edu 
Andrew Evens, DO, MSc
Rutgers Cancer Institute of New Jersey
195 Little Albany Street
New Brunswick, NJ 08901
Phone: 732-235-5459
Fax: 732-448-7894
Email: andrew.evens@rutgers.edu
IRB #: STU00200596-CR0004 Approved by NU IRB for use on or after 1/4/2021 through 1/3/2022.

NU Study Number: NU 14H09
Takeda Study Number: IISR-2013-M100150
NU_14H09-Protocol A-8 - 01.16.2020
TABLE OF CONTENTS
SCHEMA .........................................................................................................................................5
LIST OF ABBREVIATIONS ............................................................................................................6
STUDY SUMMARY .........................................................................................................................7
1.0
INTRODUCTION – BACKGROUND & RATIONALE..........................................................9
1.1
Disease Background .......................................................................................................9
1.2
Ixazomib ........................................................................................................................10
1.3
Rationale for the Current Study.....................................................................................19
2.0
OBJECTIVES & ENDPOINTS...........................................................................................20
2.1
Primary Objectives/Endpoints .......................................................................................20
2.2
Secondary Objectives/Endpoints...................................................................................20
2.3
Exploratory Objectives/Endpoints..................................................................................20
3.0
PATIENT ELIGIBILITY......................................................................................................21
3.1
Inclusion Criteria............................................................................................................21
3.2
Exclusion Criteria...........................................................................................................23
4.0
TREATMENT PLAN ..........................................................................................................24
4.1
Overview........................................................................................................................24
4.2
Treatment Schedule ......................................................................................................24
4.3
Treatment Administration ..............................................................................................25
4.4
Dose Escalation Scheme – Phase I Induction Only ......................................................26
4.5
Dose Modifications ........................................................................................................27
4.6
Concomitant Medications/Procedures...........................................................................31
4.7
CNS Prophylaxis and Treatment...................................................................................32
4.8
Supportive Care.............................................................................................................32
4.9
Duration of Therapy & Follow-Up ..................................................................................34
4.10
Removal of Subjects from Study Treatment and/or Study as a Whole .........................34
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NU Study Number: NU 14H09
Takeda Study Number: IISR-2013-M100150
NU_14H09-Protocol A-8 - 01.16.2020
4.11
Replacement of Subjects...............................................................................................35
5.0
STUDY PROCEDURES.....................................................................................................36
6.0
ENDPOINT ASSESSMENT...............................................................................................38
6.1
Primary Endpoints .........................................................................................................38
6.2
Secondary Endpoints ....................................................................................................38
6.3
Exploratory Endpoints ...................................................................................................38
6.4
Definitions......................................................................................................................38
7.0
ADVERSE EVENTS ..........................................................................................................42
7.1
Adverse Event Monitoring .............................................................................................42
7.2
Definitions & Descriptions..............................................................................................42
7.3
Adverse Event Reporting...............................................................................................44
8.0
DRUG INFORMATION ......................................................................................................46
8.1
Ixazomib ........................................................................................................................46
8.2
Doxorubicin HCL ...........................................................................................................48
8.3
Etoposide.......................................................................................................................49
8.4
Vincristine sulfate ..........................................................................................................50
8.5
Cyclophosphamide........................................................................................................51
8.6
Prednisone ....................................................................................................................52
8.7
Rituximab.......................................................................................................................53
8.8
Filgrastim .......................................................................................................................55
8.9
Pegfilgrastim..................................................................................................................55
8.10
Methotrexate..................................................................................................................56
9.0
SPECIMEN BANKING.......................................................................................................58
10.0
STATISTICAL CONSIDERATIONS ..................................................................................58
10.1
Study Design/Study Endpoints......................................................................................58
10.2
Sample Size and Accrual ..............................................................................................58
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NU Study Number: NU 14H09
Takeda Study Number: IISR-2013-M100150
NU_14H09-Protocol A-8 - 01.16.2020
10.3
Data Analyses Plans .....................................................................................................59
11.0
STUDY MANAGEMENT....................................................................................................59
11.1
Institutional Review Board (IRB) Approval and Consent...............................................59
11.2
Amendments .................................................................................................................59
11.3
Registration Procedures................................................................................................59
11.4
Instructions for Participating Sites .................................................................................60
11.5
Data Management and Monitoring/Auditing ..................................................................60
11.6
Adherence to the Protocol.............................................................................................60
11.7
Investigator Obligations.................................................................................................61
11.8
Publication Policy ..........................................................................................................61
REFERENCES ..............................................................................................................................63
APPENDIX I – PROTOCOL HISTORY OF CHANGES ................................................................65
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NU Study Number: NU 14H09
Takeda Study Number: IISR-2013-M100150
NU_14H09-Protocol A-8 - 01.16.2020
5
SCHEMA
 
*Due to high risk of CNS involvement, all patients will undergo diagnostic LP before or during 
their first treatment with DA-EPOCH-R, and if negative, IT methotrexate may be given per 
physician’s preference using institutional guidelines.
^Dose will depend on which cohort/phase patient is enrolled to – starting dose is 2.3 mg.
#1 cycle = 21 days during induction
**For select institutions, rituximab may be given outpatient 1 to 3 days prior to scheduled cycle 
Day 1 as per institutional standard of care on any cycle; for cycle 1, if urgent chemotherapy 
administration is warranted, rituximab may be given following the first cycle of EPOCH therapy on 
any day prior to start of cycle 2. 
@Maintenance therapy will be given to patients not treated with consolidative Stem Cell 
Transplant (SCT) for up to one year (if a patient is receiving clinical benefit after this period, an 
extension of ixazomib can be considered with documented approval from Takeda, the study PI 
and NU DSMC). 
Induction Therapy (6 cycles# of  DA-EPOCH-R + Ixazomib)
Drug
Dose
Route
Schedule
Etoposide
50 mg/m2/day
Continuous IV infusion
Days 1-4
Prednisone 
60mg/m2/BID
PO
Days 1-5
Vincristine
0.4 mg/m2/day
Continuous IV infusion
Days 1-4
Doxorubicin
10 mg/m2/day
Continuous IV infusion
Days 1-4
Cyclophosphamide
750 mg/m2
IV (over 90 min)
Day 5
Rituximab
375 mg/m2
IV
Day 1**
Methotrexate
12 mg
Intrathecally
Once per cycle*
Ixazomib
variable^
Orally
Day 1 & Day 8 OR 15
Adult patients with MYC-aberrant NHL
Response assessment
Maintenance therapy@
Ixazomib 4 mg on days 1, 8, and 15 of each cycle
(1 cycle = 28 days during maintenance)
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NU Study Number: NU 14H09
Takeda Study Number: IISR-2013-M100150
NU_14H09-Protocol A-8 - 01.16.2020
6
LIST OF ABBREVIATIONS
AE
Adverse Event
ALT
Alanine Aminotransferase
ANC
Absolute neutrophil count
AST
Aspartate Aminotransferase
ATD
Accelerated titration design
BUN
Blood Urea Nitrogen
CBC
Complete Blood Count
CMP
CNS
Comprehensive Metabolic Panel
Central Nervous System
COO
Cell of origin
CR
Complete Response
CT
Computed Tomography
CTO
Clinical Trials Office
CTCAE
Common Terminology Criteria for Adverse Events
DA-EPOCH-R
Dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, 
and rituximab
DHL
Double-Hit Lymphoma
DLT
Dose Limiting Toxicity
DSMC
Data and Safety Monitoring Committee
ECOG
Eastern Cooperative Oncology Group
FISH
Fluorescent in-situ hybridization
GCB
Germinal Center B-cell
IHC
IT
Immunohistochemistry
Intrathecal
IV (or iv)
LP
Intravenously
Lumbar Puncture
MTD
Maximum Tolerated Dose
NCI
National Cancer Institute
ORR
Overall Response Rate or Objective Response Rate
OS
Overall Survival
PBMCs
Peripheral Blood Mononuclear Cells
PD
Progressive Disease
PFS
Progression Free Survival
PO (or p.o.)
Per os/by mouth/orally
PR
Partial Response
R-CHOP
Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone
RP2D
Recommended phase two dose
SAE
Serious Adverse Event
SCT
Stem cell transplant
SD
Stable Disease
SGOT
Serum Glutamic Oxaloacetic Transaminase
SPGT
Serum Glutamic Pyruvic Transaminase
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NU Study Number: NU 14H09
Takeda Study Number: IISR-2013-M100150
NU_14H09-Protocol A-8 - 01.16.2020
7
STUDY SUMMARY
Title
A Phase I-II Trial of DA-EPOCH-R Plus Ixazomib as Frontline Therapy 
for Patients with MYC-aberrant Lymphoid Malignancies: The DACIPHOR 
Regimen
Version
January 16, 2020 (Amendment 8)
Study Design
Phase I-II, multicenter, open-label. Phase I dosing will consist of dose 
finding with contingent dose de-escalation only if needed; phase II will 
then commence based on the RP2D identified by phase I. Phase II will 
be an Optimal Two-Stage design.
Study Center(s)
Northwestern University (Lead Site)
Tufts University
Cleveland Clinic 
Medical College of Wisconsin
Rutgers Cancer Institute of New Jersey 
Objectives
Primary (phase I):
To evaluate the safety of ixazomib given with DA-EPOCH-R in patients 
with aggressive, MYC-aberrant lymphoid malignancies, and to determine 
the recommended phase II dose (RP2D) of the combination. 
Primary (phase II): 
To evaluate the efficacy, as measured by 12-month PFS, of ixazomib 
given with DA-EPOCH-R in patients with aggressive, MYC-aberrant 
lymphoid malignancies.
Secondary objectives: 
1.
To further evaluate the frequency and severity of toxicity.
2.
To further evaluate the clinical efficacy, as measured by RR and OS.
3.
Assess predictive value of early FDG-PET/CT scans on PFS.
4.
Assess the feasibility and outcomes of consolidation SCT.
Sample Size
Phase I: 3-9 patients
Phase II: 37-46 patients
Diagnosis & Key 
Eligibility Criteria
Adult patients with MYC-aberrant non-Hodgkin lymphoma (NHL).
Treatment Plan
Ixazomib will be given in conjunction with 6 cycles of DA-EPOCH-R. In 
patients not treated with consolidative SCT, ixazomib will continue as 
maintenance for up to one year (or longer for continued clinical benefit 
with documented approval from Takeda, the PI, and DSMC).
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NU Study Number: NU 14H09
Takeda Study Number: IISR-2013-M100150
NU_14H09-Protocol A-8 - 01.16.2020
8
Statistical Methodology
We expect to enroll 3-9 patients in phase I, and do not plan formal 
statistical analysis of these patients (although there will be a combined 
analysis for all patients in both phases for secondary endpoints).
With respect to efficacy, our null hypothesis is that DA-EPOCH-R plus 
ixazomib will yield no difference in one-year PFS as compared to that 
observed in DHL, a rate we estimate at 40% based upon historical 
controls 1. We believe that the combination of DA-EPOCH-R plus 
ixazomib will warrant further validation if we can demonstrate 
improvement in one-year PFS by approximately 20%, to a rate of 60%. 
We therefore propose an Optimal Two-Stage Design to test the null 
hypothesis that P</=0.40 versus the alternative that P>=0.60, where P 
represents one-year PFS. We propose error probability limits of α>0.05 
and β<0.20. The Optimal Two-Stage Design provides for early stoppage 
of the trial if there is sufficient indication of futility 2. Under these 
conditions, if 7 or fewer of the first 16 patients are alive and progression-
free at one year, the trial will be terminated, and DA-EPOCH-R plus 
ixazomib considered as having no greater efficacy than previously-
reported treatment regimens. However, if 8 or more patients are alive 
and progression-free, the trial will proceed, to a total enrollment of 46 
patients. If the number responding at this point is less than or equal to 
23, the combination will not be considered superior to previously-
reported regimens. Enrollment/treatment on this trial will NOT be 
stopped for sake of interim analysis; if there is evidence of futility once a 
sufficient number of patients have reached one year, any others enrolled 
before that time may continue per protocol. Patients from the first Phase 
who are treated at the MTD/RP2D and who are evaluable for response 
endpoints will be included in the Phase II efficacy analysis and will count 
towards total enrollment for Phase II.
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NU Study Number: NU 14H09
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1.0
INTRODUCTION – BACKGROUND & RATIONALE
1.1
Disease Background
The human c-MYC oncogene is responsible for malignant transformation of several types 
of lymphoma, and is a sine qua non mutation associated with Burkitt Lymphoma (BL3,4).  
However, evidence of c-MYC rearrangement or over-expression is also found in up to 
~20% of cases of Diffuse Large B-cell Lymphoma (DLBCL5), and in a recently-recognized 
provisional diagnostic category termed B-cell lymphoma, unclassifiable, with features 
intermediate between Diffuse Large B-cell and Burkitt Lymphoma (BCLU 6).  
There are various methods of detection of alterations in c-MYC, including fluorescent in-
situ hybridization (FISH) for rearrangement; FISH for gain of copy number; and 
quantification of protein expression by immunohistochemistry (IHC). While the finding of 
translocation by FISH is universally recognized as evidence of clinically meaningful 
activation of c-MYC, the significance of gain of copy number, and degree of IHC positivity 
(including a cut-off for positive vs. negative), remains ill-defined in the literature 5,7.
Moreover, it has recently been recognized that other recurrent genetic translocations 
found in lymphoma, including BCL-2 and BCL-6, can co-occur with alterations in c-MYC, 
and subsequently confer particularly poor prognoses on patients whose tumors have 
these multiple mutations 7,8. These so-called “double-hit lymphomas” (DHL) may 
represent over half of all cases of lymphoma with c-MYC mutations 7, and therefore 
would compose a substantial subset of cases of aggressive NHL.
1.1.1
Epidemiology
It is estimated that in 2010, there were 65,540 cases of NHL in the United States, 
and 20,210 deaths from the disease9. DLBCL is the most common sub-type of 
NHL, with approximately 20,000 new cases in the United States each year9.  
Chemo-immunotherapy consisting of rituximab, cyclophosphamide, doxorubicin, 
vincristine, and prednisone (R-CHOP) remains the standard first-line treatment, 
and high dose chemotherapy with rescue autologous stem cell transplant (ASCT) 
is generally the preferred second-line treatment10. However, in the rituximab era, 
the ability to salvage relapsed/refractory patients with an ASCT appears to be 
marginal, with efficacy further compromised in the subset of patients with a c-
MYC aberration. Subsequently, approximately one-third of all patients with 
DLBCL will die due to disease relapse11. Therefore, additional treatment options 
are urgently needed.  
Burkitt Lymphoma (BL) accounts for 1-2% of all lymphomas, with three 
recognized variants recognized: endemic [1]; sporadic [2]; and 
immunodeficiency-associated, which is generally observed in HIV+ patients [3].
1.1.2
Current Treatments
Since the introduction of rituximab and the advent of chemo-immunotherapy, R-
CHOP has become the most widely utilized regimen for aggressive large cell 
lymphoma. While it can achieve a durable remission in approximately 60% of 
patients, recent retrospective analysis highlight this regimen’s marginalized 
efficacy in patients harboring a c-MYC mutation. There is little prospective data 
examining the utility of alternative induction regimens such as R-Hyper CVAD or 
DA-EPOCH-R (dose-adjusted etoposide, prednisone, vincristine, 
cyclophosphamide, doxorubicin, and rituximab). However recently presented 
data analyzing a large cohort of patients with DHL suggests that DA-EPOCH-R 
may circumvent initial chemoresistance, offering a platform to build upon for 
treatment of c-MYC positive lymphoma’s.   
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NU Study Number: NU 14H09
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With respect to Burkitt’s Lymphoma, treatment was initially predicated upon 
combination regimens typically employed for acute lymphoblastic leukemia (ALL) 
consisting of induction, consolidation and maintenance phases. Subsequent 
modification to short-course, high-intensity regimens (e.g., Magrath and modified 
Magrath), seemed to improve upon survival compared to historical controls. On 
the other hand, less intensive anthracycline-based regimens, such as R-CHOP, 
effective for intermediate/aggressive lymphomas (including DLBCL]), are clearly 
inadequate for patients with BL, and yield poor results for patients with MYC-
aberrant lymphoma and patients with DLBCL with IPI >/=3. 
The successful deployment of risk adaptive approaches for patients with BL has 
led to a reduction in duration and intensity for many patients. Multi-agent 
chemotherapy regimens were developed, typically including anthracyclines, 
epipodophyllotoxins, vinca alkaloids, and alkylators, as well as methotrexate and 
cytarabine, which are cell cycle active agents and take advantage of the high 
tumor proliferation.
In order to mitigate risks of tumor lysis syndrome (TLS), some regimens (from 
French Society of Pediatric Oncology (SFOP), German Multicenter ALL Group 
(GMALL), and BFM), have employed a pre-treatment with low dose 
cyclophosphamide and prednisone. However, neither CODOX-M, Hyper-CVAD, 
nor DA-EPOCH-R, incorporate this pre-treatment strategy, and with appropriate 
precautions, have avoided significant rates of TLS. CNS involvement, and/or the 
high-risk thereof among patients with aggressive B-cell malignancies, has led to 
the use of high-dose intravenous methotrexate and cytarabine, both of which 
have CNS penetration, as well as intrathecal administration of both of these 
drugs. An important advance has been to reduce intrathecal treatment and 
eliminate whole brain radiation for prophylaxis, which has significantly reduced 
CNS toxicity.
1.2
Ixazomib
Ixazomib is an investigational, orally bioavailable, potent, reversible, specific inhibitor of 
the 20S proteasome that has demonstrated antitumor activity in in vivo models of multiple 
myeloma (MM) 19. Safety, activity and pharmacokinetics (PK) of weekly oral ixazomib 
were recently reported in phase I trials in patients with relapsed and/or refractory NHL 
14,20 and MM 21. In these studies, patients received ixazomib at doses between 0.24–3.95 
mg/m2 (dose-escalation phase). MTD was not reached in the NHL trial, and was 2.97 
mg/m2 in the MM study. Common drug-related grade ≥3 adverse events were 
thrombocytopenia, diarrhea, neutropenia, decreased appetite, fatigue, and lymphopenia.  
Drug-related peripheral neuropathy was encountered, all grade 1-2. By investigator 
assessment in 41 evaluable MM pts, responses included 1 VGPR, 5 PR, 1 MR, and 15 
with SD. In 16 evaluable patients with NHL, there were 3 PR and 4 SD. 
Ixazomib was rapidly absorbed, with a terminal half-life of 4–12 days (supporting weekly 
dosing) and a proportional increase in plasma AUC with dose. PK data were similar 
across expansion cohorts. The authors of both studies concluded from that weekly oral 
ixazomib was generally well tolerated with infrequent peripheral neuropathy, and showed 
activity in heavily pretreated populations. A separate phase I/II study of the combination 
of ixazomib with lenalidomide and dexamethasone in untreated MM patients established 
the RP2D at 2.23 mg/m2, or a 4.0 mg flat dose 17. A dose-escalation trial evaluating 
single-agent ixazomib in patients with relapsed/refractory NHL is now underway 
(ClinicalTrials.gov identifier NCT00893464), and multiple trials are now underway 
evaluating the agent in combination with IMIDs and/or glucocorticoids for the treatment of 
MM (http://clinicaltrials.gov/ct2/results?term=MLN9708). Accumulated data suggests that 
proteasome inhibition with bortezomib can be safely combined with intensive, 
anthracycline-based, combination chemotherapy in patients with untreated and 
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NU_14H09-Protocol A-8 - 01.16.2020
11
previously treated aggressive NHL, resulting in improved outcomes for those with DLBCL 
with non-GCB histology 22,23.  However, to our knowledge, no data has been reported for 
the combination of ixazomib with anthracycline-based therapy, nor are any such clinical 
trials currently underway.  
1.2.1
Clinical Experience
Ixazomib (MLN9708) has been evaluated as an oral single agent in phase 1 
studies that have included patients with advanced solid tumors, lymphoma, 
relapse/refractory MM (RRMM), and relapsed or refractory light-chain (AL) 
amyloidosis and demonstrated early signs of activity. Ongoing studies continue 
to investigate both single-agent ixazomib and ixazomib in combination with 
standard treatments. Based on encouraging preliminary data observed in 
patients with MM requiring systemic treatment, 2 phase 3 trials in newly 
diagnosed MM (NDMM) (C16014) and RRMM (C16010) patient populations are 
currently evaluating ixazomib in combination with Revlimid and dexamethasone 
(RevDex) versus placebo/RevDex. Both trials are combining ixazomib at a 
weekly dose of 4.0 mg on Days 1, 8, and 15 in a 28-day cycle to a standard dose 
of lenalidomide with a weekly dexamethasone dose of 40 mg. In addition, 
ongoing clinical pharmacology studies include evaluation of drug-drug 
interactions with ketoconazole and rifampin, effect of food, and oral 
bioavailability. Studies evaluating the safety and pharmacokinetic (PK) of 
ixazomib alone (in Japanese patients) and in combination with lenalidomide and 
dexamethasone in Asian adult patients (including Japanese patients) with a 
diagnosis of NDMM are ongoing. 
As of March 2013, preliminary clinical data is available for a total of 653 patients 
across 13 studies. The emerging safety profile indicates that ixazomib is 
generally well tolerated. The adverse events (AEs) are consistent with the class-
based effects of proteasome inhibition and are similar to what has been 
previously reported with Velcade though the severity of some, for example 
peripheral neuropathy, is less. While some of these potential toxicities may be 
severe, they can be managed by clinical monitoring and standard medical 
intervention, or, as needed, dose modification or discontinuation.
Fatigue was the most common AE reported among 384 patients treated in the 
oral (PO) studies (47%). Other common AEs reported in the pooled intravenous 
(IV) and PO safety populations include nausea, thrombocytopenia, diarrhea, and 
vomiting. Rash is also a commonly reported treatment-emergent event; however, 
there is some variety in its characterization and causality resulting in different 
preferred terms to describe it. A high-level term outline of rash events includes 
rashes, eruptions and exanthems NEC; pruritus NEC; erythemas; 
papulosquamous conditions; and exfoliative conditions. The dose escalation 
phases of most trials reported in the IB have now completed enrollment, and 
gastrointestinal (GI) symptoms were the common dose-limiting toxicities (DLTs) 
when the use of prophylactic anti-emetics was not permitted per protocol. In the 
expansion cohorts or phase 2 cohorts (as per each study), the incidence and 
severity of GI symptoms was mitigated by the use of the lower maximum 
tolerated dose (MTD)/recommended phase 2 dose (RP2D) (as per each study) 
and standard clinical usage of anti-emetics and/or antidiarrheal medications as 
deemed appropriate. Prophylactic use of anti-emetics has not been required as 
with other agents but (as outlined in Section 6.7) has been used according to 
standard practice and are effective.
The most frequent (at least 20%) treatment-emergent adverse events (TEAEs) 
reported with the PO formulation pooled from single-agent studies (n = 201) 
irrespective of causality to ixazomib, include nausea (53%), fatigue (51%), 
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diarrhea (44%), thrombocytopenia (34%), vomiting (38%), decreased appetite 
(32%), fever (21%), and anemia (21%). The most frequent (at least 20%) TEAEs 
reported with the PO formulation pooled from combination trials (irrespective of 
the combination) (n = 173), irrespective of causality to ixazomib, include diarrhea 
(47%), fatigue (44%), nausea (38%), peripheral edema (35%), constipation 
(33%), insomnia (29%), thrombocytopenia (28%), anemia (26%), vomiting (26%), 
neutropenia (25%), back pain (24%), pyrexia (23%), peripheral edema (21%, 
each), fever (20%), cough (20%), hypokalemia (20%), neutropenia (20%), and 
upper respiratory tract infection (20%). Overall rash of all grades is reported in 
approximately 50% of patients and is more common when ixazomib is given in 
combination with lenalidomide where rash is an overlapping toxicity.
1.2.2
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 
postdose. 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 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.
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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 
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.
1.2.3
Clinical Trial Experience with Oral Ixazomib
As of March 2013, a total of 507 patients with differing malignancies (multiple 
myeloma, AL amyloidosis, nonhematologic cancers, and lymphoma) have been 
treated in studies evaluating the oral ixazomib formulation. These patients have 
been treated with different doses of ixazomib either as a single-agent treatment 
(in 201 patients) or in combination with currently clinically available treatments (in 
306 patients). Information regarding the ongoing studies, patient populations, and 
doses investigated is included in Table 1-1.
Table 1-1  
Ongoing Studies of Oral Ixazomib
Trial/
Population
Description
Doses Investigated
C16003
RRMM
N = 60
PO, (TW), single agent
0.24-2.23 mg/m2, TW
MTD:  2.0 mg/m2
DLT:  rash, thrombocytopenia
Closed to enrollment
C16004
RRMM
N = 60
PO, (W), single agent
0.24-3.95 mg/m2, W
MTD:  2.97 mg/m2
DLT:  rash, nausea, vomiting, diarrhea
Closed to enrollment
C16005
NDMM
N = 65
PO, W, combination with LenDex
28 day cycle
1.68-3.95 mg/m2, W
MTD:  2.97 mg/m2
DLT:  nausea, vomiting, diarrhea, syncope
RP2D*:  4.0 mg fixed (switched to fixed dosing 
in phase 2, relevant to 2.23 mg/m2)
Closed to enrollment
C16006
NDMM
N =20
PO, TW (Arm A- 42 day cycle) and 
W (Arm B- 28 day cycle), 
combination with Melphalan and 
Prednisone
Arm Aa:  3-3.7 mg, fixed dose, TW
DLT: rash, thrombocytopenia, subileus
Arm Ba: 3- 5.5 mg, fixed dose, W
DLT: Esophageal ulcer, nausea, vomiting, 
hematemesis, thrombocytopenia, ileus, 
neurogenic bladder
MTD = 3.0 mg
C16007
RR-AL
N = 27
PO, W, single agent
4-5.5 mg, fixed dosea, W
DLT: thrombocytopenia, diarrhea, dyspnea, 
acute rise in creatinine, cardiac arrest
MTD: 4.0 mg W
C16008
NDMM
N=64
PO, TW, combination with LenDex 
21-day cycle
3.0-3.7 mg fixed dosea W
MTD: 3.0 mg
Closed to enrollment
C16009
Solid tumors, 
Lymphomas
N =54
PO, W, single agent
5.5 mg fixed doseaW
C16010
RRMM
N = 200
PO, W, combination with LenDex 
versus placebo- LenDex
4.0 mg fixed dosea W
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15
Table 1-1  
Ongoing Studies of Oral Ixazomib
C16011
RRAL
N = 4
PO, W, with Dex versus physician’s 
choice of a Dex-based regimen
4.0 mg W
C16013
RRMM
N = 9
PO, W, with LenDex
4.0 mg W
C16014
Symptomatic 
MM
N=701
PO, combination with LenDex
ixazomib 4.0 mg or matching placebo on Days 
1, 8, and 15, plus Len 25 mg on Days 1-21 (10 
mg if low creatinine clearance, with escalation 
to 15 mg if tolerated) and Dex 40 mg (or 
20 mg if >75 years old) on Days 1, 8, 15, and 
22
C16015
Symptomatic 
MM with normal 
renal function or 
severe renal 
impairment
N=28
PO, combination with Dex
Part A: ixazomib  3.0 mg on Day 1
Part B: ixazomib  4.0 mg on Days 1, 8, and 15, 
plus Dex 40 mg (or 20 mg if >75 years old) on 
Days 1, 8, 15 and 22 of a 28-day cycle
C16017
RR follicular 
lymphoma
N=58
PO, W
4.0, 5.3, and 7.0 mg, W
Treatment at RP2D once determined.
C16018
Advanced solid 
tumors or 
hematologic 
malignancies 
with varying 
degrees of liver 
dysfunction
N=45
Part A: PO, Day 1 of 15-day cycle
Part B: PO, W
1.5 mg (severe hepatic impairment), 2.3 mg 
(moderate hepatic impairment), or 4.0 mg 
(normal hepatic function)
TB-MC010034
RRMM
N = 10
PO, W
4.0 mg, W
Single agent: 4.0 mg
Combination with Rd
Abbreviations:  RRAL = Relapsed and/or refractory Primary systemic light chain (AL) amyloidosis; BSA = body surface area; 
Dex=dexamethasone; DLT = dose-limiting toxicity; IV = intravenously; LenDex = lenalidomide plus dexamethasone; MTD = 
maximum tolerated dose; NDMM = newly diagnosed multiple myeloma; PO = orally; RR= relapsed and/or refractory; RRAL= 
relapsed and/or refractory systemic light chain amyloidosis RRMM = relapsed and/or refractory multiple myeloma; TBD = to be 
determined; TW = twice weekly; W = weekly; RP2D= recommended phase 2 dose.
Note that blinded data from pivotal Studies C16010 and C16011 are not included.  
a
Approximate BSA and fixed dosing equivalence:  3 mg~ equivalent to 1.68 mg/m2 BSA dosing; 4.0 mg ~ equivalent to 2.23 
mg/m2 BSA dosing; and 5.5 mg~ equivalent to 2.97 mg/m2 BSA dosing.
1.2.4
Overview of Oral Formulation of Ixazomib
The emerging safety profile indicates that oral ixazomib is generally well tolerated 
with predominant toxicities largely reversible, able to be monitored by routine 
clinical examinations and manageable by dose reductions, discontinuation, or 
standard supportive care. From experience from phase 1 through 2 studies the 
major toxicities can be managed to allow repeat treatment cycles over periods 
extending beyond 24 months. 
In the 4 ongoing studies (C16003, C16004, C16007, and C16009) investigating 
single-agent oral ixazomib in patients with differing malignancies (multiple 
myeloma, AL amyloidosis, nonhematologic cancers, and lymphoma), a total of 
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146 patients have been treated as of April 2012. These patients have been 
treated with different doses of ixazomib as they are all phase 1 trials. An 
overview of the most frequent (at least 10%) AEs occurring in the pooled safety 
population from single-agent oral ixazomib Studies (C16003, C16004, C16007, 
and C16009) is shown in Table 1-2.
Table 1-2: Most Common (At Least 10% of Total) Treatment-Emergent AEs in Oral Single
Agent Studies
Primary System Organ Class
      Preferred Term
Oral Single Agent
Total
n = 201
n (%)
Subjects with at Least One Adverse 
Event
197 (98)
Gastrointestinal disorders
160 (80)
 Nausea
106 (53)
 Diarrhea
88 (44)
 Vomiting
77 (38)
 Constipation
46 (23)
 Abdominal pain
33 (16)
General disorders and administration 
site conditions
151 (75)
 Fatigue
103 (51)
 Pyrexia
51 (25)
 Edema peripheral
27 (13)
 Asthenia
31 (15)
Nervous system disorders
92 (46)
 Headache
29 (14)
 Dizziness
26 (13)
 Neuropathy peripheral
21 (10)
Metabolism and nutrition disorders
107 (53)
 Decreased appetite
64 (32)
 Dehydration
37 (18)
Blood and lymphatic system disorders
98 (49)
 Thrombocytopenia
68 (34)
 Anemia
42 (21)
 Neutropenia
29 (14)
 Lymphopenia
20 (10)
Skin and subcutaneous tissue 
disorders
90 (45)
 Rash maculara
23 (11)
Musculoskeletal and connective tissue 
disorders
93 (46)
 Back pain
24 (12)
 Arthralgia
28 (14)
Respiratory, thoracic and mediastinal 
disorders
78 (39)
 Cough
28 (14)
 Dyspnea
30 (15)
Infections and infestations
89 (44)
 Upper respiratory tract infection
31 (15)
Source:  ixazomib Investigator’s Brochure Edition 7
Abbreviations:  MedDRA = Medical Dictionary for Regulatory Activities, version 15.0.
Subject Incidence:  A subject counts once for each preferred term.  Percentages use the number of treated subjects as the 
denominator.
a
Note that rash maculopapular and rash macular represent the 2 most common terms used to describe rash.
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As of March 2013, there are 5 studies actively enrolling patients with multiple 
myeloma to investigate oral ixazomib in combination with standard combination 
regimens. The most frequent (at least 10%) AEs occurring in the pooled safety 
population from Studies C16005, C16006, C16008, and C16013 are shown for 
all grades (Table 1-3). Note that in combination trials, related is defined as 
related to any study drug in the combination regimen.
Table 1-3   
Most Common (At Least 10% of Total) Treatment-Emergent Adverse Events in 
Oral Combination Studies
Primary System Organ Class
      Preferred Term
Total Oral Combo Agent
(5/6/8/13)
n = 173
n (%)
Subjects with at Least One Adverse 
Event
163 (94)
Gastrointestinal disorders
139 (80)
 Nausea
65 (38)
 Diarrhea
81 (47)
 Vomiting
51 (29)
 Constipation
57 (33)
General disorders and administration 
site conditions
132 (76)
 Fatigue
76 (44)
 Pyrexia
39 (23)
 Edema peripheral
61 (35)
 Asthenia
20 (12)
Nervous system disorders
115 (66)
 Headache
28 (16)
 Dizziness
34 (20)
 Neuropathy peripheral
45 (26)
Metabolism and nutrition disorders
91 (53)
 Decreased appetite
25 (14)
 Hypokalemia
34 (20)
Blood and lymphatic system disorders
88 (51)
 Thrombocytopenia
49 (28)
 Anemia
45 (26)
 Neutropenia
43 (25)
 Lymphopenia
20 (12)
Skin and subcutaneous tissue 
disorders
102 (59)
 Rash maculopapulara
29 (17)
 Rash maculara
22 (13)
Musculoskeletal and connective tissue 
disorders
99 (57)
 Back pain
42 (24)
 Pain in extremity
31 (18)
 Arthralgia
22 (13)
Respiratory, thoracic and mediastinal 
disorders
80 (46)
 Cough
36 (21)
 Dyspnea
26 (15)
Infections and infestations
92 (53)
 Upper respiratory tract infection
35 (20)
Psychiatric disorders
73 (42)
 Insomnia
50 (29)
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Table 1-3   
Most Common (At Least 10% of Total) Treatment-Emergent Adverse Events in 
Oral Combination Studies
Primary System Organ Class
     Preferred Term
Total Oral Combo Agent
(5/6/8/13)
n = 173
n (%)
Source:  Ixazomib Investigator’s Brochure Edition 7
Abbreviations:  MedDRA = Medical Dictionary for Regulatory Activities, version 15.0.
Subject Incidence:  A subject counts once for each preferred term.  Percentages use the number of treated subjects as the 
denominator. 
Data from ongoing blinded pivotal trials (C16010) are not included.
a
Note that rash maculopapular and rash macular represent the 2 most common terms used to describe rash.  
The clinical experience with ixazomib also shows early signs of antitumor activity 
as evidenced by at least a 50% reduction in disease burden in some patients and 
prolonged disease stabilization in others across all ongoing trials. The antitumor 
activity has been seen with single-agent ixazomib, when combined with 
established therapies, and across the malignancies studied (advanced solid 
tumors13, NHL and Hodgkin lymphoma14, relapsed and/or refractory multiple 
myeloma [RRMM15], relapsed or refractory systemic light chain amyloidosis 
[RRAL16], and newly diagnosed multiple myeloma [NDMM17,18]) to date.
Though additional data are needed to characterize the clinical benefit of this 
drug, the emerging data supports the ongoing development of ixazomib.
1.2.5
Relapsed and/or Refractory Multiple Myeloma (RRMM)
The early development of ixazomib in patients with RRMM involves 2 studies 
(C16003 and C16004) with similar objectives, but each investigated 1 of the 2 
dosing schedules commonly used with the first-in-class proteasome inhibitor, 
VELCADE.
Study C16003 is an open-label, dose escalation, phase 1 study of ixazomib 
dosing on a twice-weekly schedule on Days 1, 4, 8, and 11 of a 21-day cycle in 
adult patients with RRMM. Study C16004 is an open-label, dose escalation, 
phase 1 study of ixazomib dosing on a weekly schedule on Days 1, 8, and 15 of 
a 28-day cycle in adults patients with RRMM. Both studies have now completed 
enrollment. The DLTs in Study C16003 were rash macular and thrombocytopenia 
and the DLTs in C16004 were nausea, diarrhea, vomiting, and erythema 
multiforme.
In the dose escalation component of both studies, patients had multiple myeloma 
that had relapsed following at least 2 lines of therapy that must have included 
bortezomib, thalidomide (or lenalidomide), and corticosteroids. In both studies, 
when the MTD was established, cohorts of patients representing the 
heterogeneous patient population currently seen in clinical practice were to be 
enrolled into 1 of 4 expansion cohorts, including a relapsed and refractory cohort, 
a carfilzomib cohort, a proteasome inhibitor-naïve cohort, and a VELCADE-
relapsed cohort.
Final study results are currently being analyzed, but preliminary data suggest that 
ixazomib has anti-tumor activity in heavily pretreated MM patients, with durable 
responses/disease control, and is generally well tolerated. 
1.2.6
Newly Diagnosed Multiple Myeloma (NDMM)
Multiple research paths are being explored in patients with NDMM with a focus 
on evaluating ixazomib in combination with agents commonly used across 
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treatment settings. The development of ixazomib in combination with 
lenalidomide with dexamethasone (LenDex) in patients with NDMM who are 
transplant eligible or ineligible involves 2 studies (C16005 and C16008) with 
similar study designs except for a few key differences, namely the schedules of 
ixazomib and dexamethasone. Ixazomib is also being evaluated in combination 
with melphalan and prednisone (MP) for patients who are not transplant eligible 
due to age or coexisting morbidity (in Study C16006). All 3 studies are phase 1/2, 
with phase 1 focusing on safety and phase 2 on efficacy (and further 
characterization of safety). 
1.3
Rationale for the Current Study
The clinical benefit of ixazomib continues to be studied in a comprehensive and global 
development plan that involves studies sponsored by Takeda. 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. Therefore, we propose to conduct this phase I-II 
study to evaluate the incorporation of ixazomib into a DA-EPOCH-R backbone in adult 
patients with MYC-aberrant non-Hodgkin lymphoma (NHL). 
The dosing schedule and regimen for dose adjusted EPOCH-R will follow established 
protocols. The dose of ixazomib will start at 2.3 mg weekly when given concurrently with 
DA-EPOCH-R. This dose is predicated on phase I data from patients with MM, wherein 
the recommended single-agent dose was established at 4 mg. Given the risk of 
overlapping hematological and neurological toxicity with concomitant cytotoxic and 
neurotoxic agents, the previous MTD was decreased by 50% for dosing cohort 1.  
During phase I, an accelerated titration design (ATD) will be employed to more 
efficaciously determine the MTD of ixazomib in combination with DA-EPOCH-R. By this 
model 24, single-subject cohorts will be enrolled until the MTD is encountered, after which 
expansion to 3-subject cohorts will be undertaken. When used as single-agent 
maintenance, ixazomib will be dosed at 4mg weekly. The MTD will equate the RP2D for 
ixazomib in phase II. Phase II will be an Optimal Two-Stage design. Approximately 3-9 
patients are anticipated for Phase I, and 46 patients for Phase II.
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2.0
OBJECTIVES & ENDPOINTS
2.1
Primary Objectives/Endpoints
2.1.1
Phase I
The primary objective of the phase I portion will be to evaluate the safety of 
ixazomib given with DA-EPOCH-R in patients with aggressive, MYC-aberrant 
lymphoid malignancies, and to determine the recommended phase II dose 
(RP2D) of the combination.
The endpoint for this will be dose-limiting toxicity (DLT), defined as the 
occurrence of ≥ Grade 3 toxicity (using CTCAE v 4.03), experienced during the 
first cycle (3 weeks or 21 days) of study treatment, except for cytopenias. Grade 
5 cytopenias will also be considered DLTs. The MTD will constitute the RP2D.
2.1.2
Phase II
The primary objective of the phase II portion will be to evaluate the efficacy, as 
measured by 12-month PFS, of ixazomib given with DA-EPOCH-R in patients 
with aggressive, MYC-aberrant lymphoid malignancies.
PFS will be defined as the time elapsed between treatment initiation and tumor 
progression or death from any cause, with censoring of patients who are lost to 
follow-up. The 12-month PFS will be defined as the percentage of patients alive 
and progression free 12 months from start of therapy. 
2.2
Secondary Objectives/Endpoints
All secondary endpoints will consist of combined analysis of patients from both phase I 
and phase II. 
2.2.1
Further evaluate the frequency and severity of toxicity.
Adverse events will be defined as those included in CTCAE v 4.03.  The 
occurrence and severity of each will be recorded.
2.2.2
Further evaluate the clinical efficacy, as measured by response rate and OS.
Anti-tumor activity will be defined as the detection of SD, PR, or CR by CT or 
PET/CT, and/or resolution of marrow-only involvement. CR and PR will each be 
assessed according to the Revised Response Criteria for Malignant Lymphoma.  
Assessments will be performed after cycles 2 and 6, then at the discretion of the 
treating investigator.
OS will be defined as freedom from death by any cause.  
2.2.3
Assess the predictive value of FDG-PET/CT scans on PFS.
Patients will be categorized as either FDG-PET (+) or (-) at interim and end-of
treatment imaging.
2.3
Exploratory Objectives/Endpoints
2.3.1
Determine the impact of cell of origin (COO) upon response rate, PFS, and OS.
COO will be defined as GCB and non-GCB via the Hans algorithm (applicable 
only to patients with DLBCL).
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2.3.2
Assess the feasibility and outcomes of consolidation SCT.
Patients will be grouped by whether consolidative SCT was performed in first 
remission, with PFS compared across groups (SCT vs. non-SCT).
3.0
PATIENT ELIGIBILITY
The target population for this study is patients with MYC-aberrant NHL. This will be a multicenter 
trial conducted at Northwestern University, Tufts University, Cleveland Clinic, Medical College of 
Wisconsin, and Rutgers Cancer Institute. Northwestern University will serve as the lead site and 
coordinating center for this study. 
A total of up to 54 subjects will be needed for this trial for this phase I/II trial (3-9 for phase I and 
up to 46 for phase II). Potential patients may be referred to the Principal Investigator (PI) at 
Northwestern University, Dr. Barbara Pro (312-695-4537), Dr. Andreas Klein at Tufts Medical 
Center (617-636-8227), Dr. Deepa Jagadeesh at Cleveland Clinic (216-444-0857) and Dr. Mehdi 
Hamadani at Medical College of Wisconsin, and Dr. Andrew Evens at Rutgers Cancer Institute.
Eligibility will be evaluated by the study team according to the following criteria. Eligibility waivers 
are not permitted. Subjects must meet all of the inclusion and none of the exclusion criteria to be 
registered to the study. Study treatment may not begin until a subject is registered. Please refer 
to Section 11 for complete instructions regarding registration procedures.
3.1
Inclusion Criteria
3.1.1
Patients must have a histological diagnosis of any of the following (all stages 
allowed):

DLBCL (including transformation from a previously indolent NHL, so long as 
no prior systemic treatment was given for the indolent NHL)

B-cell lymphoma, unclassifiable

Burkitt lymphoma

MYC+ plasmablastic lymphoma by histology. 
NOTE: Histology must be CD20-positive, as measured according to standard 
institutional practice(s) for determining CD20 expression. CD20 
positivity/expression must be clearly documented. 
3.1.2
Patients must have measurable disease (defined as ≥ 1.5 cm in diameter).
3.1.3
Patients may have any of the following: 

MYC-overexpression (> 40%) by IHC; 

MYC-amplification (>4 copies), as determined by FISH

MYC-rearrangement, as determined by FISH
3.1.4
The following results must be available or pending at time of registration, though 
results will not affect enrollment/treatment:

BCL-2 rearrangement by FISH

BCL-6 rearrangement by FISH
NOTE: Although not required, it is encouraged that MYC and BCL-2 be 
measured by immunohistochemistry (IHC) and clearly documented. 
3.1.5
Patients must be age ≥ 18 years.
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3.1.6
Patients must exhibit an ECOG performance status of 0-3.
3.1.7
Patients must meet the following clinical laboratory criteria:

ANC ≥ 1,000/mm3

Platelets ≥ 75,000/mm3

Total bilirubin ≤ 1.5 x ULN

AST(SGOT)/ALT(SPGT) ≤ 3 X institutional ULN

Calculated creatinine clearance ≥ 30 mL/min
NOTE: ANC and platelet requirements do not apply to patients with marrow 
involvement of lymphoma (any extent).
NOTE: Platelet transfusions to help patients meet eligibility criteria are not 
allowed within 3 days before registration. 
NOTE: Exceptions can be granted from PI for instances of Gilbert’s disease, 
and/or primarily indirect bilirubinemia, if due to recent transfusion and/or 
hemolysis.
3.1.8
Patients with HIV infection are eligible, provided they meet all of the following 
criteria: 

No history of AIDS-defining conditions or other HIV related illness

CD4+ cells nadirs >350/mm3 within 28 days prior to registration

Treatment sensitive HIV and, if on anti-HIV therapy, HIV viral load < 50 
copies/mm3 within 28 days prior to registration
3.1.9
Female patients must meet one of the following criteria:

Postmenopausal for at least 1 year prior to registration 

Surgically sterile

Of childbearing potential and agree to practice 2 effective methods of 
contraception, at the same time, from the time of signing the informed 
consent form through 12 months after the last dose of study drug

Of childbearing potential and agree to practice true abstinence when this is in 
line with the preferred and usual lifestyle of the subject. 
NOTE: periodic abstinence [e.g., calendar, ovulation, symptothermal, post-
ovulation methods] and withdrawal are not acceptable methods of contraception. 
3.1.10
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

Agree to practice true abstinence when this is in line with the preferred and 
usual lifestyle of the subject.
NOTE: periodic abstinence [e.g., calendar, ovulation, symptothermal, post-
ovulation methods] and withdrawal are not acceptable methods of contraception. 
3.1.11
Females of childbearing potential (FOCBP) must have a negative pregnancy test 
within 7 days prior to registration on study.
3.1.12
Patients must have the ability to understand and the willingness to sign a written 
informed consent prior to registration on study.
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3.2
Exclusion Criteria
3.2.1
Patients who have any prior chemoimmunotherapy are not eligible.
NOTE: The use of steroids to control the disease is permitted and does not have 
a washout period. 
3.2.2
Patients who have had major surgery within 4 weeks prior to registration are not 
eligible.
3.2.3
Patients who have had radiotherapy within 14 days before registration are not 
eligible.
NOTE: If the involved field is small, 7 days will be considered a sufficient interval 
between treatment and administration of the ixazomib.
3.2.4
Patients who have an infection requiring systemic antibiotic therapy or other 
serious infection within 14 days before study enrollment are not eligible.
3.2.5
Patients who have 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 are not eligible.
3.2.6
Patients who have undergone systemic treatment, within 14 days prior to 
registration, with strong CYP3A inducers (rifampin, rifapentine, rifabutin, 
carbamazepine, phenytoin, phenobarbital), or use of Ginkgo biloba or St. John’s 
wort are not eligible.
3.2.7
Patients who have a clinically active hepatitis B or C virus infection are not 
eligible. 
NOTE: Those with documented evidence of past exposure to HBV or HCV may 
enroll so long as the respective viral load is negative AND subject is willing/able 
to take appropriate antiviral prophylaxis to prevent reactivation; please refer to 
section 5.0 for baseline testing requirements. 
3.2.8
Patients with any serious medical or psychiatric illness that could, in the 
investigator’s opinion, potentially interfere with the completion of treatment 
according to this protocol are not eligible.
3.2.9
Patients who have a known allergy to any of the study medications, their 
analogues, or excipients in the various formulations of any agent are not eligible.
3.2.10
Patients who have a known GI disease or GI procedure that could interfere with 
the oral absorption or tolerance of ixazomib including difficulty swallowing are not 
eligible.
3.2.11
Patients who have been 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 are not eligible.
NOTE: Patients with nonmelanoma skin cancer or carcinoma in situ of any type 
are not excluded if they have undergone complete resection.
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3.2.12
Patients who have ≥ Grade 3 peripheral neuropathy, or Grade 2 with pain on 
clinical examination during the screening period are not eligible.
3.2.13
Patients who are participating in other clinical trials, including those with other 
investigational agents not included in this trial, within 30 days of registration and 
throughout the duration of this trial are not eligible. 
3.2.14
Female patients who are nursing or have a positive pregnancy test during 
screening are not eligible.
4.0
TREATMENT PLAN
4.1
Overview
Ixazomib will be given in conjunction with 6 cycles of DA-EPOCH-R. During phase I, an 
accelerated titration design (ATD) will be employed to more efficaciously determine the 
MTD of ixazomib in combination with DA-EPOCH-R. The dosing schedule and regimen 
for dose adjusted EPOCH-R will follow established protocols. The dose of ixazomib will 
start at 2.3 mg weekly (for phase I patients) when given concurrently with DA-EPOCH-R. 
Single-subject cohorts will be enrolled until the MTD is encountered, after which 
expansion to 3-subject cohorts will be undertaken. The MTD from phase I will equate the 
RP2D for ixazomib given in conjunction with DA-EPOCH-R. 
The MTD was established at cohort 2. As of August 10, 2016, all patients will be treated 
with ixazomib at 3mg during induction.
In patients who are not then treated with consolidative SCT, ixazomib will continue as 
maintenance for up to one year (if a patient is receiving clinical benefit after this period, 
an extension of ixazomib can be considered with documented approval from Takeda, the 
study PI and Northwestern University’s Data and Safety Monitoring Committee (DSMC). 
When used as single-agent maintenance, ixazomib will be dosed at 4mg weekly. 
NOTE: If a patient has dose reduced the ixazomib during the treatment phase (when it 
was given in combination with chemotherapy) and now enters the maintenance phase 
(where ixazomib will be administered as a single agent), the patient should start 
maintenance at the full dose of ixazomib (rechallenge at 4 mg weekly), not at the reduced 
dose; subsequent dose reductions may be considered if the patient does not tolerate the 
4 mg dose during maintenance. 
4.2
Treatment Schedule
4.2.1
Induction
Induction therapy will consist of 6 cycles of combination DA-EPOCH-R with 
ixazomib. During induction treatment, ixazomib will be given twice per cycle (1 
cycle = 21 days during induction); the first dose will be given on day 1 and the 
second on either day 8 or 15. Based on existing experience with single-agent 
ixazomib, continuous weekly dosing without interruption can lead to toxicity. 
Therefore, during induction when ixazomib is administered with DA-EPOCH-R, 
ixazomib should be given on day 1, then as permitted by toxicity assessment on 
EITHER day 8 or 15, but not both. In other words, those who tolerate ixazomib 
dosing on day 1 and 8 of induction should NOT receive a dose on day 15, and 
those in whom day 8 ixazomib is held for toxicity can be given a day 15 dose if 
otherwise permitted by parameters of the trial. 
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In order to receive day 8 or 15 doses of ixazomib, patients must meet criteria 
specified below:

ANC must be ≥ 1,000/mm3

Platelet count must be ≥ 75,000/mm3

All other non-hematologic toxicity (except for alopecia) must have resolved to 
≤ Grade 1 or to the patient’s baseline condition
  
4.2.2
Maintenance
Patients who do not go on to be treated with consolidative SCT will be treated 
with maintenance ixazomib for up to 1 year (or longer for continued clinical 
benefit with documented approval from Takeda, the PI, and DSMC. Similar to 
induction, maintenance with uninterrupted ixazomib may not be well-tolerated; 
therefore during maintenance treatment, ixazomib 4 mg will be given days 1, 8, 
and 15 of each cycle (1 cycle = 28 days during maintenance), and no drug will be 
given on day 22. NOTE: If a patient has dose reduced the ixazomib during the 
treatment phase (when it was given in combination with chemotherapy) and now 
enters the maintenance phase (where ixazomib will be administered as a single 
agent), they should start maintenance at the full dose of ixazomib (rechallenge at 
4 mg weekly), not at the reduced dose; subsequent dose reductions may be 
considered if the patient does not tolerate the 4 mg dose during maintenance.  
4.3
Treatment Administration
4.3.1
Ixazomib
Patients should be instructed to swallow ixazomib capsules whole, with water, 
and not to break, chew, or open the capsules. Capsules should be taken on an 
empty stomach (no food or drink) at least 1 hour before or 2 hours after a meal.  
Each capsule should be swallowed separately with a sip of water.  A total of 
approximately 8 ounces (240 mL) of water should be taken with the capsules. 
During induction, patients should take ixazomib in the hospital or clinic after labs 
have been assessed for toxicity on Day 1 and either Day 8 or 15 (see section 
4.2.1). During maintenance, ixazomib will be dispensed on Day 1 of each cycle 
after labs have been assessed for toxicity. During the first two cycles of 
maintenance (Cycle 7 and 8), patients should have labs assessed before dosing 
on Day 8 and 15. Thereafter, Day 1 labs can be used for dosing on Day 1, 8, and 
15.  
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. Patients will be given a medication diary to keep track of all 
doses.
4.3.2
DA-EPOCH-R
Etoposide, vincristine, cyclophosphamide, doxorubicin, rituximab, and 
prednisone will all be obtained from commercial supply, and will be given per 
institutional guidelines for a total of 6 cycles of induction for all patients. For 
select institutions, rituximab may be given as an outpatient per institutional 
standard of care 1-3 days prior to the scheduled cycle day 1 for any cycle; for 
cycle 1, if urgent chemotherapy administration is warranted, rituximab may be 
given after the first cycle of EPOCH. All drugs will be given by IV route, except 
prednisone, which will be given orally (IV methylprednisolone may be substituted 
at discretion of treating investigator). The initial dosing cohort will consist of DA-
EPOCH-R given in the standard fashion along with ixazomib at a starting dose of 
2.3 mg (see 4.3.1 for ixazomib schedule). The DA-EPOCH-R regimen is 
summarized in the table below. 
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Table 4-1: DA-EPOCH-R Dosing Route & Schedule for Each Cycle of 
Induction
Drug
Dose
Route
Schedule
Etoposide
50 mg/m2/day
Continuous IV 
infusion
Days 1-4
Prednisone 
60 
mg/m2/BID
PO
Days 1-5*
Vincristine
0.4 
mg/m2/day
Continuous IV 
infusion
Days 1-4
Doxorubicin
10 mg/m2/day
Continuous IV 
infusion
Days 1-4
Cyclophosphamide
750 mg/m2
IV (over 90 min)
Day 5
Rituximab
375 mg/m2
IV
Day 1**
Methotrexate
12 mg
Intrathecally
Once per 
cycle***
*Dosing schedule and administration for prednisone may vary if appropriate per 
institutional standards or physician discretion.
**For select institutions, rituximab may be given outpatient 1-3 days prior to the 
scheduled cycle day 1 per institutional standard of care for any cycle; for cycle 1, 
if urgent chemotherapy administration is warranted, rituximab may be given after 
the first cycle of EPOCH therapy on any day prior to start of cycle 2. In addition, if 
the Rituximab infusion is delayed for any reason and spans longer than one day, 
the dosing schedule can be adjusted appropriately.
*** Due to high risk of Central Nervous System (CNS) involvement, all patients 
will undergo diagnostic lumbar puncture (LP) per institutional standards before or 
during their first treatment with DA-EPOCH-R. If negative, IT methotrexate (or 
equivalent, see section 4.7) may be given per physician’s preference using 
institutional guidelines. 
All patients must receive either 1 dose of neulasta within 72 hours of completion 
of each cycle of DA-EPOCH-R, or must receive neupogen, 5mcg/kg (rounded to 
300 mcg or 480 mcg) daily for 10 days starting within 72 hours of completion of 
each cycle of DA-EPOCH-R.
4.4
Dose Escalation Scheme – Phase I Induction Only
During Phase I, an accelerated titration design (ATD) will be employed to more 
efficaciously determine the MTD of ixazomib in combination with DA-EPOCH-R. The 
MTD will equate the RP2D for ixazomib in Phase II. Single-subject cohorts will be 
enrolled until MTD is encountered, after which expansion to 3-subject cohorts will be 
undertaken. The cohort-specific doses are provided in the table below. 
Table 4-2: Dose Escalation Scheme for Induction – Phase I Only
Cohort
Ixazomib Dose (mg)
Days of Administration
1
2.3
1 and either 8 or 15
2
3
1 and either 8 or 15
3
4
1 and either 8 or 15
Dosing of ixazomib will not exceed 4 mg; if no DLTs are experienced at 2.3 mg and 3 mg 
single-patient cohorts, the 4 mg cohort will enroll 3 patients to evaluate for toxicity. If no 
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DLT are experienced among 3 patients at 4 mg, this will be declared the RP2D. If, 
however, 1 or more patients experiences DLT at the 4 mg cohort, an additional 2 patients 
will be treated at the 3 mg level (for 3 total patients at this dose level). If 1 or more 
patients at the 3 mg level experience DLT, an additional 2 patients will be treated at the 
2.3 mg level (for 3 total patients at this dose level). Therefore, phase I will treat between 5 
and 9 patients. If unacceptable toxicity is observed at 2.3mg dose, enrollment will be 
suspended for re-evaluation of dose-finding strategy. 
MTD was established at cohort 2. As of August 10, 2016, all patients will be treated with 
ixazomib at 3mg during induction.
4.4.1
Dose Limiting Toxicities
Dose limiting toxicities will be defined as the occurrence of any ≥ Grade 3 drug-
related toxicity (using CTCAE v 4.03), experienced during cycle 1 (the first 21 
days) of study treatment, except for cytopenias. Since cytopenias are expected, 
particularly in later cycles, the omission of drug at day 8 and 15 for hematologic 
toxicity will not, by itself, be considered a DLT. However, grade 5 cytopenias will 
be considered DLTs.
4.5
Dose Modifications
4.5.1
Induction Chemotherapy Dose Modifications
Dose modifications for DA-EPOCH-R should be utilized as appropriate per 
standard practice for patients outside the DLT evaluation window during 
induction therapy. Doses may be delayed as clinically warranted up to 3 weeks, 
and patients do not need to come off study for dose delays during induction.
For occurrence of motor or sensory neuropathy during induction, see footnote c 
below for suggested modifications of vincristine.
Table 4-3: DA-EPOCH-R Dose Adjustments for Intra-Patient Dose Modification
Dose Levels
-2
-1
1a
2
3
4
5
6
7
Adjusted Agentsa
Doxorubicin (mg/m2/day)
10
10
10
12
14.4
17.3
20.7
24.8
29.8
Etoposide (mg/m2/day)
50
50
50
60
72
86.4
103.7
124.4
149.3
Cyclophosphamide 
(mg/m2/day)
480
600
750
900
1080
1296
1555
1866
2239
Non-Adjusted Agents
Rituximab (mg/m2)
375
375
375
375
375
375
375
375
375
Vincristineb,c(mg/m2/day)
0.4b,c
0.4b,c
0.4b,c
0.4b,c
0.4b,c
0.4b,c
0.4b,c
0.4b,c
0.4b,c
Prednisoneb (mg/m2 BID)
60b
60b
60b
60b
60b
60b
60b
60b
60b
Methotrexated (mg)
12d
12d
12d
12d
12d
12d
12d
12d
12d
Ixazomib
 
MTDe 
 
MTDe
 
MTDe
 
MTDe
 MTDe
 MTDe
 MTDe
 MTDe
 
MTDe
a. Level 1 is the starting dose for DA-EPOCH-R. Dose adjustments above starting dose level (level 1) apply to etoposide, 
doxorubicin and cyclophosphamide. Dose adjustments below starting dose level (level 1) apply to cyclophosphamide only.
b. The dose of prednisone and vincristine can be modified at the treating physician’s discretion for older patients with poor 
tolerance. 
c. It is suggested that the dose of vincristine is reduced 25% or 50% for grade 2 or 3 motor neuropathy, respectively, and 
reduced by 50% for grade 3 sensory neuropathy.
d. For CSF negative patients who are considered at high risk of CNS disease, intrathecal (IT) chemotherapy should be given 
per physician’s preference using institutional guidelines.
e. The dose of ixazomib may be reduced for toxicities ≥Grade 3, other than cytopenias, after discussion with the PI. If 
ixazomib is interrupted for > 3 weeks, DSMC approval must be obtained in order for patients to resume treatment per 
Section 4.5.2.1.
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Table 4-4: Criteria for Dose Adjustment of DA-EPOCH-R
ANC > 500/µL on all measurements
Increase 1 dose level
ANC < 500/µL on 1 or 2 measurements (3-4 days apart)
Maintain current dose level
ANC < 500/µL > 3 measurements (3-4 days apart)
Decrease 1 dose level
Platelets < 25,000 on > 1 measurement
Decrease 1 dose level
4.5.2
Dose Delays/Modifications for Ixazomib
4.5.2.1 Dose Delays (Induction and Maintenance)
Treatment with ixazomib will use a cycle length of 28 days (with 
scheduled doses on day 1 and either day 8 or 15 of induction, and days 
1, 8, and 15 of each maintenance cycle). For a new cycle of treatment to 
begin during both induction and maintenance, the patient must meet the 
following criteria:

ANC must be ≥ 1,000/mm3

Platelet count must be ≥ 75,000/mm3

All other non-hematologic toxicity (except for alopecia) must have 
resolved to ≤ Grade 1 or to the patient’s baseline condition
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 re-evaluate. The maximum 
delay before treatment should be permanently discontinued will be 3 
weeks; however, delays of longer than 3 weeks may be considered on a 
case-by-case basis with notification to the QAM and upon receipt of 
DSMC approval.
Please refer to the Tables 4-5, 4-6, and 4-7 below for ixazomib dose 
delays and modifications during maintenance therapy for both 
hematologic and non-hematologic toxicities. NOTE: Once maintenance 
ixazomib is reduced for any toxicity, the dose may not be re-escalated.
Table 4-5: Ixazomib Dose Adjustments During Maintenance
Dose Level
Dose (mg)
Starting Dose*
4.0
-1
3.0
-2
2.3
-3
Discontinue
*The starting dose for maintenance ixazomib will be 4.0 mg.
NOTE: If a patient has dose reduced the ixazomib during the treatment 
phase (when it was given in combination with chemotherapy) and now 
enters the maintenance phase (where ixazomib will be administered as 
a single agent), they should start maintenance at the full dose of 
ixazomib (rechallenge at 4 mg weekly), not at the reduced dose; 
subsequent dose reductions may be considered if the patient does not 
tolerate the 4 mg dose during maintenance.  
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Table 4-6: Ixazomib Dose Modifications 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.  

CBC with differential should be repeated at 
least every other day until the ANC and/or 
platelet counts have exceeded the 
prespecified values (see above) on at least 2 
occasions.  

Upon recovery, ixazomib may be reinitiated 
at 1 dose level lower. 
Dose Modifications for Subsequent Treatment Cycles

Delay of > 2 weeks in the start of a 
subsequent cycle due to lack of toxicity 
recovery (ANC < 1.0  109/L, platelet count 
< 75  109/L, or other nonhematologic 
toxicities > Grade 1 or not to the patient’s 
baseline condition)

Hold ixazomib until resolution as per criteria 
above.

Upon recovery, reduce ixazomib by 1 dose 
level.

The maximum delay before treatment should 
be discontinued will be 3 (unless DSMC 
approved – see above).
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), reduce 
ixazomib by 1 dose level at the 
start of that next 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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Table 4-7: Ixazomib Dose Modifications for 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
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) 
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
New or worsening Grade 4 
peripheral neuropathy
Discontinue study drug
N/A
Rash
Grade 2 Rash
Symptomatic recommendations
May consider dose 
modifications and symptom 
management.
Grade 3 Rash
Reduce by 1 dose level.
Other
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
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 non hematologic 
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 
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31
4.6
Concomitant Medications/Procedures
4.6.1
Required Concomitant Medications/Procedures
The following are required during induction therapy:

Bactrim DS with dosing per institutional guidelines (or equivalent if 
allergic).

Omeprazole 20 mg/day PO (or equivalent).

Stimulant laxative/stool softener (e.g., Pericolace®) 2 tablets PO BID 
(adjusted as necessary) or institutional preference for prevention of 
constipation.

Lactulose 20 g PO Q6 hours PRN until resolution or institutional 
preference for treatment of constipation.

Acetaminophen 650 mg PO and diphenhydramine 50-100 mg IV or PO 
30 to 60 minutes prior to starting each rituximab infusion.

Hepatitis B & C surface Ag+ patients should receive lamivudine, 
entecavir, tenofovir or equivalent per institutional guidelines during 
therapy and until at least 12 weeks beyond completion of induction 
therapy.  

Fluid deficit should be corrected before initiation of treatment and during 
treatment.
4.6.2
Prohibited Concomitant Medications/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 to use. A DDI with a strong inducer would 
decrease ixazomib exposure:
o
Strong CYP3A inducers:  rifampin, rifapentine, rifabutin, 
carbamazepine, phenytoin, and phenobarbital
o
The dietary supplements St John’s wort and Ginkgo biloba are 
not permitted.

The following procedures are prohibited during the study:
o
Any antineoplastic treatment with activity against lymphoma 
except for drugs in this treatment regimen.
o
Radiation therapy (the requirement for local radiation therapy 
generally indicates disease progression).
o
Platelet transfusions to help patients meet eligibility criteria are 
not allowed within 3 days prior to registration.
4.6.3
Permitted Concomitant Medications/Procedures 
The following medications and procedures are permitted during the study:

Antiemetics, including 5-HT3 serotonin receptor antagonists, are 
recommended for emesis if it occurs once treatment is initiated; 
prophylactic anti-emetics may be used at the discretion of the 
investigator (NOTE: dexamethasone should not be administered as an 
anti-emetic). Fluid deficit should be corrected before initiation of study 
drug and during treatment.

Loperamide or other antidiarrheal should be used for symptomatic 
diarrhea at discretion of the investigator (once infectious causes are 
excluded). The dose and regimen will be according to institutional 
guidelines. IVF should be given to prevent volume depletion.

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 use of a topical, IV, or 
oral steroid (e.g., prednisone ≤ 10 mg per day or equivalent) is 
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permitted.  Management of a Grade 3 rash may require intravenous 
antihistamines or corticosteroids. 

Growth factors (e.g., G-CSF, GM-CSF, recombinant erythropoietin) are 
permitted. Their use should follow published guidelines and/or 
institutional practice; however, alternative usage may be reviewed with 
the Takeda Clinical or Medical Representative. Erythropoietin will be 
allowed in this study. Their use should follow published guidelines and/or 
institutional practice.

Patients should be transfused with red cells and platelets as clinically 
indicated and according to institutional guidelines.

Patients 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.

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.

Steroids used to control a patient’s lymphoma are permitted and have no 
washout prior to starting study treatment.
NOTE: Although no specifically prohibited, nonsteroidal anti-inflammatory 
drugs (NSAIDs) should be avoided with impaired renal function given 
reported NSAID-induced renal failure in patients with decreased renal 
function.
4.7
CNS Prophylaxis and Treatment
Due to high risk of CNS involvement, all patients will undergo diagnostic Lumbar 
Puncture (LP) before or during the first cycle of DA-EPOCH-R, and if negative, IT 
methotrexate may be given per treating physician’s preference using institutional 
standards. If the CSF is cytologically positive at the time CNS prophylaxis is scheduled to 
begin, the patient should receive active treatment of the CSF with methotrexate per 
institutional standards. 
4.8
Supportive Care
4.8.1
Reactivation of Herpes Infection
Please see 4.6.3 for permitted therapies.
4.8.2
Nausea and/or Vomiting
Please see 4.6.3 for permitted therapies. Fluid deficit should be corrected before 
initiation of study drug and during treatment.
4.8.3
Diarrhea
Please see 4.6.3 for permitted therapies.
4.8.4
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 
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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.
4.8.5
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. Therapy can be reinitiated at a reduced 
level upon recovery of platelet counts. A rare risk is thrombotic thrombocytopenic 
purpura (TTP), a rare blood disorder where blood clots form in small blood 
vessels throughout the body characterized by thrombocytopenia, petechiae, 
fever, or possibly more serious signs and symptoms. TTP should be managed 
symptomatically according to standard medical practice.
4.8.6
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 (see above).  
Ixazomib administration should be modified as noted as per dose modification 
recommendations in the protocol when neutropenia occurs. Therapy can be 
reinitiated at a reduced level upon recovery of ANCs.
4.8.7
Antibiotic Prophylaxis
Antibiotic prophylactic medications are permitted and encouraged during study 
treatment. Regimens should follow institutional standards. Recommendations 
include:
o    Bactrim® DS twice daily Monday, Wednesday, Friday
o    Acyclovir 400mg once daily
o    Fluconazole 100mg once daily
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4.8.8
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.
4.8.9
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.
4.8.10
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.
4.8.11
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. Should this occur, appropriate medical 
treatment should be utilized.
4.9
Duration of Therapy & Follow-Up
Study treatment will include induction therapy (6 cycles of 21 days each) followed by up 
to 1 year of maintenance therapy (1 cycle = 28 days during maintenance). In the absence 
of treatment delays due to adverse events, maintenance treatment may continue for up to 
one year or until:

Disease progression

Inter-current illness that prevents further administration of treatment

Unacceptable adverse event(s)

Patient decides to withdraw from the study, OR

General or specific changes in the patient’s condition render the patient unacceptable 
for further treatment in the judgment of the investigator.
During follow-up, patients will be followed with at least one clinic visit every three months, 
for one year after removal from treatment or until death, whichever occurs first. Patients 
removed from treatment for unacceptable adverse events will be followed until resolution 
or stabilization of the adverse event.
4.10
Removal of Subjects from Study Treatment and/or Study as a Whole
Patients can be taken off the study treatment and/or study as a whole at any time at their 
own request, or they may be withdrawn at the discretion of the investigator for safety, 
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behavioral or administrative reasons. The reason(s) for discontinuation must be clearly 
documented on the appropriate eCRF and may include:

Patient voluntarily withdraws from treatment (follow-up permitted)

Patient withdraws consent (no follow-up permitted)

Patient is unable to comply with protocol requirements

Patient demonstrates disease progression 

Patient experiences unacceptable toxicity 

Treating physician determines that continuation on the study would not be in the 
patient’s best interest

Patient becomes pregnant 

Patient develops a second malignancy that requires treatment which would interfere 
with this study

Patient becomes lost to follow-up (LTF) 
4.11
Replacement of Subjects
Subjects who receive at least 1 dose of investigational treatment are evaluable for 
toxicity. However, should a patient come off treatment within the DLT period for any 
reason other than a DLT (e.g. patient refusal, unrelated adverse event), an additional 
patient may be added to the cohort at the discretion of the QAM and DSMC. 
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5.0
STUDY PROCEDURES
Table 5-1: Study Procedures
Screening
On Treatment
Off Treatment
Time Period
Baseline10
Induction (C1-6)7
Maintenance (C7+)7
Off Treatment15
Follow-up9
Day 1
(± 3 days)
Day 8, 15
(± 3 days)
Day 1 
(± 3 days)
Day 8 
(± 3 days)
Day 15 
(± 3 days)
Assessment or Activity
Informed Consent
X
Medical history 
X
Physical exam1
X
X1
X
X
ECOG status
X
X1
X
X
Concomitant medications
X
X
X
X
Toxicity assessment
X
X
X
X
X
Disease Assessment2
X
X2
X2
X
X
CBC with diff4
X4
X
X4
X
X
X
Chemistry panel4
X4
X
X4
X
X
X
Pregnancy test3
X
Hep B & C screen11
X11
MYC and BCL2 status by 
FISH and IHC5, 6
X10
Peripheral blood banking8
X8
X8
Lumbar Puncture12
X
X12
DA-EPOCH-R 
administration13
X
Ixazomib administration14
X
X14
X
X
X
1 Includes vital signs (pulse, blood pressure) and height (baseline only) and weight. Physical exam and ECOG PS do not need to be repeated at 
C1D1 if performed as part of screening within 7 days prior.
2 Tumor assessment will be by means of PET/CT at baseline, after cycle 2 of induction (within 7 days of the start of cycle 3), and at the “Off 
Treatment” visit. Tumor assessments will also occur after induction (within 2 weeks of starting maintenance) and every 6 months 
thereafter and may consist of PET/CT or CT alone at the treating investigator’s discretion. Patients who are unable to get PET imaging for 
any reason will NOT be precluded from participation. While diagnostic-quality CT is encouraged, it is not required.
3 Serum test for females of child-bearing potential is required within 7days prior to registration.
4 Patients will have CBC with differential and Chemistry panel drawn at screening (≤14 days from registration) as well as prior to dosing at each 
study visit. Labs are not required at time points where dosing does not take place (for example, if a patient receives ixazomib day 8 and 
not day 15, labs are not required on day 15; labs are not required for patients who discontinue therapy prior to the maintenance period).
5 Patients MUST have a tumor that is MYC+ by FISH or IHC for enrollment, but other results may be pending and are not required to for 
eligibility/registration purposes.

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6 FISH status for all patients and for all three markers (MYC, BCL2, and BCL6) should be reported as +/- for translocation (aka rearrangement), 
and if negative for translocation, by any reported gain of copy number or amplification (including number of copies for MYC translocation). 
IHC is preferred but not required for enrollment.
7 During induction, one cycle = 3 weeks or 21 days; during maintenance, one cycle = 4 weeks or 28 days. For patients who do not receive SCT, 
maintenance will begin after C6 (Cycle 7 will start at Cycle 6 Day 22 +/- 7 days) and will consist of ixazomib treatment on Days 1, 8 and 15 
of each cycle for up to 1 year from the start of Cycle 7. If a patient is receiving clinical benefit after this period, an extension of ixazomib 
treatment can be considered with documented approval from Takeda, the PI, and DSMC.
8 Phase II patients, only if patient agrees to optional blood draws: One red top tube and one green top tube will be drawn on day 1 of induction 
cycles 1 & 2, and day 1 of the first 3 maintenance cycles. Blood will be frozen and stored in the Biorepository of the Pathology Core 
Facility at Northwestern University for future, unspecified use.
9 Patients will be followed with at least one clinic visit every three months, for one year after removal from treatment or until death, whichever 
occurs first, to document disease progression and survival status. Patients removed from treatment for unacceptable adverse events will 
be followed until resolution or stabilization of the adverse event
10 Screening assessments must be completed within 28 days prior to registration (with the exception of labs, which must be within 14 days, FISH 
and IHC, which may be assessed within an indefinite window, and Hepatitis B & C which may be within 42 days).  
11 Patients must have baseline HBV surface Ag and HCV ab at a minimum ≤ 42 days (6 weeks) prior to registration. If either is positive, patients 
should have viral load of the corresponding infection (HBV or HCV) documented. NOTE: patients who are HBV surface Ag+ MUST agree 
to treatment/prophylaxis with appropriate antiviral therapy in order to be enrolled.
12 All patients should have a lumbar puncture (LP) per institutional standards before or during the first cycle of DA-EPOCH-R. Additional lumbar 
punctures will then be performed following the standard of care and treating physician’s discretion. The initial LP will determine a patient’s 
CNS involvement to dictate the recommended prophylactic treatment with methotrexate (see section 4.7)
13 DA-EPOCH-R will be administered Day 1-5 of each cycle during induction (a total of 6 cycles).  See section 4.3.2 for treatment and dosing 
details as well instructions on methotrexate administration. The DA-EPOCH-R regimen will follow institutional standards and details are 
provided in the protocol for convenience.
14 Ixazomib is an oral pill that will be administered on Day 1 and either Day 8 or Day 15 of each cycle during induction (see section 4.2.1 for 
laboratory requirements). Day 8 dosing should be administered unless held for toxicities, in which case, patients should be re-challenged 
on Day 15. During Phase I, each patient’s dose will depend on the cohort assignment (either 2.3mg, 3mg, or 4mg). During Phase II, all 
patients will be dosed at the MTD determined during Phase I. Once a patient has completed 6 cycles of induction, he or she may continue 
maintenance therapy with ixazomib alone on days 1, 8, and 15 of each cycle for up to one year. Maintenance dosing will begin at a 
standard dose of 4mg for all patients.  See Table 4-5 for permitted dose modifications during the maintenance phase.
15 An end of treatment visit will occur 21 days after the last study treatment (+/- 7 days)16 During the first 2 cycles of maintenance therapy (Cycle 7 
and 8), labs should be assessed weekly prior to ixazomib dosing. Thereafter, labs from Day 1 of each cycle can be used for dosing on Day 
1, 8 and 15.

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6.0
ENDPOINT ASSESSMENT
Patients must complete at least 2 cycles of induction therapy and undergo a subsequent 
disease response assessment to be evaluable for response endpoints; patients who 
complete less than 2 cycles will be evaluable for toxicity endpoints only.
6.1
Primary Endpoints
The primary endpoint for the phase I portion of the study will be dose-limiting toxicity 
(DLT), defined as the occurrence of ≥ Grade 3 toxicity (using CTCAE v 4.03), 
experienced during the first cycle (3 weeks or 21 days) of study treatment, except for 
cytopenias. Grade 5 cytopenias will also be considered DLTs. All patients who receive at 
least one dose of ixazomib will be evaluable for this endpoint.
The primary endpoint of the phase II portion will be 12-month PFS. PFS will be defined 
as the time elapsed between treatment initiation and tumor progression or death from any 
cause, with censoring of patients who are lost to follow-up. The 12-month PFS will be 
defined as the percentage of patients alive and progression free 12 months from start of 
therapy. 
6.2
Secondary Endpoints
All secondary endpoints will consist of combined analysis of patients from both phase I 
and phase II. 
Adverse events will be defined as those included in CTCAE v 4.03.  The occurrence and 
severity of each will be recorded. Responses will be determined by categorizing patients 
as SD, PR, or CR by CT or PET/CT, and/or resolution of marrow-only involvement. CR 
and PR will each be assessed according to the Revised Response Criteria for Malignant 
Lymphoma (see definitions in section 6.4 below). Assessments will be performed after 
cycle 2 and after induction therapy (prior to start of maintenance therapy), and then at the 
discretion of the treating investigator. OS will be defined as freedom from death by any 
cause.  To assess the predictive value of FDG-PET/CT scans on PFS, patients will be 
categorized as either FDG-PET (+) or (-) at interim and end-of-treatment imaging.
6.3
Exploratory Endpoints
Cell of origin (COO) will be defined as GCB and non-GCB via the Hans algorithm 
(applicable only to patients with DLBCL). These results will be correlated with response 
rate, PFS, and OS. Patients will be grouped by whether consolidative SCT was 
performed in first remission, with PFS compared across groups (SCT vs. non-SCT), in 
order to assess the feasibility and outcomes of consolidation SCT.
6.4
Definitions
Response and progression will be evaluated using 2007 Revised Response Criteria for 
Malignant Lymphoma (modified). Please refer to definitions below and summarized in the 
table.
6.4.1
Complete Remission (CR)
The designation of CR requires the following (Table 5): 
1.
Complete disappearance of all detectable clinical evidence of disease and 
disease-related symptoms, if present before therapy. 
2.
A post-treatment residual mass of any size is permitted as long as it is PET 
negative. If a pretreatment PET scan was negative, all lymph nodes and 
nodal masses must have regressed on CT to normal size (≤1.5 cm in their 
greatest transverse diameter for nodes > 1.5 cm before therapy). Previously 
involved nodes that were 1.1 to 1.5 cm in their long axis and more than 1.0 
cm in their short axis before treatment must have decreased to ≤ 1.0 cm in 
their short axis after treatment. 
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3.
The spleen and/or liver, if considered enlarged before therapy on the basis of 
a physical examination or CT scan, should not be palpable on physical 
examination and should be considered normal size by imaging studies, and 
nodules related to lymphoma should disappear. However, determination of 
splenic involvement is not always reliable because a spleen considered 
normal in size may still contain lymphoma, whereas an enlarged spleen may 
reﬂect variations in anatomy, blood volume, the use of hematopoietic growth 
factors, or causes other than lymphoma. 
6.4.2
Partial Response (PR)
The designation of PR requires all of the following:
1.
At least a 50% decrease in sum of the product of the diameters (SPD) of up 
to six of the largest dominant nodes or nodal masses. These nodes or 
masses should be selected according to all of the following: they should be 
clearly measurable in at least 2 perpendicular dimensions; if possible they 
should be from disparate regions of the body; and they should include 
mediastinal and retroperitoneal areas of disease whenever these sites are 
involved. 
2.
No increase should be observed in the size of other nodes, liver, or spleen.
3.
Splenic and hepatic nodules must regress by ≥50% in their SPD or, for 
single nodules, in the greatest transverse diameter. 
4.
With the exception of splenic and hepatic nodules, involvement of other 
organs is usually assessable and no measurable disease should be present.
5.
Bone marrow assessment is irrelevant for determination of a PR if the 
sample was positive before treatment. However, if positive, the cell type 
should be specified (e.g., large-cell lymphoma or small neoplastic B cells). 
Patients who achieve a CR by the above criteria, but who have persistent 
morphologic bone marrow involvement, will be considered partial 
responders. When the bone marrow was involved before therapy and a 
clinical CR was achieved, but with no bone marrow assessment after 
treatment, patients should be considered partial responders. 
6.
No new sites of disease should be observed. 
7.
If the PET scan was positive before therapy, the post-treatment PET should 
be positive in at least one previously involved site. 
8.
If the pretreatment PET scan was negative, CT criteria should be used.
6.4.3
Stable Disease (SD)
Stable disease (SD) is defined as the following:
1.
A patient is considered to have SD when he or she fails to attain the criteria 
needed for a CR or PR, but does not fulfill those for progressive disease (see 
below). 
2.
The PET should be positive at prior sites of disease with no new areas of 
involvement on the post-treatment CT or PET. 
3.
If the pretreatment PET was negative, there must be no change in the size of 
the previous lesions on the post-treatment CT scan.
6.4.4
Relapsed Disease (after CR)/Progressive Disease (after PR, SD)
1.
Lymph nodes should be considered abnormal if the long axis is more than 
1.5 cm regardless of the short axis. If a lymph node has a long axis of 1.1 to 
1.5 cm, it should only be considered abnormal if its short axis is more than 
1.0. Lymph nodes ≤ 1.0 x ≤ 1.0 cm will not be considered as abnormal for 
relapse or progressive disease. 
2.
Appearance of any new lesion more than 1.5 cm in any axis during or at the 
end of therapy, even if other lesions are decreasing in size. Increased FDG 
uptake in a previously unaffected site should only be considered relapsed or 
progressive disease after confirmation with other modalities. In patients with 
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no prior history of pulmonary lymphoma, new lung nodules identified by CT 
are mostly benign.  Thus, a therapeutic decision should not be made solely 
on the basis of the PET without histologic confirmation. 
3.
At least a 50% increase from nadir in the SPD of any previously involved 
nodes, or in a single involved node, or the size of other lesions (e.g., splenic 
or hepatic nodules). To be considered progressive disease, a lymph node 
with a diameter of the short axis of less than 1.0 cm must increase by ≥ 50% 
and to a size of 1.5 x 1.5 cm or more than 1.5 cm in the long axis. 
4.
At least a 50% increase in the longest diameter of any single previously 
identified node more than 1 cm in its short axis. 
5.
Lesions should be PET positive if disease lesions were PET positive before 
therapy, unless the lesion is too small to be detected with current PET 
systems (<1.5 cm in its long axis by CT). Measurable extranodal disease 
should be assessed in a manner similar to that for nodal disease. For these 
recommendations, the spleen is considered nodal disease. Disease that is 
only assessable (e.g., pleural effusions, bone lesions) will be recorded as 
present or absent only, unless, while an abnormality is still noted by imaging 
studies or physical examination, it is found to be histologically negative.
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7.0
ADVERSE EVENTS
This study will be conducted in compliance with the Data Safety Monitoring Plan (DSMP) of the 
Robert H. Lurie Comprehensive Cancer Center of Northwestern University. The level of risk 
attributed to this study requires High Intensity Monitoring as outlined in the DSMP. In addition, the 
study will abide by all safety reporting regulations, as set forth in the Code of Federal 
Regulations.
7.1
Adverse Event Monitoring
Adverse event data collection and reporting, which are required as part of every clinical 
trial, are done to ensure the safety of subjects enrolled in the studies as well as those 
who will enroll in future studies using similar agents. Adverse events are reported in a 
routine manner at scheduled times during a trial (see Section 5 for time points). In 
addition, certain adverse events must be reported in an expedited manner to allow for 
optimal monitoring and patient safety and care. 
All patients experiencing an adverse event, regardless of its relationship to study drug, 
will be followed until: 

the adverse event resolves or the symptoms or signs that constitute the adverse 
event return to baseline; 

any abnormal laboratory values have returned to baseline; 

there is a satisfactory explanation other than the study drug for the changes 
observed; or

death.
7.2
Definitions & Descriptions
7.2.1
Adverse Event
An adverse event (AE) is any untoward medical occurrence in a patient receiving 
study treatment and which 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 an experimental intervention, whether or not related to 
the intervention. 
Recording of AEs should be done in a concise manner using standard, 
acceptable medical terms. In general, AEs are not procedures or measurements, 
but should reflect the reason for the procedure or the diagnosis based on the 
abnormal measurement. Preexisting conditions that worsen in severity or 
frequency during the study should also be recorded (a preexisting condition that 
does not worsen is not an AE). Further, a procedure or surgery is not an AE; 
rather, the event leading to the procedure or surgery is considered an AE.
If a specific medical diagnosis has been made, that diagnosis or syndrome 
should be recorded as the AE whenever possible.  However, a complete 
description of the signs, symptoms and investigations which led to the diagnosis 
should be provided. For example, if clinically significant elevations of liver 
function tests are known to be secondary to hepatitis, “hepatitis” and not 
“elevated liver function tests” should be recorded. If the cause is not known, the 
abnormal test or finding should be recorded as an AE, using appropriate medical 
terminology (e/g/ thrombocytopenia, peripheral edema, QT prolongation).
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7.2.2
Severity of AEs
All adverse events will be graded according to the NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.03. The CTCAE v4 is available at 
http://ctep.cancer.gov/reporting/ctc.html
If no CTCAE grading is available, the severity of an AE is graded as follows:

Mild (grade 1): the event causes discomfort without disruption of normal daily 
activities.

Moderate (grade 2): the event causes discomfort that affects normal daily 
activities.

Severe (grade 3): the event makes the patient unable to perform normal daily 
activities or significantly affects his/her clinical status.

Life-threatening (grade 4): the patient was at risk of death at the time of the 
event.

Fatal (grade 5): the event caused death.
7.2.3
Serious Adverse Events (SAEs)
All SAEs, regardless of attribution, occurring from time of signed informed 
consent, through 30 days after the last administration of study drug, must be 
reported upon discovery or occurrence.
An SAE is defined in regulatory terminology as any untoward medical occurrence 
that:

Results in death.
If death results from (progression of) the disease, the disease should be 
reported as event (SAE) itself.

Is life-threatening.
The patient was at risk of death at the time of the event; it does not refer to 
an event that hypothetically might have caused death if it were more severe.

Requires in-patient hospitalization or prolongation of existing 
hospitalization for ≥ 24 hours.

Results in persistent or significant disability or incapacity.

Is a congenital anomaly/birth defect.

Is an important medical event.
Any event that does not meet the above criteria, but that in the judgment of 
the investigator jeopardizes the patient, may be considered for reporting as a 
serious adverse event. The event may require medical or surgical 
intervention to prevent one of the outcomes listed in the definition of “Serious 
Adverse Event“. 
For example: allergic bronchospasm requiring intensive treatment in an 
emergency room or at home; convulsions that may not result in 
hospitalization; development of drug abuse or drug dependency.
7.2.4
Unanticipated Problems Involving Risks to Subject or Others
A UPIRSO is a type of SAE that includes events that meet ALL of the following 
criteria:

is unexpected (in terms of nature, severity, or frequency) given the 
procedures described in the research protocol documents (e.g., the IRB-
approved research protocol and informed consent document) and the 
characteristics of the human subject population being studied

is related or possibly related to participation in the research ("possibly 
related" means there is a reasonable possibility that the incident, experience, 
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or outcome may have been caused by the procedures involved in the 
research); and 

suggests that the research places human subjects or others at a greater risk 
of harm (including physical, psychological, economic, or social harm) than 
was previously known or recognized, even if no harm has actually occurred. 
7.3
Adverse Event Reporting
7.3.1
Routine Reporting
All routine adverse events, such as those that are expected, or are unlikely or 
definitely not related to study participation, are to be reported on the appropriate 
eCRF according to the time intervals noted in the study table. Routine AEs will be 
reviewed by the Data Monitoring Committee (DSMC) according to the study’s 
phase and risk level, as outlined in the DSMP. 
7.3.2
Determining if Expedited Reporting is Required
This includes all events that occur within 30 days of the last dose of protocol 
treatment. Any event that occurs more than 30 days after the last dose of 
treatment and is attributed (possibly, probably, or definitely) to the agent(s) must 
also be reported accordingly.
1)
Identify the type of adverse event using the NCI CTCAE v 4.03.
2)
Grade the adverse event using the NCI CTCAE v 4.03.
3)
Determine whether the adverse event is related to the protocol therapy.  
Attribution categories are as follows:

Definite: AE is clearly related to the study treatment.

Probable: AE is likely related to the study treatment.

Possible: AE may be related to the study treatment.

Unlikely: AE not likely to be related to the study treatment.

Unrelated: AE is clearly NOT related to the study treatment.
4)
Determine the prior experience of the adverse event.
Expected events are those that have been previously identified as 
resulting from administration of the agent. An adverse event is 
considered unexpected, for expedited reporting purposes only, when 
either the type of event or the severity of the event is not listed in:

the current protocol

the drug package insert

the current Investigator’s Brochure
7.3.3
Expedited Reporting of SAEs/Other Events
7.3.3.1 Reporting to the Northwestern University QAM/DSMC
All SAEs must be reported to the assigned QAM within 24 hours of 
becoming aware of the event (croqualityassurance@northwestern.edu). 
Completion of the NU CTO SAE Form is required.
The completed form should assess whether or not the event qualifies as 
a UPIRSO. The report should also include:

Protocol description and number(s)

The patient’s identification number

A description of the event, severity, treatment, and outcome (if 
known)

Supportive laboratory results and diagnostics

The hospital discharge summary (if available/applicable)

Country of incidence
All SAEs will be reported to, and reviewed by, the DSMC per the DSMP.
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7.3.3.2 Reporting to the Northwestern University IRB
The following information pertains to the responsibilities of the lead site 
(Northwestern University). Additional participating sites should follow 
their local IRB guidelines for reporting to their local IRBs.

Any death of an NU subject that is unanticipated in nature and at 
least possibly related to study participation will be promptly reported 
to the NU IRB within 24 hours of notification. 

Any death of a non-NU subject that is unanticipated and at least 
possibly related and any other UPIRSOs will be reported to 
Northwestern University and to the NU IRB within 5 working days of 
notification.

Information pertaining to an NU subject that fits into any of the 
categories listed on the Reportable New Information page will be 
reported to the NU IRB within 5 business days of knowledge or 
notification.
7.3.3.3 Reporting to the FDA 
The FDA will be notified within 7 calendar days of any SAE that is 
associated with study treatment, is unexpected, and is fatal or life-
threatening.
The FDA will be notified within 15 calendar days of any SAE that is 
associated with the study treatment, unexpected, and serious but not 
fatal or life-threatening. This includes any previous SAEs that were not 
initially deemed reportable, but are later determined to meet the criteria 
for reporting (i.e. by the DSMC).
All other SAEs will be reported on an annual basis as part of the annual 
FDA report.
7.3.3.4 Reporting to Takeda Pharmaceuticals
Regardless of expectedness or causality, all SAEs must also be reported 
to Takeda Pharmacovigilance or designee:

Fatal and Life Threatening SAEs within 24 hours but no later 
than 4 calendar days from observation or awareness of the event

All other serious (non-fatal/non-life threatening) events 
within 4 calendar days of observation or awareness of the event
The NU CTO SAE report form will be completed and submitted for all 
SAEs requiring reporting to Takeda Pharmacovigilance. Reports will 
include event term(s), serious criteria, intensity of the event(s), and 
causality of the event(s). Follow-up information on the SAE may be 
requested by Takeda.  
The NU PI is responsible to ensure that the SAE reports are sent to 
Takeda Pharmacovigilance (or designee) from all sites participating in 
the study. Sub-investigators must report all SAEs to the NU CTO QAM 
(as outlined above). NU must also provide Takeda Pharmacovigilance 
with a copy of all communications with applicable regulatory authorities 
related to the study product(s) as soon as possible but no later than 4 
calendar days of such communication.
The contact for reporting is:
Takeda Pharmacovigilance or Designee
SAE and Pregnancy Reporting Contact Information
FAX Number 1-800-963-6290
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NU Study Number: NU 14H09
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NU_14H09-Protocol A-8 - 01.16.2020
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Email: TakedaOncoCases@cognizant.com 
If a woman becomes pregnant or suspects that she is pregnant while 
participating in this study, she must inform the investigator and NU CTO 
QAM immediately and permanently discontinue study drug. The QAM 
must fax a completed Pregnancy Form to the Takeda Department of 
Pharmacovigilance or designee. The pregnancy must be followed for the 
final pregnancy outcome.
If a female partner of a male patient becomes pregnant during the male 
patient’s participation in this study, the QAM must also immediately fax a 
completed Pregnancy Form to the Takeda Department of 
Pharmacovigilance or designee. Every effort should be made to follow 
the pregnancy for the final pregnancy outcome.
A product complaint is a verbal, written, or electronic expression that 
implies dissatisfaction regarding the identity, strength, purity, quality, or 
stability of a drug product.  Individuals who identify a potential product 
complaint situation should immediately contact MedComm Solutions 
(see below) and report the event. Whenever possible, the associated 
product should be maintained in accordance with the label instructions 
pending further guidance from a Takeda Quality representative.
For Product Complaints, call MedComm Solutions at:
877-674-3784 (877 MPI DRUG) 
Product complaints in and of themselves are not AEs.  If a product 
complaint results in an SAE, an SAE form should be completed and sent 
to Takeda Pharmacovigilance.
 
8.0
DRUG INFORMATION
8.1
Ixazomib
8.1.1
Other names 
MLN9708
8.1.2
Classification - type of agent
Ixazomib is an orally bioavailable, potent, reversible, specific inhibitor of the 20S 
proteasome that has demonstrated antitumor activity in in vivo models of multiple 
myeloma (MM) 19
8.1.3
Mode of action
Ixazomib has demonstrated antitumor activity in in vivo models of multiple 
myeloma (MM).
8.1.4
Storage and stability
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 at a temperature under 30ºC. Do not freeze. 
Ensure that the drug is used before the retest expiry date provided by Takeda. 
Expiry extensions will be communicated accordingly with updated documentation 
to support the extended shelf life.
Ixazomib capsules dispensed to the patient for take-home dosing should remain 
in the blister packaging and refrigerated as noted above until the point of use. 
The investigative site is responsible for providing the medication to the patient in 
the correct daily dose configurations, along with a medication diary for tracking all 
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47
doses. 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 at a temperature under 30ºC for the 
duration of each cycle. Medication should not be frozen. 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.
8.1.5
Protocol Dose & Administration
During induction treatment, ixazomib will be given orally twice per cycle (1 cycle 
= 21 days); the first dose will be on day 1 and the second on either day 8 or 15). 
The starting dose for phase I will be 2.3 mg. During maintenance treatment, 
ixazomib 4 mg will be given days 1, 8, and 15 of each cycle (1 cycle = 28 days 
during maintenance).
8.1.6
Preparation
Ixazomib is an anticancer drug and as with other potentially toxic compounds 
caution should be exercised when handling ixazomib capsules. 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.
8.1.7
Incompatibilities
None known.
8.1.8
Availability & Supply 
Ixazomib will be supplied by Takeda Pharmaceuticals 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
To order drug, the Clinical Trial Material Form (see separate attachment) must be 
completed and faxed to Takeda (1-866-422-4797) for approval. Questions may 
be directed to Jim McNamara at 617-444-1619 or 
james.mcnamara@takeda.com.
NOTE: 

Orders are shipped Monday – Wednesday.

Orders requests must be provided at least once week in advance of 
when drug is needed at the site.

Emergency orders may be accommodated on a case by case basis.  
8.1.9
Side effects
Adverse drug reactions such as thrombocytopenia, diarrhea, fatigue, nausea, 
vomiting, and rash have been associated with ixazomib treatment.
8.1.10
Return and Retention of Study Drug
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.
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NU Study Number: NU 14H09
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8.2
Doxorubicin HCL
Please refer to the FDA-approved package insert for doxorubicin for product information, 
extensive preparation instructions, and a comprehensive list of adverse events.
8.2.1
Other Names
Adriamycin PFSTM, Adriamycin RFSTM, Rubex®, hydroxydaunorubicin,
hydroxydaunomycin, ADR
8.2.2
Classification – type of agent
Anthracycline antibiotic.
8.2.3
Mode of Action
Intercalation between adjoining nucleotide pairs in the DNA helix causes 
inhibition of DNA and DNA-dependent RNA synthesis. Free radical generation is 
responsible for cardiac toxicity. Doxorubicin also inhibits topoisomerase II.
8.2.4
Storage & Stability
Intact vials of doxorubicin solution should be stored in the refrigerator. Intact vials 
of powder for reconstitution should be stored at room temperature. Reconstituted 
solutions are stable for 7 days at room temperature and 15 days under 
refrigeration when protected from light. Commercially available solutions labeled 
as such are intended to be multidose vials. Compatibility and stability studies 
were conducted by the Pharmaceutical Development Service [60], Pharmacy 
Department, NIH Clinical Center, simulating concentrations of each drug that 
would be applicable to this trial. Admixtures of vincristine, doxorubicin, and 
etoposide in 0.9% Sodium Chloride Injection, in polyolefin-lined IV bags were 
stable for up to 72 hours at room temperature, provided that the concentration of 
etoposide was < 250 mcg/ml.
8.2.5
Protocol Dose & Administration
Doxorubicin will be administered as a 96-hour continuous IV infusion, along with 
vincristine and etoposide in the same infusion solution. The chemotherapy will be 
administered with a suitable infusion pump via a central venous access device. 
8.2.6
Preparation
Reconstitute the vials of doxorubicin powder with 5, 10, 25, or 50 mL, 
respectively, of sodium chloride for injection, USP, resulting in a concentration of 
2 mg/mL. Doxorubicin will be admixed in 0.9% sodium chloride, along with 
vincristine IV for infusion over 24, 48 or 72 hours. Etoposide may be mixed with 
doxorubicin and vincristine, or it may be infused separately. See reference 49 for 
specific compatibility and stability information base on concentration of each 
agent.
8.2.7
Incompatibilities
Physically incompatible with heparin, fluorouracil, aminophylline, cephalothin,
dexamethasone, diazepam, hydrocortisone, and furosemide.
8.2.8
Availability & Supply
Doxorubicin is commercially available as a lyophilized powder for reconstitution 
in 10, 20, 50, and 100 mg vials. Also available are 2 mg/mL solutions for injection 
in 10, 20, 50, and 200 mg vials. 
8.2.9
Side Effects
Hematologic: Leukopenia (dose-limiting), thrombocytopenia, anemia. Nadir in 10-
14 days with recovery usually in 21 days. 
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Dermatologic: alopecia (usually complete; reversible) radiation recall reactions; 
increased sensitivity to sunlight. 
Gastrointestinal: nausea and vomiting (doxorubicin is generally considered 
moderately to highly emetogenic), anorexia, diarrhea, mucositis (stomatitis, 
esophagitis). 
Cardiovascular: cardiomyopathy may occur and is related to total cumulative 
lifetime dose. The risk for cardiomyopathy increases with total doses > 450 
mg/m2. ECG changes and less often, arrhythmias, are seen. Rarely, sudden 
death has occurred. 
Other: Red discoloration of urine for 24-48 hours after drug administration. 
Doxorubicin is a vesicant and can cause tissue necrosis if extravasated, 
especially at the concentration usually employed for bolus injections (i.e., 2 
mg/mL).
8.3
Etoposide
Please refer to the FDA-approved package insert for etoposide for product information, 
extensive preparation instructions, and a comprehensive list of adverse events.
8.3.1
Other Names
VePesid®, Epidophyllotoxin, VP-16, EPEG, NSC# 141540
8.3.2
Classification – type of agent
Podophyllotoxin derivative
8.3.3
Mode of Action
Etoposide inhibits the enzyme topoisomerase II, nucleoside transport,
and incorporation, and causes DNA breakage
8.3.4
Storage & Stability
Intact vials of etoposide for injection should be stored at room temperature and 
protected from light. Compatibility and stability studies were conducted by the 
Pharmaceutical Development Service [60], Pharmacy Department, NIH Clinical 
Center, simulating concentrations of each drug that would be applicable to this 
trial. Admixtures of vincristine, doxorubicin, and etoposide in 0.9% Sodium 
Chloride Injection, in polyolefin-lined IV bags were stable for up to 72 hours at 
room temperature, provided that the concentration of etoposide was < 250 
mcg/ml.
8.3.5
Protocol Dose & Administration
Etoposide will be administered as a 96- hour continuous IV infusion, along with 
vincristine and doxorubicin. The chemotherapy will be administered with a 
suitable infusion pump via a central venous access device. 
8.3.6
Preparation
Etoposide will be admixed in 0.9% sodium chloride for IV infusion over 24, 48 or 
72 hours. Etoposide may be mixed with doxorubicin and vincristine or it may be 
infused separately. See reference 49 for specific compatibility and stability 
information based on concentration of each agent. Infusion solutions should be 
changed every 24 hours. The volume of the infusion solution will be determined 
by the 24 hour etoposide dose. If etoposide ≤ 150 mg per 24 hours, then dilute 
drugs in 500 mL 0.9% sodium chloride; if etoposide > 150 mg per 24 hours, then 
dilute drugs in 1000 mL 0.9% sodium chloride.
8.3.7
Incompatibilities
None known.
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8.3.8
Availability & Supply
Etoposide is commercially available as a solution for injection in 5 mL, 7.5 mL, 25 
mL, and 50 mL vials containing 20 mg/mL.
8.3.9
Side Effects
Myelosuppression, predominantly neutropenia and thrombocytopenia, is the 
most common toxicity associated with etoposide. Nausea and vomiting range 
from mild to severe in severity, depending on the dose. At the dose used in this 
study, etoposide is moderately highly emetogenic. Mucositis is also more 
common at the dose used in this study. Alopecia is likely. Hypotension is 
associated with too rapid administration of etoposide. This would be unlikely to 
occur in this trial.
8.4
Vincristine sulfate
Please refer to the FDA-approved package insert for vincristine sulfate for product 
information, extensive preparation instructions, and a comprehensive list of adverse 
events.
8.4.1
Other Names
VCR, Leurocristine sulfate, Oncovin®, Vincasar PFS, LCR
8.4.2
Classification – type of agent
Vinca alkaloid (tubulin inhibitor).
8.4.3
Mode of Action
Vincristine binds to tubulin, a protein that forms microtubules, thus interfering with 
spindle formation during metaphase and causing cessation of cellular mitosis.
8.4.4
Storage & Stability
Unopened vials should be stored under refrigeration and protected from light. 
Commercially available solutions labeled as such are intended to be multidose 
vials. Compatibility and stability studies were conducted by the Pharmaceutical 
Development Service [49], Pharmacy Department, NIH Clinical Center, 
simulating concentrations of each drug that would be applicable to this trial. 
Admixtures of vincristine, doxorubicin, and etoposide in 0.9% Sodium Chloride 
Injection, in polyolefin-lined IV bags were stable for up to 72 hours at room 
temperature, provided that the concentration of etoposide was < 250 mcg/ml.
8.4.5
Protocol Dose & Administration
Vincristine will be administered as a 96-hour continuous IV infusion, along with 
etoposide and doxorubicin (see “Storage & Stability” above). The chemotherapy 
will then be administered with a suitable infusion pump via a central venous 
access device. 
8.4.6
Preparation
Vincristine will be admixed in 0.9% sodium chloride for IV infusion over 24, 48 or 
72 hours. Etoposide may be mixed with doxorubicin and vincristine or it may be 
infused separately. See reference 49 for specific compatibility and stability 
information based on concentration of each agent. Infusion solutions should be 
changed every 24 hours. The volume of the infusion solution will be determined 
by the 24 hour etoposide dose. If etoposide ≤ 150 mg per 24 hours, then dilute 
drugs in 500 mL 0.9% sodium chloride; if etoposide > 150 mg per 24 hours, then 
dilute drugs in 1000 mL 0.9% sodium chloride. Infusion solutions should be 
protected from light.
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8.4.7
Incompatibilities
Furosemide; some in-line filters; polysiloxan containers used in portable delivery 
services.
8.4.8
Availability & Supply
Vincristine is commercially available in 1 mL, 2 mL, and 5 mL vials in a 
concentration of 1 mg/mL.
8.4.9
Side Effects
The most common toxicity associated with vincristine is neurotoxicity. Peripheral 
manifestations of neurotoxicity include: numbness of extremities, paresthesias, 
loss of deep tendon reflexes, neuropathic pain and muscle weakness. GI 
manifestations of neurotoxicity include constipation, and adynamic ileus. Cranial 
nerve manifestations include: diplopia, hoarseness, tinnitus, jaw pain (the latter 
usually occurring with the first dose of vincristine). Orthostatic hypotension & 
SIADH may also be seen. Vincristine is a vesicant and may cause tissue 
necrosis upon extravasation. This is more likely with bolus injections as opposed 
to dilute infusions
8.5
Cyclophosphamide
Please refer to the FDA-approved package insert for cyclophosphamide for product 
information, extensive preparation instructions, and a comprehensive list of adverse 
events.
8.5.1
Other Names
Cytoxan®; Neosar®, CTX, CPM
8.5.2
Classification – type of agent
Cyclophosphamide is a prodrug biotransformed to active alkylating metabolites 
by a mixed function microsomal oxidase system.
8.5.3
Mode of Action
Cyclophosphamide metabolites are thought to disrupt cell division primarily by 
crosslinking DNA strands. Cyclophosphamide is considered cell cycle phase 
non-specific.
8.5.4
Storage & Stability
Intact vials should be stored at room temperature. Reconstituted and diluted 
solutions are stable for 24 hours at room temperature and 6 days if refrigerated.
8.5.5
Protocol Dose & Administration
The total dose of cyclophosphamide will be administered by IV.
All patients should receive hydration with normal saline per institutional 
guidelines. 
8.5.6
Preparation
Reconstitute 100 mg, 200 mg, 500 mg, 1 gram and 2 gram vials with 5, 10, 25, 
50, or 100 mL of sterile water for injection or normal saline to give a final 
concentration of 20 mg/mL. Vigorous shaking and/or gentle warming may be 
necessary for non– lyophilized preparations. Bacteriostatic water for injection 
(paraben preserved only) may be used; benzyl alcohol derivatives may NOT be 
used.
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8.5.7
Incompatibilities
Cyclophosphamide undergoes metabolic activation via cytochrome P450 3A4 in 
the liver and may potentially interact with any drug affecting the same isoenzyme. 
Inhibitors of 3A4 (e.g., itraconazole) could theoretically inhibit activation and 
inducers of 3A4 (e.g., phenytoin) could theoretically enhance activation of 
cyclophosphamide to active alkylating species. For the most part, such 
interactions have not yet been documented clinically. 
8.5.8
Availability & Supply
Commercially available as a powder for reconstitution in 100 mg, 200 mg, 500 
mg, 1 gram, and 2 gram vials.
8.5.9
Side Effects
Myelosuppression, hemorrhagic cystitis (patients must be well-hydrated before, 
during, and after treatment and have adequate renal function). Syndrome of 
inappropriate antidiuretic hormone (SIADH), fatigue, alopecia, anorexia, nausea, 
vomiting, hyperuricemia, azoospermia, amenorrhea, cardiotoxicity (myocardial 
necrosis) usually at doses higher than those used in this study 
8.6
Prednisone
Please refer to the FDA-approved package insert for prednisone for product information 
and a comprehensive list of adverse events.
8.6.1
Other Names
Deltasone, Orasone, Medicorten, Panasol-S, Liquid-Pred
8.6.2
Classification – type of agent
Adrenal corticosteroid
8.6.3
Mode of Action
Prednisone is a potent synthetic glucocorticoid that affects almost every body 
system. It has anti-inflammatory, immunosuppressant, and minimal 
mineralocorticoid activity, and antineoplastic properties. As an antineoplastic 
agent, prednisone may bind to specific proteins (receptors) within the cell forming 
a steroid-receptor complex. Binding of the receptor-steroid complex with nuclear 
chromatin alters mRNA and protein synthesis within the cell.
8.6.4
Storage & Stability
Store tablets, solutions and syrup in tightly closed containers at room 
temperature.
8.6.5
Protocol Dose & Administration
Oral.
8.6.6
Preparation
Not applicable.
8.6.7
Incompatibilities
None known.
8.6.8
Availability & Supply
Commercially available in 1, 2.5, 5, 10, 20, 25, and 50 mg tablets, or as an oral 
solution or syrup - 5 mg/5 ml (in 5% alcohol); solution concentrate - 5 mg/ml (with 
30% alcohol).
IRB #: STU00200596-CR0004 Approved by NU IRB for use on or after 1/4/2021 through 1/3/2022.

NU Study Number: NU 14H09
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8.6.9
Side Effects
Side effects likely to be encountered with intermittent high doses include: GI 
(dyspepsia, ulceration), insomnia, and hyperglycemia. Occasionally a “withdrawal 
syndrome” after short-term high doses, such as in this study, manifest muscle 
aches and pains. Immunosuppression with risk of infection is also seen.
8.7
Rituximab
Please refer to the FDA-approved package insert for rituximab for product information, 
extensive preparation instructions, and a comprehensive list of adverse events.
8.7.1
Other Names
Rituxan, IDEC-C2B8, chimeric anti-CD20 monoclonal antibody
8.7.2
Classification – type of agent
Antibody.
8.7.3
Mode of Action
Rituximab is a chimeric murine/human gamma 1 kappa monoclonal antibody 
(Chinese hamster ovary [CHO] transfectoma). It recognizes the CD20 antigen 
expressed on normal B cells and most malignant B-cell lymphomas. It binds with 
high affinity to CD20-positive cells, performs human effector functions in vitro, 
and depletes B cells in vivo. The Fab domain of rituximab binds to the CD20 
antigen on B-lymphocytes and the Fc domain recruits immune effector functions 
to mediate B-cell lysis in vitro. The biological effect is manifested by B-cell 
depletion in peripheral blood, lymph nodes, and bone marrow.
8.7.4
Storage & Stability
Intact vials should be stored under refrigeration. Dilute solutions for infusion (1-4 
mg/mL) are stable for 24 hours under refrigeration, and for an additional 24 hours 
at room temperature.
8.7.5
Protocol Dose & Administration
Rituximab will be administered as an IV infusion at 375 mg/m2 on day 1 of each 
cycle of DA-EPOCH-R, immediately prior to the start of chemotherapy. Oral pre-
medication 650 mg of acetaminophen and 50-100 mg diphenhydramine 
hydrochloride will be administered 30 to 60 minutes prior to starting each infusion 
of rituximab. The first rituximab infusion should be started at 50 mg/hr, and 
increased in 50-mg/hr increments every 30 minutes to a maximum rate of 400 
mg/hr. If this rate of escalation is well tolerated the second and subsequent 
infusions can begin at a rate of 100 mg/hr and increase in 100 mg/hr increments 
every 30 minutes to a maximum of 400 mg/hr. CAUTION: DO NOT 
ADMINISTER AS AN INTRAVENOUS PUSH OR BOLUS.
8.7.6
Preparation
The desired dose of rituximab should be diluted in 0.9% NaCl or DW to a final 
concentration of 1-4 mg/mL. The solution should be mixed by gently inverting the 
bag.
8.7.7
Incompatibilities
Do not mix or dilute rituximab with other drugs. No incompatibilities between 
rituximab and polyvinylchloride or polyethylene bags have been observed.
8.7.8
Availability & Supply
Rituximab is commercially available in 10 mL and 50 mL single-use vials 
containing 100 mg or 500 mg rituximab solution, respectively, at a concentration 
of 10 mg/mL.
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NU Study Number: NU 14H09
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NU_14H09-Protocol A-8 - 01.16.2020
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8.7.9
Side Effects
The most severe serious adverse events associated with rituximab include 
severe infusion reactions, tumor lysis syndrome, and severe mucocutaneous 
reactions. Severe infusion reactions consisting of hypoxia, pulmonary infiltrates, 
acute respiratory distress syndrome, myocardial infarction, ventricular fibrillation 
or cardiogenic shock may be fatal. Most reported fatal reactions occurred within 
24 hours of the first dose of rituximab. 
Tumor lysis syndrome resulting in renal failure has been described, and 
occasional fatalities noted. Tumor lysis syndrome is more likely in patients with 
high numbers of circulating malignant cells (≥ 25,000/μL). Severe 
mucocutaneous reactions associated with rituximab include Stevens-Johnson 
syndrome and toxic epidermal necrolysis. The onset of these reactions has been 
from 1-3 weeks. 
Less severe infusion reactions are common with rituximab. These include fever, 
chills, and dyspnea. The mechanism of rituximab infusion reactions is thought to 
be secondary to release of cytokines. If a reaction occurs, then the infusion 
should be stopped until the symptoms resolve, and then restarted at a 50% 
slower rate. 
Recent reports describe hepatitis B reactivation with fulminant hepatitis, hepatic 
failure and death in some patients with hematologic malignancies treated with 
rituximab. The majority of these patients received rituximab in combination with 
chemotherapy. The median time to diagnosis of hepatitis was approximately 4 
months after starting rituximab and approximately 1 month after the last dose. 
Exacerbation or reactivation of other viral infections has also been reported with 
rituximab. Recent reports describe JC virus reactivation leading to progressive 
multifocal leukoencephalopathy (PML) in patients who were receiving rituximab. 
Patients presenting with new neurologic findings (e.g., major changes in vision, 
unusual eye movements, loss of balance or coordination, confusion) should be 
evaluated for PML.
8.8
Filgrastim
Please refer to the FDA-approved package insert for product information, extensive 
preparation instructions, and a comprehensive list of adverse events.
8.8.1
Other Names
G-CSF; r-met HuG-CSF; Granulocyte Colony Stimulating Factor; Neupogen®
8.8.2
Classification – type of agent
Recombinant granulocyte-colony stimulating factor
8.8.3
Mode of Action
Filgrastim is a protein produced by E. Coli into which has been inserted the 
human G-CSF gene. Filgrastim differs from the natural protein in that the N-
terminal amino acid is a methionine and it is not 0-glycosylated. G-CSF functions 
as a hematopoietic growth factor; it increases the proliferation, differentiation, 
maturation and release of precursor cells into mature blood cells of the neutrophil 
lineage. G-CSF has demonstrated in vitro effects on mature neutrophils, 
including an increase expression of chemotactic receptors, enhanced
phagocytosis and intracellular killing of certain organisms, as well as enhanced
killing of target cells that are bound by antibodies.
IRB #: STU00200596-CR0004 Approved by NU IRB for use on or after 1/4/2021 through 1/3/2022.

NU Study Number: NU 14H09
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8.8.4
Storage & Stability
Intact vials and prefilled syringes should be stored in the refrigerator at 2-8° 
Centigrade (36-46° Fahrenheit). Do not freeze.
8.8.5
Protocol Dose & Administration
Filgrastim will be administered as a subcutaneous injection. In both arms, the 
daily dose will be 480 mcg.
8.8.6
Preparation
The desired dose of rituximab should be diluted in 0.9% NaCl or DW to a final 
concentration of 1-4 mg/mL. The solution should be mixed by gently inverting the 
bag.
8.8.7
Incompatibilities
Do not dilute with saline at any time; product may precipitate.
8.8.8
Availability & Supply
Commercial filgrastim is available in 1 mL and 1.6 mL vials containing 300 mcg 
and 480 mcg filgrastim, and in prefilled syringes containing 300 mcg/0.5 mL or 
480mcg/0.8 mL.
8.8.9
Side Effects
The most common side effect associated with filgrastim is medullary bone pain. 
Bone pain is usually reported as mild or moderate and, if necessary, may be 
treated with non-opioid or opioid analgesics.
8.9
Pegfilgrastim
Please refer to the FDA-approved package insert for product information, and a 
comprehensive list of adverse events.
8.9.1
Other Names
Neulasta®
8.9.2
Classification – type of agent
Pegfilgrastim is a covalent conjugate of recombinant methionyl human G-CSF 
(filgrastim) and monomethoxypolyethylene glycol.
8.9.3
Mode of Action
Similar to filgrastim.
8.9.4
Storage & Stability
Intact syringes should be stored under refrigeration and protected from light. 
Pegfilgrastim syringes are reportedly stable at room temperature for up to 48 
hours prior to injection, if protected from light. Syringes that are frozen 
unintentionally may be allowed to thaw in the refrigerator. Pegfilgrastim syringes 
that have been frozen a second time should be discarded.
8.9.5
Protocol Dose & Administration
The dosage of pegfilgrastim is a single subcutaneous injection of 6 mg 
administered within 72 hours after completing the cycle. Pegfilgrastim will be 
administered as a subcutaneous injection.
8.9.6
Preparation
Not applicable.
IRB #: STU00200596-CR0004 Approved by NU IRB for use on or after 1/4/2021 through 1/3/2022.

NU Study Number: NU 14H09
Takeda Study Number: IISR-2013-M100150
NU_14H09-Protocol A-8 - 01.16.2020
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8.9.7
Incompatibilities
Similar to filgrastim.
8.9.8
Availability & Supply
Pegfilgrastim is commercially available prefilled single-dose syringes containing 6 
mg/0.6 mL of pegfilgrastim (10 mg/mL).
8.9.9
Side Effects
The most common side effect associated with pegfilgrastim is bone pain. Bone 
pain is usually reported as mild or moderate, and, if necessary, may be treated 
with non- opioid or opioid analgesics. 
Other reported side effects include reversible elevations in LDH, alkaline 
phosphatase, and uric acid. These laboratory abnormalities are not usually of 
clinical significance and do not require any intervention
8.10
Methotrexate
Please refer to the FDA-approved package insert for product information and a 
comprehensive list of adverse events.
8.10.1
Other Names
MTX, amethopterin
8.10.2
Classification – type of agent
Methotrexate is a folate antimetabolite.
8.10.3
Mode of Action
Methotrexate competitively inhibits dihydrofolate reductase (DHFR); the affinity of 
methotrexate for DHFR is about one thousand-fold that of folate. DHFR catalyzes 
the conversion of dihydrofolate to the active tetrahydrofolate. Folic acid is needed 
for the de novo synthesis of the nucleoside thymidine, required for DNA 
synthesis. Also, folate is essential for purine and pyrimidine base biosynthesis, 
so synthesis will be inhibited. Methotrexate, therefore, inhibits the synthesis of 
DNA, RNA, thymidylates, and proteins.
8.10.4
Storage & Stability
Unopened vials of methotrexate should be stored at room temperature, and 
protected from light.
8.10.5
Protocol Dose & Administration
In this study, methotrexate will be administered as an intrathecal injection of 12 
mg.
8.10.6
Preparation
For intrathecal injection: reconstitute to a concentration of 1-5 mg/mL with an 
appropriate sterile, preservative free medium such as Sodium Chloride Injection, 
USP.
8.10.7
Incompatibilities
The use of NSAIDs, probenecid, salicylates, or sulfonamides may prolong 
methotrexate levels and enhance toxicity.
8.10.8
Availability & Supply
Methotrexate is commercially available in 2 mL (25 mg/mL) vials or 20 mg, 25, 
mg, 50 mg, or 100 mg vials for reconstitution. Read the manufacturer’s package 
labeling carefully for solution concentrations.
IRB #: STU00200596-CR0004 Approved by NU IRB for use on or after 1/4/2021 through 1/3/2022.

NU Study Number: NU 14H09
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8.10.9
Side Effects
Toxicities associated with intrathecal administration: arachnoiditis, ataxia, coma, 
confusion, dementia, encephalopathy, headache, paresis, seizures
IRB #: STU00200596-CR0004 Approved by NU IRB for use on or after 1/4/2021 through 1/3/2022.

NU Study Number: NU 14H09
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9.0
SPECIMEN BANKING
During the phase II portion of the study, patients may agree to have one red top tube and one 
green top tube drawn on day 1 of induction Cycles 1 & 2 (pre-dose), and day 1 of the first 3 
maintenance cycles. These samples will be drawn at the time of standard of care draws. Blood 
will be frozen and stored in the Biorepository of the Pathology Core Facility at Northwestern 
University for future, unspecified use. Frozen samples from all sites will be shipped in batches to 
the Biorepository at the following address:
ATTN: Jeremy Mathews
Pathology Core Facility
Northwestern University
Robert H. Lurie Comprehensive Cancer Center
710 N. Fairbanks Ct
Olson Pavilion Room 8419 
Chicago, IL 60611
Office (312)503-3753
Pager (312)695-8675
email:jmathews@northwestern.edu 
10.0
STATISTICAL CONSIDERATIONS
10.1
Study Design/Study Endpoints
Phase I dosing will consist of dose finding with ATD, as specified in previous sections.  
Phase II will then commence based on the RP2D identified by Phase I.
10.2
Sample Size and Accrual
Approximately 3-9 patients are anticipated for Phase I, and 46 patients for Phase II. 
Patients from the first Phase who are treated at the MTD/RP2D and who are evaluable 
for response endpoints will be included in the Phase II efficacy analysis and will count 
towards total enrollment for Phase II. The phase I sample size is based on clinical 
consideration. As such, we expect to enroll a minimum of 5 patients, and a maximum of 
9, in Phase I, and do not plan additional formal statistical analysis of these patients.
With respect to efficacy, our null hypothesis is that DA-EPOCH-R plus ixazomib will yield 
no difference in one-year PFS as compared to that observed in DHL, a rate we estimate 
at 40% based upon historical controls 1.  We believe that the combination of DA-EPOCH-
R plus ixazomib will warrant further validation if we can demonstrate improvement in one-
year PFS by approximately 20%, to a rate of 60%. The Phase II sample size is 
determined based on Simon’s two stage design using PFS as the binary endpoint. We 
propose an Optimal Two-Stage Design to test the null hypothesis that P</=0.40 versus 
the alternative that P>=0.60, where P represents one-year PFS.  We propose error 
probability limits of α>0.05 and β<0.20.  The Optimal Two-Stage Design provides for 
early stoppage of the trial if there is sufficient indication of futility 2.  Under these 
conditions, if seven or fewer of the first 16 patients are alive and progression-free at one 
year, the trial will be terminated, and DA-EPOCH-R plus ixazomib considered as having 
no greater efficacy than previously-reported treatment regimens.  However, if eight or 
more patients are alive and progression-free, the trial will proceed, to a total enrollment of 
46 patients.  If the number responding at this point is less than or equal to 23, the 
combination will not be considered superior to previously-reported regimens. 
Enrollment/treatment on this trial will NOT be stopped for sake of interim analysis; if there 
is evidence of futility once a sufficient number of patients have reached one year, any 
others enrolled before that time may continue per protocol.
Should the study unexpectedly close early due to reasons other than efficacy (e.g. loss of 
funding/continued support from Takeda, or other unforeseen reasons that are outside of 
IRB #: STU00200596-CR0004 Approved by NU IRB for use on or after 1/4/2021 through 1/3/2022.

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59
the PI’s control), sample size and statistical plan may be amended at that time, if deemed 
appropriate by the biostatistician and PI.   
10.3
Data Analyses Plans
Data will be summarized for baseline, for phase 1, for phase 2, and for safety analyses. 
Most of these analyses will be descriptive and estimative in nature. PFS and OS will be 
estimated by Kaplan-Meier methods, which will account for loss to follow up.
11.0
STUDY MANAGEMENT
11.1
Institutional Review Board (IRB) Approval and Consent 
It is expected that the IRB will have the proper representation and function in accordance 
with federally mandated regulations. The IRB should approve the consent form and 
protocol.
In obtaining and documenting informed consent, the investigator should comply with the 
applicable regulatory requirement(s), and should adhere to Good Clinical Practice (GCP) 
and to ethical principles that have their origin in the Declaration of Helsinki.
Before recruitment and enrollment onto this study, the patient will be given a full 
explanation of the study and will be given the opportunity to review the consent form. 
Each consent form must include all the relevant elements currently required by the FDA 
Regulations and local or state regulations. Once this essential information has been 
provided to the patient and the investigator is assured that the patient understands the 
implications of participating in the study, the patient will be asked to give consent to 
participate in the study by signing an IRB approved consent form.
Prior to a patient’s participation in the trial, the written informed consent form should be 
signed and personally dated by the patient and by the person who conducted the 
informed consent discussion.
11.2
Amendments
Amendments to the protocol will be initiated and maintained by the assigned Medical 
Writer. Requests for revisions may come from multiple sources, including but not limited 
to the Principal Investigator, study team, drug company, or FDA.   All amendments will be 
subject to the review and approval of the appropriate local, institutional, and 
governmental regulatory bodies, as well as by Janssen Scientific Affairs. Amendments 
will be distributed by the lead institution (Northwestern) to all affiliate sites upon approval 
by the Northwestern University IRB.
11.3
Registration Procedures
Patients may not begin protocol treatment prior to registration. All patient registrations will 
be registered centrally through the Clinical Trials Office (CTO) at Northwestern University 
before enrollment to study. Please contact the assigned Quality Assurance Monitor 
(QAM) or email the QA Department (croqualityassurance@northwestern.edu) for 
questions regarding patient registration.  
Prior to registration, eligibility criteria must be confirmed by the assigned QAM. The study 
coordinator will screen all subjects for potential registration via the web-based application 
NOTIS (Northwestern Oncology Trial Information System), which is available at: 
https://notis.nubic.northwestern.edu. Please note that a username and password is 
required to use this program, and will be provided during site activation prior to training 
on the NOTIS system.
BEFORE a patient can be treated on study, please complete and submit the following 
items to confirm eligibility and receive an identification number:
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
Patient’s signed and dated informed consent form (upload to NOTIS and keep 
original hard copy in a secure location/study chart)

Eligibility checklist (signed and dated by the treating physician – upload to NOTIS)

Eligibility eCRF (complete in NOTIS)

Copy of the pathology report (upload to NOTIS)
Training on eCRF completion will be provided at the time of site activation. Please refer 
to the eCRF demonstration videos on the CTO website for additional instructions on 
registering a patient.
The QAM will review the registration, register the patient, assign a subject identification 
number, and send a confirmation of registration to study personnel. Registration will then 
be complete and the patient may begin study treatment.
11.4
Instructions for Participating Sites
Before the study can be initiated at any site, the following documentation must be 
provided to the Clinical Trials Office at Northwestern University:

Signed and completed Letter of Invitation to participate in the study.

Signed copy of Northwestern University’s Data Monitoring Committee policy 
pertaining to data submission.

Draft informed consent form should for review/approval prior to submission to the 
local IRB

A copy of the official IRB approval letter for the protocol and informed consent. 

CVs and medical licensure for the local PI and any sub-investigators who will be 
involved in the study at the site.

Form FDA 1572 appropriately filled out and signed with appropriate documentation.
Additional activities may be required prior to site activation (i.e. contract execution, study-
specific training). Full requirements will be outlined in a memo upon receipt of the signed 
Letter of Invitation.
11.5
Data Management and Monitoring/Auditing
This study will be conducted in compliance with the Data Safety Monitoring Plan (DSMP) 
of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University. The 
level of risk attributed to this study requires High Intensity Monitoring, as outlined in the 
DSMP. The assigned QAM, with oversight from the Data Monitoring Committee, will 
monitor this study in accordance with the study phase and risk level. 
11.6
Adherence to the Protocol
Except for an emergency situation in which proper care for the protection, safety, and 
well-being of the study patient requires alternative treatment, the study shall be 
conducted exactly as described in the approved protocol. 
11.6.1
11.6.1
Emergency Modifications
Investigators may implement a deviation from, or a change of, the protocol to 
eliminate an immediate hazard(s) to trial subjects without prior IRB approval. 
For any such emergency modification implemented, an IRB modification form 
must be completed within 5 business days of making the change, and the QAM 
must be notified within 24 hours of such change. 
11.6.2
Other Protocol Deviations
All other deviations from the protocol must be reported to the assigned QAM 
using the appropriate form.
IRB #: STU00200596-CR0004 Approved by NU IRB for use on or after 1/4/2021 through 1/3/2022.

NU Study Number: NU 14H09
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A protocol deviation is any change, divergence, or departure from the study 
design or procedures of a research protocol that is under the investigator's 
control and that has not been approved by the Institutional Review Board (IRB). 
Protocol deviations must be reported according to the policies and procedures of 
the IRB of record.
A protocol deviation may be considered an instance of Reportable New 
Information (RNI) if it:

Has harmed or increased the risk of harm to one or more research 
participants.

Has compromised the rights and welfare of the research subject

Has damaged the scientific integrity of the data collected for the study.

Results from willful or knowing misconduct on the part of the investigator(s).

Demonstrates serious or continuing noncompliance with federal regulations, 
State laws, or University policies.
11.7
Investigator Obligations
The Principal Investigator is responsible for the conduct of the clinical trial at the site in 
accordance with Title 21 of the Code of Federal Regulations and/or the Declaration of 
Helsinki. The PI is responsible for personally overseeing the treatment of all study 
patients. The PI must assure that all study site personnel, including sub-investigators and 
other study staff members, adhere to the study protocol and all FDA/GCP/NCI 
regulations and guidelines regarding clinical trials both during and after study completion.
The Principal Investigator at each institution or site will be responsible for assuring that all 
the required data will be collected, entered onto the appropriate eCRFs, and submitted 
within the study-specific timeframes. Periodically, monitoring visits may be conducted and 
the Principal Investigator will provide access to his/her original records to permit 
verification of proper entry of data. The study may also be subject to routine audits by the 
Audit Committee, as outlined in the DSMP. 
11.8
Publication Policy
All potential publications and/or data for potential publications (e.g. manuscripts, abstracts, posters, 
clinicaltrials.gov releases) must be approved in accordance with the DSMC Data Release Policies and 
Processes. The assigned QAM will prepare a preliminary data set for DSMC approval no later than 3 
months after the study reaches its primary completion date, as defined by ClinicalTrials.gov. This is the 
date that the final patient was examined or received an intervention for the purposes of final collection of 
data for the primary outcome, whether the clinical trial concluded according to the pre-specified protocol 
or was terminated. If the investigator would like data release to be approved by the DSMC prior to when 
study design specifies, and/or prior to three months after a study’s primary completion date, the PI must 
send a written request for data approval to the QAM which includes justification. Requests must be made 
a minimum of six to eight weeks in advance of the expected deadline. The request will be presented to 
the DSMC at their next available meeting. Any DSMC decisions regarding data release will be provided to 
the PI. If the request is approved, the QAM will present the data set to the DSMC for approval. A final, 
DSMC-approved dataset, as applicable, will then be released 6-8 weeks after the request was made. The 
investigators are expected to use only DSMC-approved data and statistical analyses any time they are 
disseminating trial data. The investigators must send a copy of the draft abstract/poster/manuscript to the 
study’s biostatistician and assigned QAM to confirm that the DSMC-approved data and statistical 
analyses are used appropriately. Once the biostatistician and QAM gives final approval, the publication 
may be submitted to external publisher.
IRB #: STU00200596-CR0004 Approved by NU IRB for use on or after 1/4/2021 through 1/3/2022.

NU Study Number: NU 14H09
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Gupta N, e.a. Clinical Pharmacokinetics of Intravenous and Oral MLN9708, An Investigational 
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13.
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.
14.
Assouline S, e.a. MLN9708, a Novel, Investigational Proteasome Inhibitor, in Patients with 
Relapsed/Refractory Lymphoma: Results of a Phase 1 Dose-Escalation Study. ASH Annual 
Meeting Abstract 2672(2011).
15.
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.
16.
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.
17.
Kumar S, e.a. 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). ASH Annual Meeting Abstract 653(2012).
18.
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.
19.
Kupperman, E., et al. Evaluation of the proteasome inhibitor MLN9708 in preclinical models of 
human cancer. Cancer Res 70, 1970-1980 (2010).
20.
Martin P, e.a. Weekly MLN9708, an investigational proteasome inhibitor, in patients with 
relapsed/refractory lymphoma: Phase I dose-escalation study. hematol oncol 31 (Suppl. I): 151-
200, #301 (2013).
21.
Kumar S, e.a. Weekly MLN9708, an investigational oral proteasome inhibitor (PI), in 
IRB #: STU00200596-CR0004 Approved by NU IRB for use on or after 1/4/2021 through 1/3/2022.

NU Study Number: NU 14H09
Takeda Study Number: IISR-2013-M100150
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relapsed/refractory multiple myeloma (MM): Results from a phase I study after full enrollment. J 
Clin Oncol 31 (suppl; abstr 8514)(2013).
22.
Dunleavy, K., et al. Differential efficacy of bortezomib plus chemotherapy within molecular 
subtypes of diffuse large B-cell lymphoma. Blood 113, 6069-6076 (2009).
23.
Ruan, J., et al. Bortezomib plus CHOP-rituximab for previously untreated diffuse large B-cell 
lymphoma and mantle cell lymphoma. Journal of clinical oncology : official journal of the 
American Society of Clinical Oncology 29, 690-697 (2011).
24.
Le Tourneau, C., Lee, J.J. & Siu, L.L. Dose escalation methods in phase I cancer clinical trials. J 
Natl Cancer Inst 101, 708-720 (2009).
25.
Common Terminology Criteria for Adverse Events (CTCAE). 2010.
IRB #: STU00200596-CR0004 Approved by NU IRB for use on or after 1/4/2021 through 1/3/2022.

NU Study Number: NU 14H09
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APPENDIX I – PROTOCOL HISTORY OF CHANGES
Amendment 1 (Version 2.0) – July 13, 2015
Section(s) 
Affected
Initial
2.0 Version
Rationale
Sections 2.1.1 (Primary 
Objectives/Phase I) , 
4.4.1 (Dose Limiting 
Toxicities) and 6.1 
(Primary endpoints)
N/A
DLT definitions modified to include 
Grade 5 cytopenias
FDA review panel 
suggestion
Amendment 2 (Version 3.0) –  Nov 30, 2015
Section(s) Affected
2.0 Version
3.0 Version
Rationale
Face Page
N/A
IND number added
Administrative
Face Page, Patient 
Eligibility (Sec 3.0)
Listed Adam 
Petrich as PI and 
IND holder and 
Mitul Gandhi as 
Sub-Investigator
Lists Barbara Pro as PI and IND 
holder, removes Mitul Gandhi as 
Sub-Investigator, and adds Jason 
Kaplan as Sub-Investigator
Administrative 
due to transition 
in faculty
Signature Page
Includes signature 
page
Removes signature page
Administrative
Schema
Listed prednisone 
dosing as daily
Lists prednisone dosing as BID 
(twice daily)
Clarification  
Schema
“SCT”
“Stem Cell Transplant (SCT)”
Clarification
List of Abbreviations
n/a
Additional abbreviations included 
(CNS, IT, LP)
Clarification
Inclusion criteria (Sec 
3.1.3, 3.1.7and 3.1.10)
Sec 3.1.3 – 
Criteria listed 
only Myc-
rearrangement
Platelets and 
bone marrow 
involvement 
listed in one 
note
Sec 3.1.10 - 
negative 
pregnancy test 
within # days
Sec 3.1.3 – Criteria broadened to 
include Myc-
rearrangement/amplification/over-
expression
Sec 3.1.7 – Bone marrow 
involvement listed first for 
emphasis and only applies to ANC 
and platelet exceptions 
Sec 3.1.10 - negative pregnancy 
test within 28 days
To allow 
participation for 
subjects with 
the expanded 
criteria.
Revised for 
clarity
Information on 
the # of days 
was 
inadvertently 
missed
Exclusion criteria (Sec 
3.2.1 and 3.2.7)
Patient can have 
1 cycle of prior 
chemotherapy
The note for this 
exclusion criteria 
only referred to 
prior exposure 
to HBV without 
describing the 
assay method
Prior chemotherapy should have a 
washout period of 3 weeks, and 
steroids are permitted
Clarified the note to include prior 
exposure to both HBV & HCV and 
the assay to be used for detection. 
Clarification on 
prior treatment
To improve 
clarity 
Ixazomib (Sec 4.3.1.)
n/a
Adds language that dosing will occur 
after labs in the hospital or clinic 
during induction and day 1 of 
maintenance. Also adds that patients 
should have weekly labs assessed 
during cycles 7 and 8.
Improved clarity 
for dosing 
instructions
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DA-EPOCH-R (Sec 
4.3.2)
n/a
Adds “inpatient” to administration 
summary
Adds stipulation for Rituximab 
spanning longer than one day
Clarification
Allows flexibility 
in DA-EPOCH-R 
administration, 
which is 
standard of care
DA-EPOCH-R (Sec 
4.3.2), CNS Prophylaxis 
and Treatment (Sec 4.7)
n/a
Adds clarifications on LP 
requirements and “per institutional 
standards”
Allows flexibility in 
DA-EPOCH-R 
administration,
Maintenance Therapy 
Dose Modifications for 
Ixazomib (Sec 4.5.2)
Table: “Ixazomib 
Dose 
Adjustments”
Table: “Ixazomib Dose Adjustments 
During Maintenance”
Clarification to 
distinguish 
Induction from 
Maintenance
Concomitant Medications 
(Sec 4.6.1)
Listed Lamivudine 
or Tenofovir as 
antiviral 
treatments.
To add Entecavir as an alternative to 
Lamuvidine/Tenofovir for treatment of 
Heb B/C in the case subjects may 
test positive for past exposure to the 
virus during baseline screening but 
may be not be clinically active.
Per discussions 
with PI
Permitted Concomitant 
Medications/Procedures 
(Sec 4.6.3)
n/a
Lists steroids used to control 
lymphoma as permitted medication
Per discussions 
with PI
Supportive Care (Sec 
4.8)
n/a
Adds Antibiotic Prophylaxis (Sec 
4.8.7) as permitted/recommended 
supportive care
Per discussions 
with PI
Replacement of Subjects 
(Sec 4.11)
Subjects who 
complete less than 
1 cycle will be 
replaced.
“Subjects who receive at least 1 dose 
of investigational treatment are 
evaluable for toxicity. However, 
should a patient come off treatment 
within the DLT period for any reason 
other than a DLT (e.g. patient refusal, 
unrelated adverse event) an 
additional patient may be added to 
the cohort at the discretion of the 
QAM and DSMC.”
Clarification 
requested by 
QAM
Column for “After 
C2 of Induction 
AND between 
Induction & 
Maintenance”
Column separated into three: 
“Induction (C1-6): Day 1”
“Induction (C1-6): Day 8/15”
“Maintenance(C7+): Day 1 (+/- 1 day)
Revised for clarity
Footnote 2: 
PET/CT required 
until maintenance
PET/CT only required at baseline 
and after cycle 2 induction. 
Thereafter, PET/CT or CT alone both 
acceptable. Also clarifies timing with 
windows
Allows 
investigator 
discretion and 
clarity
Footnote 3: 
Pregnancy test 
within 28 days
Footnote 3: Pregnancy test within 7 
days
Aligns more 
closely with 
standard 
requirements
MYC and BCL2 by 
FISH and IHC 
listed as 4 
separate rows
MYC and BCL2 by FISH and IHC 
combined into a single row with 
details in footnotes 5 and 6
Combined for 
simplification
Study Procedures (Sec 
5.0)
Footnote 6:  “With 
the exception of 
Footnote 6: “IHC is preferred but not 
required for enrollment”
Clarification to 
specifically 
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MYC by FISH, 
tests can be done 
before or after 
enrollment”
address IHC
Footnote 7: n/a
Footnote 7: Adds language about 
maintenance treatment dosing, 
timing, and windows
Added for clarity
Footnote 10: All 
labs were required 
within 14 days
Footnote 10: FISH and IHC have no 
window for registration
FISH and IHC are 
not time-sensitive
n/a
Footnote 11: Adds specific language 
for HBV and HCV requirements
Added for clarity
n/a
Adds row for “Lumbar Puncture” and 
Footnote 12 for details
Added for clarity
n/a
Adds row for “DA-EPOCH-R 
Administration” and Footnote 13 for 
details
Added for clarity
n/a
Adds row for “Ixazomib 
Administration” and Footnote 14 for 
details
Added for clarity
“Off Treatment” 
column does not 
include timing
Adds Footnote 15 to say that visit 
should occur 21 days (+/- 7 days) 
from last study treatment
Added for clarity
n/a
Adds Footnote 16 to say that labs 
must be checked weekly at Cycle 7 
and Cycle 8 prior to ixazomib dosing 
Added for clarity
Specimen Banking (Sec 
9.0)
Temperature 
conditions for 
shipment was not 
clear
Specified that samples for specimen 
banking from affiliate sites must be 
shipped frozen.
To improve clarity
Amendment 3 (Version 4.0) –  Mar 3, 2016
Section(s) Affected
3.0 Version
4.0 Version
Rationale
Cover page, Eligibility 
(Sec 3.0)
Listed “Tufts 
University School 
of Medicine”
Changes to “Tufts Medical 
Center”
Administrative 
correction
Schema, DA-EPOCH-R 
Administration (Sec 
4.3.2), Induction Therapy 
Dose Modifications (Sec 
4.5.1), Study Table (Sec 
5.0 #13)
All chemo agents 
for DA-EPOCH-R 
were to be given 
inpatient with 
Rituximab on Day 
1
Allows for Rituximab to be given 
in an outpatient setting per 
institutional standard of care 1 to 
3 days prior to day 1 or after 
EPOCH during Cycle 1
Institutional standard 
of care does not 
always allow for 
inpatient Rituximab. 
Added language 
allows flexibility for 
affiliate sites
List of Abbreviations
n/a
Additional abbreviations included 
(DHL, GCB)
Clarification
Eligibility (Sec 3.0)
Included template 
instructions 
inadvertently
Removes template instructions
Clarification
Inclusion Criteria (Sec 
3.1.1)
Included an 
incomplete 
statement: “B-cell 
lymphoma, 
unclassifiable, with 
features 
intermediate 
Removes comparative language 
to rea simply: “B-cell lymphoma, 
unclassifiable”
Clarification; PI 
believes initial 
language was a 
mistake
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NU Study Number: NU 14H09
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between DLBCL”
Exclusion Criteria (Sec 
3.2.1)
Allowed for 
patients to have 
one cycle of NHL 
chemotherapy 
prior to starting 
study treatment
Also allows patients who have 
had no prior chemotherapy
Per PI discussion; 
simplifies treatment 
plan, assessment 
schedule and study 
objectives
Induction Therapy Dose 
Modifications (Sec 4.5.1)
n/a
Listed Ixazomib 
dose as “TBD” 
in table of dose 
levels
Patients do not need to come 
off study for dose delays during 
induction
Changes dose level to “MTD”
Allows flexibility 
since the study 
treatment is 
expected to cause 
cytopenia 
Clarification – the 
dose will be 
determined during 
the study
Study Procedures (Sec 
5.0)
#1: n/a
#2: n/a
#4: Listed TMA 
at screening
#5: MYC+ must 
be confirmed by 
FISH
#1: Includes a 7-day window for 
physical exam and ECOG 
status at C1D1
#2: Encourages diagnostic CT 
but it is not required
#4: Moves TMA to C1D1
#5: MYC+ can be confirmed by 
FISH and IHC
PI feels a 7 day 
window is 
appropriate & 
allows flexibility
Clarification
QA request – TMA 
isn’t needed for 
registration
Clarification to be 
consistent with 
Inclusion 3.1.3
Schema, DA-EPOCH-R 
(Sec 4.3.2)
Rituximab allowed 
to be given 
outpatient if 
necessary 
Clarifies that rituximab can be 
given outpatient at select 
institutions.
The intent of allowing 
outpatient rituximab 
was for the inclusion 
of an external site. 
For consistency, 
sites should not 
switch internally 
between outpatient 
and inpatient 
administration.
Study Procedures (Sec 
5.0)
#10,11: All labs 
were to be 
assessed within 
14 days of 
registration, 
including Hep B 
and C
#10,11: Hepatitis B and C can 
now be assessed within 28 
days of registration
PI feels that Hepatitis 
testing can have a 
longer window
Pharmacokinetics and 
Drug Metabolism (Sec 
1.2.2)
Outdated data 
about ixazomib 
metabolism and its 
interactions with 
CYP isozymes
Contains updated metabolism 
data taken directly from Takeda’s 
newest protocol template. 
To align with updated 
drug data from 
sponsor
Exclusion Criteria (Sec 
3.2.6), 
Prohibited Concomitant 
Medications (Sec 4.6.2), 
Permitted Concomitant 
Medications (Sec 4.6.3) 
Excluded the use 
of strong inhibitors 
of CYP1A2, strong 
inhibitors of 
CYP3A, and 
strong CYP3A 
Now only excludes CYP3A 
inducers
CYP1A2 and CYP3A inhibitors 
are not excluded
Updated metabolism 
data for ixazomib 
suggest that 
concomitant 
treatment with such 
inhibitors is 
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inducers 
acceptable
Amendment 4 (Version 5.0) –  December 14th, 2016
Section(s) Affected
4.0 Version
5.0 Version
Rationale
Cover Page; 
Study Summary; 
3.0 (Patient Eligibility)
n/a
Adds Reem Karmali as 
Northwestern sub-
investigator and Deepa 
Jagadeesh as sub-
investigator at Cleveland 
Clinic
Administrative – 
added faculty and 
affiliate site
Cover Page; 
1.3 (Rationale for the 
Current Study); 
4.6.3 (Permitted 
Concomitant Medications 
/ Procedures); 7.3.3.4 
(Reporting to Takeda 
Pharmaceuticals); 8.1.4 
(Storage and Stability); 
8.1.8 (Availability & 
Supply)
Lists funding source as 
Millennium 
Pharmaceuticals
Changes funding source to 
Takeda Pharmaceuticals
Administrative – 
funding source 
changed name
Schema; 4.3.2 (DA-
EPOCH-R); 4.5.1 
(Induction Chemotherapy 
Dose Modifications); 
4.7 (CNS Prophylaxis 
and Treatment)
Patients to receive IT 
methotrexate with each 
cycle if  diagnostic LP is 
negative
Adds that IT methotrexate 
will be given per physician’s 
discretion using institutional 
guidelines
Clarification – 
standard of care 
procedures may 
mean that 
methotrexate is not 
given with every 
cycle for these 
patients
Schema; 
Study Summary; 
4.1 (Overview); 4.2.2 
(Maintenance)
Patients may receive 
maintenance ixazomib 
for up to one year “or as 
long as deriving benefit”
Changes language to say: 
“if a patient is receiving 
clinical benefit after this 
period, an extension of 
ixazomib can be considered 
with documented approval 
from Takeda, the study PI 
and NU DSMC”
Clarification – a 
discussion will need 
to take place for any 
possible extension of 
ixazomib 
Study Summary
Listed short title of 
protocol as “DA-EPOCH-
R plus Ixazomib in MYC-
aberrant NHL
Removes short title
Administrative – short 
title not required; 
removed to avoid 
discrepancies
2.1.1 (Phase I Primary 
Objective); 4.4.1 (Dose 
Limiting Toxicities)
CTCAE v4.0
References CTCAE v4.03
Administrative update
3.1.3 (Inclusion Criteria)
Specifies that FISH for 
MYC-rearrangement 
does not require central 
review
Removes language “does 
not require central 
review”
Not relevant
4.1 (Overview); 4.4 
(Dose Escalation 
Schema – Phase I 
Induction Only)
n/a
Adds the following 
statement to reflect the 
completion of the phase I 
portion of the study:
“The MTD was 
established at cohort 2. 
As of August 10, 2016, all 
The Phase I portion is 
now complete and 
MTD established at 
3mg ixazomib
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patients will be treated 
with ixazomib at 3mg 
during induction.”
 
4.3.2 (DA-EPOCH-R)
Chemotherapy to be 
given inpatient
Removes “inpatient” 
reference and replaces 
with “per institutional 
guidelines”
To allow for varied 
methods of 
administration at 
affiliate sites
4.3.2 (DA-EPOCH-R); 
4.4 (Dose Escalation 
Schema – Phase I 
Induction Only); 
4.5 (Dose Modifications); 
5.0 (Study Procedures)
n/a
Adds consecutive table 
numbers to all existing 
tables
Clarification for easier 
referencing
4.4.1 (Dose Limiting 
Toxicities)
DLT is defined as any 
Grade 3 toxicity during 
cycle 1
Adds that DLT is defined 
as any Grade 3 drug-
related toxicity during 
cycle 1
Clarification 
4.5.1 (Induction 
Chemotherapy Dose 
Modifications)
Listed specific 
instructions and dose 
levels for DA-EPOCH-R 
dose adjustments to be 
strictly followed.
States that doses may be 
delayed as clinically 
warranted up to 3 weeks, 
and that dose 
modifications will take 
place as appropriate per 
institutional guidelines. 
Adds specific exceptions 
(as footnotes) to dose 
adjustment guidelines for 
vincristine, prednisone, 
and methotrexate.
Standard of care DA-
EPOCH-R 
administration includes 
specific exceptions for 
dose modifications of 
prednisone and 
vincristine, specifically 
for older patients and 
neuropathy for 
vincristine.
4.5.2 (Dose Modifications 
for Ixazomib [Induction 
and Maintenance])
Dose modifications were 
listed for ixazomib during 
maintenance only
Now includes instructions 
for ixazomib dose delays 
and modifications during 
both induction and 
maintenance. Dose 
delays can take place 
during either induction or 
maintenance. Dose 
modifications can only 
take place during 
maintenance, and this 
has been clarified with 
two separate sections. 
Clarification; the PI 
feels that it is clinically 
appropriate to delay 
ixazomib during 
induction as well as 
maintenance but keep 
the dose level 
consistent while its 
given with 
chemotherapy
4.6.1 (Required 
Concomitant 
Medications/Procedures)
Listed Bactrim DS as 1 
table three times 
weekly
HepB/C sAg+ patients 
should receive 
lamivudine, entecavir, 
or tenofovir
Lists Bactrim DS given 
“with dosing per 
institutional guidelines”
HepB/C sAg+ patients 
should receive those 
medications listed or 
equivalent per 
institutional guidelines 
To allow for varying 
regimens at affiliate 
sites
5.0 (Study Procedures)
n/a
n/a
#1: Respirations were 
required as part of vital 
Adds windows of ±3 
days to each study visit
Adds a footnote (#4) to 
clarify timing of CBC 
Clarification to avoid 
deviations
Clarification
Respirations not 
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signs
#2: PET/CT required 
at “time of diagnosis”
Listed TMA as a 
requirement 
#10: Labs to be 
completed within 14 
days of registration, 28 
days for other 
procedures. Includes 
longer window for 
patients who 
completed prior chemo
#11: HBV and HCV 
testing was required 
within 28 days of 
registration
and Chemistry labs
Removes “respirations” 
from vital signs
#2: PET/CT required at 
baseline
Removes TMA 
requirement
#10: All screening 
procedures to be 
completed within 28 
days with exception of 
labs. Remove longer 
window.
#11: HBV and HCV 
testing is now required 
≤42 days (6 weeks) 
prior to registration
clinically necessary
#2: Clarification; time 
of diagnosis is likely 
earlier than the 28 
days prior to 
registration
TMA was not being 
performed and is not 
needed
#10: Overall window 
is more inclusive of 
all procedures. 
Patients are not 
allowed to have prior 
chemo.
#11: The window has 
been extended as 
the PI feels is 
clinically appropriate
5.0 (Study Procedures, 
#8); 9.0 (Specimen 
Banking)
Study labs were to be 
drawn at baseline, only 
for Phase II patients
Study labs should be 
drawn on day 1 of 
induction cycles 1 & 2, 
rather than baseline, and 
only for Phase II patients 
who agree to optional 
blood draws
An additional time point 
was added for study 
labs, and all samples 
were made optional to 
accommodate affiliates
Amendment 5  –  December 5th, 2017
Approved by Scientific Review Committee: December 4, 2017
Section(s) Affected
Amd 5 Version
Amd 5 Version
Rationale
Cover Page
Included Jason Kaplan 
as sub-I
Removes Jason Kaplan 
and adds Valerie Nelson 
as sub-I
Administrative faculty 
updates; Jason Kaplan 
has left the institution, 
and Lake Forest will be 
utilized for patient care 
on this study. 
Cover Page, Study 
Summary, 3.0 (Patient 
Eligibility)
n/a
Adds Medical College of 
Wisconsin as an affiliate 
site
Administrative 
Heading
n/a
Adds NU and Takeda 
study numbers for 
reference
Administrative 
4.3.2 (DA-EPOCH-R)
n/a
Adds statement: “*Dosing 
schedule and 
administration for 
prednisone may vary if 
appropriate per 
institutional standards or 
physician discretion.”
Per standard of care, 
variance in dosing 
should be permitted.
Amendment 6  –  May 22, 2018
Approved by Scientific Review Committee: May 26, 2018
Section(s) Affected
Amd 5 Version
Amd 6 Version
Rationale
Cover Page; Study 
Summary; 3.0 (Patient 
Eligibility)
PI at Tufts University 
was listed as Andrew 
Evens 
Updates Tufts PI to 
Andreas Klein and adds 
Rutgers University as 
sub-site with Andrew 
Administrative change; 
Andrew Evens is now 
affiliated with Rutgers 
and is still participating 
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NU_14H09-Protocol A-8 - 01.16.2020
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Evens as PI 
in the study. Andreas 
Klein has taken over at 
Tufts.
3.1.8 (Inclusion Criteria)
n/a
Adds clarification of HIV 
allowance. Patients with 
HIV are eligible for the 
study if they meet specific 
criteria
Clarification from 
Takeda
8.1.4 (Storage & Stability 
– Ixazomib)
Ixazomib was to be 
stored at 2ºC to 8ºC 
(36ºF to 46ºF)
Ixazomib should now be 
stored under 30ºC and 
not frozen
To align with updated 
storage information for 
new supply of ixazomib 
issued by Takeda
8.5.5 (Protocol Dose & 
Administration)
Referred to a table for 
specific saline dosing for 
hydration
Removes reference to 
specific dosing and states 
that saline should be 
given “per institutional 
guidelines”
There was no table to 
be referenced, and PI 
feels that institutional 
practice is acceptable
Amendment 7  –  May 8, 2019
Approved by Scientific Review Committee: May 20, 2019
Section(s) Affected
Amendment 6 Version
Amendment 7 Version
Rationale
Cover Page
Listed Alfred Rademaker 
as the biostatistician
Replaces Alfred 
Rademaker with Borko 
Jovanovic as the new 
biostatistician
Administrative 
research staffing 
change
Cover Page and 
Throughout
The Coordinating Center 
was referred to as the 
Clinical Research Office 
(CRO)  
The Coordinating Center 
is referred to as its new 
name, the Clinical Trials 
Office (CTO)
Administrative update 
to account for a 
change in the 
Coordinating Center’s 
name; the Coordinating 
Center itself remains 
the same
List of Abbreviations and 
Throughout
Committee name listed 
as “Data Monitoring 
Committee”
Committee name updated 
to “Data and Safety 
Monitoring Committee”
Administrative update 
to account for a 
change in the 
Committee’s name; the 
Committee itself 
remains the same
Inclusion Criterion 3.1.1
N/A
Adds a note to clarify that 
histology must be CD20-
positive to be eligible
Clarification due to the 
mechanism of action of 
rituximab to target 
CD20.
Inclusion Criterion 3.1.9
Stated: Females of 
childbearing potential 
must use contraception 
through 90 days after 
the last dose of study 
drug
States: Females of 
childbearing potential 
must use contraception 
through 12 months after 
the last dose of study 
drug
Updated to align with 
new safety 
recommendations for 
rituximab
Sections 4.1, 4.2, and 
4.5.2.1 (Treatment Plan); 
Table 5-1 footnote 14 
(Study Procedures)
N/A
Added note stating: If a 
patient has dose reduced 
the ixazomib during the 
treatment phase (when it 
was given in combination 
with chemotherapy) and 
Clarification that aligns 
with what had already 
been stated in Sections 
1.3, 4.1, and 5.0.
IRB #: STU00200596-CR0004 Approved by NU IRB for use on or after 1/4/2021 through 1/3/2022.

NU Study Number: NU 14H09
Takeda Study Number: IISR-2013-M100150
NU_14H09-Protocol A-8 - 01.16.2020
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now enters the 
maintenance phase 
(where ixazomib will be 
administered as a single 
agent), they should start 
maintenance at the full 
dose of ixazomib 
(rechallenge at 4 mg 
weekly), not at the 
reduced dose.
Table 4-3, Footnote e
Stated: Dose delays are 
permitted for any length 
necessary
Sates: If ixazomib is 
interrupted for > 3 weeks, 
DSMC approval must be 
obtained in order for 
patients to resume 
treatment per Section 
4.5.2.1.
Corrected discrepancy 
to match Section 
4.5.2.1
Section 6 (Endpoints)
Stated: Patients must 
complete at least 2 
cycles of induction 
therapy to be evaluable 
for response endpoints.
States:  Patients must 
complete at least 2 cycles 
of induction therapy and 
undergo a subsequent 
disease response 
assessment to be 
evaluable for response 
endpoints.
Clarification requested 
by the PI 
Section 10.2 (Sample 
Size and Accrual)
N/A
States: Should the study 
unexpectedly close early 
due to reasons other than 
efficacy (e.g. loss of 
funding/continued support 
from Takeda, or other 
unforeseen reasons that 
are outside of the PI’s 
control), sample size and 
statistical plan may be 
amended at that time, if 
deemed appropriate by 
the biostatistician and PI.   
Insertion of standard 
language to account 
for future 
circumstances that 
may merit a change to 
the statistical plan
Throughout
N/A
Corrects minor 
grammatical and 
formatting changes
Administrative update
Amendment 8  –  January 16, 2020
Section(s) Affected
Amendment 7 Version
Amendment 8 Version
Rationale
Title Page and 
Throughout
Protocol version dated 
May 8, 2019  
(Amendment 7)
Updated to protocol 
version dated January 16, 
2020 (Amendment 8)
Administrative update
Table of Contents
N/A
Updates page numbers
Administrative update
Study Summary;
Section 10.2 (Sample 
Size and Accrual)
N/A
Adds the following text:
Patients from the first 
Phase who are treated at 
the MTD/RP2D and who 
are evaluable for 
response endpoints will 
Clarification. Updates 
the statistical analysis 
plan to specify which 
subjects will be 
included in the sample 
population for the 
Phase II efficacy 
IRB #: STU00200596-CR0004 Approved by NU IRB for use on or after 1/4/2021 through 1/3/2022.

NU Study Number: NU 14H09
Takeda Study Number: IISR-2013-M100150
NU_14H09-Protocol A-8 - 01.16.2020
73
be included in the Phase 
II efficacy analysis and 
will count towards total 
enrollment for Phase II.
analysis. 
Section 7.2.4 (UPIRSO);
Section 7.3.3.2 
(Reporting to the NU 
IRB)
Section 7.3.3 (Expedited 
Reporting of SAEs/Other 
Events); 
Section 11.2 
(Amendments);
Section 11.6.2 (Other 
Protocol Deviations);
Section 11.8 (Publication 
Policy)
N/A
Updates standard 
language to align with 
new Northwestern 
University protocol 
template
Administrative update
Throughout
n/a
Minor corrections to 
typographical errors, 
style, and formatting.
Administrative update.
IRB #: STU00200596-CR0004 Approved by NU IRB for use on or after 1/4/2021 through 1/3/2022.