Clinical trial NCT03323151
Conditions: Mantle-Cell Lymphoma
Keywords: Relapsed Mantle-Cell Lymphoma Refractory Mantle-Cell Lymphoma Ixazomib Ibrutinib Proteasome Inhibitor Bruton's Tyrosine Kinase Inhibitor
Sponsor: PrECOG, LLC.
Start date: 2018-08-13; Completion date: 2023-09-07
Enrollment: 43 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Patients with mantle cell lymphoma (MCL) that has relapsed (come back) or refractory (progressed on treatment) will receive ixazomib and ibrutinib.

Ibrutinib has been approved by the Food and Drug Administration (FDA) as treatment for patients with mantle cell lymphoma who have received at least one prior therapy.

Ixazomib is in a class of medications called proteasome inhibitors. Cancer cells depend on proteasome to provide this protein metabolism (turnover) function to regulate their growth and survival. Ixazomib disrupts a cancer cells' ability to survive by blocking the proteasome and disrupting protein metabolism. This may help to slow down the growth of cancer or may cause cancer cells to die.

The purpose of this study is to see whether the addition of ixazomib to ibrutinib chemotherapy is effective in treating people who have relapsed or refractory MCL and to examine the side effects associated with ixazomib in combination with ibrutinib.

Detailed description:
MCL is a rare subtype of non-Hodgkin lymphoma that is considered incurable with conventional therapy. For relapsed patients, Ibrutinib, lenalidomide, and bortezomib are all approved by the FDA but are not curative. Novel approaches are required to improve outcomes for patients with relapsed/refractory MCL.

This is an open-label study that will be done in 2 phases. Phase I will test different doses of ixazomib and ibrutinib to determine the maximum safe and tolerated dose. In Phase I, patients who have already received ibrutinib, may participate if they meet certain criteria (i.e., have not received ibrutinib for at least 3 months).

Phase II will find out the effects, good and/or bad, of ixazomib in combination with ibrutinib. In Phase II, patients will be separated into 2 groups, patients who have never received a Bruton's Tyrosine Kinase (BTK) inhibitor and patients who have received a BTK inhibitor. This study is designed to examine the effectiveness of this drug in treating patients with MCL.

Patients will be treated until progression or unacceptable toxicity.

Tumor assessments will be performed approximately every 3 months for the first year of treatment, then every 6 months until progression.

Mandatory bone marrow and tumor tissue samples (i.e., obtained during a previous procedure or biopsy) are required at baseline. Mandatory research blood samples will also be collected.

Arms: arm 1: Ixazomib and Ibrutinib will be given by mouth until progression or unacceptable toxicity. arm 2: Patients who are BTK-Naive will receive Ixazomib and Ibrutinib by mouth until progression or unacceptable toxicity. arm 3: Patients previously treated with a BTK will receive Ixazomib and Ibrutinib by mouth until progression or unacceptable toxicity.
Interventions: intervention 1: Ixazomib intervention 2: Ixazomib intervention 3: Ibrutinib intervention 4: Ibrutinib
Intervention descriptions: intervention 1: Ixazomib 3 mg by mouth on days 1, 8 and 15 by mouth days 1-28 of a 28 day cycle. Dose may be escalated (Ixazomib 4 mg) dependent on dose-limiting toxicities. Note: Ixazomib dose will not be de-escalated but remain at 3 mg. intervention 2: Ixazomib 4 mg by mouth on days 1, 8 and 15 of a 28 day cycle until progression or unacceptable toxicity. intervention 3: Ibrutinib 560 mg by mouth days 1-28 of a 28 day cycle. Dose may be de-escalated (Ibrutinib 420 mg) or escalated (Ibrutinib 560 mg) dependent on dose-limiting toxicities. intervention 4: Ibrutinib 560 mg by mouth days 1-28 of a 28 day cycle until progression or unacceptable toxicity.

Protocol documents:
SAP_002.pdf: 
PrECOG Protocol Number: PrE0404 
Date: 10/12/2018 
 
 
 
PrE0404: Statistical Analysis Plan 
A Phase I/II Study of Ixazomib and Ibrutinib in 
Relapsed/Refractory Mantle Cell Lymphoma 
 
NCT#: 
NCT03323151 
Version Number: 
1 
Version Date: 
10/12/2018 
 


Statistical Analysis Plan  
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Protocol: PrE0404 
Version: 1 / 12-Oct-2018 
1 
 
 
 
Statistical Analysis Plan 
Study Number 
PrE0404 
Version 
1 
Date 
12-October-2018 
A Phase I/II Study of Ixazomib and Ibrutinib in Relapsed/Refractory Mantle Cell Lymphoma 


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DOCUMENT: 
 Statistical Analysis Plan 
 
PROTOCOL 
  
 
Number: 
 PrE0404 
 
Title: 
 A Phase I/II Study of Ixazomib and Ibrutinib in 
Relapsed/Refractory Mantle Cell Lymphoma 
 
Date: 
 Version 1.0:  
20 September 2017 
 
  
SAP STATUS 
 Final  
SAP VERSION AND 
DATE 
 Version: 1   Date: 12 October 2018 
 
SPONSOR: 
 PrECOG, LLC 
1818 Market Street 
Suite 3000 
Philadelphia, PA 19103 
 
 
PREPARED BY: 
 
 
Biostatistician 
Quality Data Services, Inc. 
 
 
  
 




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TABLE OF CONTENTS 
 
SIGNATURES / APPROVAL PAGE .......................................................................... 3 
LIST OF ABBREVIATIONS ...................................................................................... 6 
1. INTRODUCTION ................................................................................................... 8 
1.1. Objective of the Statistical Analysis Plan ............................................................... 8 
2. STUDY OBJECTIVES ............................................................................................ 8 
2.1. Primary Objectives ............................................................................................... 8 
2.2. Secondary Objectives ............................................................................................ 8 
2.3. Exploratory Objectives (Outside of scope of this analysis plan) .............................. 9 
2.4. Study Endpoints ................................................................................................... 9 
2.4.1. Efficacy Endpoints ............................................................................................... 9 
2.4.2. Safety Endpoints .................................................................................................. 9 
3. STUDY DESIGN ..................................................................................................... 9 
3.1. Study Design ......................................................................................................... 9 
3.1.1. Phase I ................................................................................................................ 9 
3.1.2. Phase II ............................................................................................................. 10 
3.2. Study Duration ................................................................................................... 11 
3.3. Study Population ................................................................................................ 11 
3.4. Randomization and Blinding ............................................................................... 12 
3.5. Treatment Administration .................................................................................. 12 
3.5.1. Phase I .............................................................................................................. 12 
3.5.2. Phase II ............................................................................................................. 13 
3.6. Study Procedures and Assessments ..................................................................... 13 
4. GENERAL STATISTICAL CONSIDERATIONS ................................................. 13 
4.1. Determination of Sample Size.............................................................................. 13 


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4.2. Methodology ....................................................................................................... 13 
4.3. Handling of Dropouts or Missing Data ................................................................ 14 
4.4. Interim Analyses and Data Monitoring ............................................................... 14 
4.5. Multi-center Studies ............................................................................................ 14 
4.6. Multiple Comparisons / Multiplicity .................................................................... 14 
4.7. Analysis Populations ........................................................................................... 15 
4.7.1. Safety Population ............................................................................................... 15 
4.7.2. Modified Intent-to-Treat (mITT) Population ......................................................... 15 
4.7.3. Maximum Tolerated Dose Efficacy (MTDE) Population ........................................ 15 
5. STUDY POPULATION CHARACTERISTICS ..................................................... 15 
5.1. Patient Accountability and Patient Disposition .................................................... 15 
5.2. Demographics and Baseline Characteristics ........................................................ 15 
6. SAFETY ANALYSIS ............................................................................................ 16 
6.1. Adverse Events ................................................................................................... 16 
6.2. Study Drug Administration and Dose Compliance ............................................... 17 
7. EFFICACY ANALYSIS ........................................................................................ 17 
7.1. Primary and Secondary Efficacy Endpoint Analyses ........................................... 17 
8. SUMMARY OF CHANGES FROM PROTOCOL-SPECIFIED ANALYSES ......... 19 
9. REPORTING CONVENTIONS ............................................................................ 19 
10. REFERENCES .................................................................................................... 20 
APPENDIX 1.  STUDY PROCEDURES AND ASSESSMENTS................................. 21 
 
 
 
 


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LIST OF ABBREVIATIONS  
Abbreviation/Acronym 
Definition 
25(OH) 
25-hydroxy vitamin D 
AE 
Adverse event 
ALT 
Alanine Aminotransferase 
ANC 
Absolute Neutrophil Count 
AST 
Aspartate Aminotransferase 
BTK 
Bruton’s Tyrosine Kinase 
CBC 
Complete blood count 
CR 
Complete Response 
CRF 
Case Report Form 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLT 
Dose-Limiting Toxicity 
ECOG 
Eastern Cooperative Oncology Group 
EDTA 
Ethylenediaminetetraacetic acid 
FFPE 
Formalin-Fixed Paraffin-Embedded 
FISH 
Fluorescence in Situ Hybridization 
H&E 
Hematoxylin & Eosin 
ICH 
International Conference on Harmonisation 
IV 
Intravenous 
LDH 
Lactate Dehydrogenase 
MCL 
Mantle Cell Lymphoma 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligrams 
MIPI 
Mantle Cell Lymphoma International Prognostic Index 
mITT 
Modified Intent-to-Treat Population 
mL 
milliliter 
MRI 
Magnetic Resonance Imaging 
MTD 
Maximum Tolerated Dose 
MTDE 
Maximum Tolerated Dose Efficacy Population 
ORR 
Overall Response Rate 
OS 
Overall survival 
PCR 
Polymerase chain reaction 


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PD 
Progressive disease 
PET 
Positron Emission Tomography 
PFS 
Progression-free survival 
PR 
Partial response 
QDS 
Quality Data Services 
RP2D 
Recommended Phase II Dose 
SAP 
Statistical Analysis Plan 
SD 
Standard deviation OR Stable disease 
SPD 
Sum of the product of (the two largest perpendicular) diameters 
TEAE 
Treatment-emergent adverse event 
TLF 
Tables, listings, and figures 
Un 
Unevaluable 
WBC 
White Blood Cells 
 
 


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1.   INTRODUCTION 
1.1.   Objective of the Statistical Analysis Plan 
This statistical analysis plan (SAP) describes the planned analysis of the safety and efficacy data from this 
study. A detailed description of the associated planned tables, listings, and figures (TLFs) to be presented 
in any reporting of the results of the study, including manuscripts for consideration in academic journals, 
will be included in the accompanying mock TLFs document. 
The intent of this document is to provide guidance for the analysis of safety and efficacy data and to 
describe any applicable statistical procedures. In general, the analyses come directly from the protocol, 
unless they have been modified by agreement between PrECOG, LLC and Quality Data Services, Inc. 
(QDS). A limited amount of information concerning this study (e.g., objectives, study design) is 
summarized to help the reader interpret the accompanying TLF templates. Attached signatures indicate 
approval of the statistical analyses sections of the SAP and the accompanying TLF templates. These 
sections must be agreed upon prior to database lock. When the SAP and TLF templates are agreed upon 
and finalized, they will serve as the template for generation of the TLFs that will be the basis of the safety 
and efficacy results described in any reporting of the results of the study. 
This SAP supersedes the statistical considerations identified in the protocol; where considerations are 
different, they will be so identified and a rationale for the change provided. Any substantial deviations 
from this SAP will be agreed upon between PrECOG, LLC and QDS and documented in an Amendment 
to the SAP.   
2.   STUDY OBJECTIVES 
2.1.   Primary Objectives 
• 
Phase I: To determine the maximum tolerated dose (MTD) of ixazomib in combination with 
ibrutinib in patients with relapsed/refractory mantle cell lymphoma (MCL) 
• 
Phase II: To determine the complete response (CR) rate of ixazomib in combination with 
ibrutinib in relapsed/refractory MCL in ibrutinib-pretreated and ibrutinib-naïve patients 
2.2.   Secondary Objectives 
• 
Phase I: To evaluate regimen-related toxicities for the combination of ixazomib and ibrutinib in 
relapsed/refractory MCL 
• 
Phase I: To evaluate preliminary evidence of efficacy by describing the overall response rate 
(ORR) for the combination 
• 
Phase I: To evaluate evidence of efficacy by describing the median progression-free (PFS) and 
overall survival (OS) for patients treated with this combination 
• 
Phase II: To evaluate the ORR of the combination of ixazomib and ibrutinib 
• 
Phase II: To evaluate PFS and OS for patients treated with the combination 
• 
Phase II: To further evaluate regimen-related toxicity for patients treated with ixazomib and 
ibrutinib 


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2.3.   Exploratory Objectives (Outside of scope of this analysis plan) 
• 
To evaluate the efficacy of the combination in patients previously treated with proteasome 
inhibitors or ibrutinib 
• 
To evaluate the prognostic importance of high risk cytogenetic alterations in patients with 
relapsed/refractory MCL receiving ixazomib and ibrutinib 
• 
To evaluate the prognostic significance of vitamin D deficiency in patients with 
relapsed/refractory MCL 
• 
To assess the frequency and impact of recurrent mutations in patients with relapsed/refractory 
MCL 
 
2.4.   Study Endpoints 
2.4.1.   Efficacy Endpoints 
• 
Complete Response (CR) rate during phase II 
• 
Overall Response Rate (ORR) 
• 
Overall Survival (OS) 
• 
Progression-Free Survival (PFS)  
2.4.2.   Safety Endpoints  
• 
Dose-Limiting Toxicities, during Phase I 
• 
Treatment-Related Adverse Event Incidence 
• 
Dose Compliance 
3.   STUDY DESIGN 
3.1.   Study Design 
3.1.1.   Phase I  
The phase I portion of the study is a dose finding trial using a standard 3+3 design.  The primary objective 
is to determine the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) of the 
combination dose of ixazomib and ibrutinib in adult male and female patients with relapsed or refractory, 
pathologically proven mantle cell lymphoma (MCL).  Both ibrutinib-pretreated and ibrutinib-naïve 
patients will be enrolled.  Patients must not have been exposed to the combination of proteasome inhibitor 
and Bruton’s tyrosine kinase inhibitor, but, if ibrutinib-pretreated, must have discontinued ibrutinib at 
least 3 months prior to starting study therapy.  Planned dose levels are listed in the table below.  
Dose Level  
Ixazomib  
(Days 1, 8, 15 of a 28-Day Cycle) 
Ibrutinib  
(Days 1-28 of a 28-Day Cycle) 
-1  
3 mg  
420 mg  
1 (Starting Dose) 
3 mg  
560 mg  
2  
4 mg  
560 mg  
 


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There will be no dose escalation above Dose Level 2 or dose reduction below Dose Level -1.  If dose 
level 1 is too toxic, the dose will be de-escalated to Level -1.  Patients shall continue therapy until 
progression or unacceptable toxicity. 
Patients will be assessed for DLT through the conclusion of Cycle 1 (i.e., prior to Cycle 2, Day 1).  
Patients experiencing progression or who are non-adherent to the study regimen and/or assessments will 
be removed from study therapy and replaced for the purposes of DLT assessment.  Patients who miss 5 
consecutive doses of ibrutinib for reasons unrelated to toxicity or who experience an ixazomib dose delay 
of >72 hours for reasons unrelated to toxicity will not be considered DLTs.  These patients will be 
replaced for the purposes of DLT assessment and determination of the MTD/RP2D but may continue 
study therapy at the discretion of the investigator.  Patients who experience DLTs may also continue on 
study therapy.  Dose Limiting Toxicities for the Phase I study are defined according to the following 
table:  
 
Any toxicity-related dose delay >7 days of ibrutinib or ixazomib or inability to 
complete 3 doses of ixazomib within the first cycle due to toxicity shall constitute 
a DLT. A delay of >7 days of the start of Cycle 2 due to toxicity shall also 
constitute a DLT 
Grade 3 
Non-Hematologic Toxicity aside from Grade 3 diarrhea, nausea, or vomiting 
which resolves within 48 hours of supportive care. 
Grade 3 
Thrombocytopenia with significant bleeding (defined as acute bleeding requiring a 
transfusion and/or hospitalization). 
Grade 4 
Thrombocytopenia 
Grade 4 
Febrile Neutropenia lasting longer than 7 days. To meet criteria for DLT, patients 
must remain febrile and neutropenic for >7 days. If a patient remains neutropenic 
but the fever resolves within 7 days, it shall not constitute a DLT. 
Grade 4 
Non-Hematologic Toxicity 
Grade 5 
Any Toxicity 
 
All patients will complete a PET/CT at the time of study enrollment.  Thereafter, restaging will include 
chest/abdomen/pelvis CT after cycles 3, 6, 9, and 12, and then every 6 months while on study therapy. 
PET/CT or MRI may be substituted for CT at the discretion of the treating investigator, especially in 
cases where lesions are not readily noted on CT or for patients unable to receive IV contrast dye. Patients 
who discontinue study therapy for reasons other than disease progression will have CTs performed every 
6 months until progression and/or initiation of a new therapy.  Tumor response will be assessed by the 
investigator in accordance with the Lugano criteria. 
3.1.2.   Phase II 
The phase II portion of the study will begin once the MTD/RP2D has been determined from the phase I 
portion of the study.  Adult male and female patients with relapsed or refractory, pathologically proven 
mantle cell lymphoma (MCL) will be enrolled into two cohorts, based on prior ibrutinib treatment: 


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ibrutinib-pretreated and ibrutinib-naïve.  Any patient who meets the eligibility criteria will be allowed to 
enroll in the appropriate cohort without any stipulations regarding prior ibrutinib exposure, except that 
patients must have tolerated prior ibrutinib (i.e., not discontinued therapy due to toxicity) and must not 
have been exposed to the combination of proteasome inhibitor and BTK inhibitor.  Patients will receive 
therapy at the RP2D, with ibrutinib administered continuously daily and ixazomib administered on days 
1, 8, and 15 of a 28-day cycle.  Patients will be treated until disease progression or unacceptable toxicity, 
with dose modifications and delays handled as described in Section 6.5 of the protocol.  
All patients will complete a PET/CT at the time of study enrollment.  Thereafter, restaging will include 
chest/abdomen/pelvis CT after cycles 3, 6, 9, and 12, and then every 6 months while on study therapy. 
PET/CT or MRI may be substituted for CT at the discretion of the treating investigator, especially in 
cases where lesions are not readily noted on CT or for patients unable to receive IV contrast dye. Patients 
who discontinue study therapy for reasons other than disease progression will have CTs performed every 
6 months until progression and/or initiation of a new therapy.  Tumor response will be assessed by the 
investigator in accordance with the Lugano criteria. 
3.2.   Study Duration 
The study will consist of two phases – a Phase I part designed to evaluate safety and tolerability of the 
dose combination and find the maximum tolerated dose and a Phase II part designed to evaluate the 
efficacy of the dose combination and further evaluate its safety and tolerability.  Both phases will consist 
of a Screening Period, an indefinite number of 28-day treatment cycles, and Follow-Up.  The Follow-Up 
visit will occur 30 +/- 7 days after last dose of study therapy.  If a patient is removed from treatment for 
reason(s) other than progression, the patient will be followed with regular tumor assessments per standard 
of care until progression or start of new treatment.  
 
Patients will receive protocol therapy until any one of the following: 
• 
Disease progression per LUGANO criteria or clinical progression 
• 
Toxicities considered unacceptable by either the patient or the investigator, despite optimal 
supportive care and dose modifications 
• 
Adverse events or treatment delays requiring discontinuation of ixazomib based on dose 
modification guidelines in Section 6.5.1 of the study protocol 
• 
Development of an inter-current illness that prevents further administration of study treatment 
• 
Extraordinary Medical Circumstances; i.e., the constraints of this protocol becoming detrimental 
to the patient's health 
• 
Withdrawal of consent or inability to comply with study procedures. 
3.3.   Study Population 
A minimum of 6 and a maximum of 12 patients will be enrolled into the Phase I portion of the study.  The 
exact number will depend upon the number of dose limiting toxicities observed and the dose levels at 
which those toxicities are observed.  For the Phase II portion of the study, 36 patients will be enrolled into 
each of the two cohorts – ibrutinib-naïve and ibrutinib-pretreated – in effort to obtain 31 eligible, treated 
patients in each cohort.  This will result in a maximum accrual of 84 patients for the full study.  Patients 
who discontinue from the study will not be replaced. 
The study population will consist of adult males and females with relapsed or refractory, pathologically 
proven mantle cell lymphoma (MCL).  Patients enrolled into the Phase I portion of the study must not 
have been exposed to the combination of proteasome inhibitor and Bruton’s tyrosine kinase inhibitor, but, 


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if ibrutinib-pretreated, must have discontinued ibrutinib at least 3 months prior to starting study therapy.  
For the Phase II portion of the study, anyone enrolling into the ibrutinib-pretreated cohort must have 
tolerated prior ibrutinib (i.e., not discontinued therapy due to toxicity) and patients enrolling in either 
Phase II cohort must not have been exposed to any combination of proteasome inhibitor and BTK 
inhibitor.   
3.4.   Randomization and Blinding 
Randomization will not be used to determine starting treatment level for any patient in either phase of the 
study.  Patients in the Phase I portion of the study will be assigned to one of three set combination dose 
levels of ibrutinib and ixazomib specified in the protocol.  An individual patient’s starting dose will be 
based upon the number of dose-limiting toxicities observed among prior patients in the study.  All 
patients in the Phase II portion of the study, regardless of cohort, will be assigned to the same starting 
combination dose of ibrutinib and ixazomib determined from the Phase I portion of the study to be the 
maximum tolerated dose.  All doses of ibrutinib and ixazomib will be administered to patients in open-
label fashion.  
3.5.   Treatment Administration 
3.5.1.   Phase I  
Patients will be enrolled to the phase I study through a standard 3 + 3 design.  Dose escalation shall occur 
according to the table below: 
Dose Level  
Ixazomib  
(Days 1, 8, 15 of a 28-Day Cycle) 
Ibrutinib  
(Days 1-28 of a 28-Day Cycle) 
-1  
3 mg  
420 mg  
1 (Starting Dose) 
3 mg  
560 mg  
2  
4 mg  
560 mg  
 
The first three patients will be accrued to Dose Level 1 (3 mg ixazomib and 560 mg ibrutinib). Patients 
will receive therapy at the maximum tolerated dose from the Phase I portion of the study, with ixazomib 
administered orally on days 1, 8, and 15 of a 28-day cycle and ibrutinib administered orally daily on all 
28 days of each cycle.  Patients shall continue therapy until progression or unacceptable toxicity. 
Patients may delay therapy (ibrutinib and/or ixazomib) up to 1 week in Phase I, Cycle 1.  In this case, 
subsequent doses of ixazomib must be >72 hours from the prior dose.  As a result, for Phase I, Cycle 1 
only, patients who delay a dose due to toxicity may delay subsequent doses up to 1 week to allow for at 
least a 3-day period between doses of ixazomib. 
Missed doses, regardless of cycle, can always be taken as soon as the patient remembers provided that the 
next scheduled dose is 72 hours or more away.  However, patients on Phase I, Cycle 2 and subsequent 
cycles will not make up any ixazomib doses that are delayed >72 hours due to toxicity. 
For Cycle 1, patients will receive all ixazomib doses in clinic after a provider assessment. For all 
subsequent cycles, patients are only required to be seen in clinic on day 1 of the cycle. 
Patients who experience a DLT may continue on study therapy.  Patients who continue will be subject to 
dose modifications and/or delays as detailed in sections 6.5.1 and 6.5.2 of the study protocol.  


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3.5.2.   Phase II 
Patients will receive therapy at the maximum tolerated dose from the Phase I portion of the study, with 
ixazomib administered orally on days 1, 8, and 15 of a 28-day cycle and ibrutinib administered orally 
daily on all 28 days of each cycle.  Patients will continue therapy until they have evidence of progression, 
unacceptable toxicity, or withdrawal of consent. 
Missed ixazomib doses may be taken as soon as the patient remembers provided that the next scheduled 
dose is 72 hours or more away; however, patients will not make up any ixazomib doses that are delayed 
>72 hours due to toxicity.
For Cycle 1, patients will receive all ixazomib doses in clinic after a provider assessment.  For all 
subsequent cycles, patients are only required to be seen in clinic on day 1 of the cycle. 
Dose modifications and/or delays in response to toxicities or other adverse events of interest will follow 
the guidelines detailed in sections 6.5.1 and 6.5.2 of the study protocol. 
3.6.   Study Procedures and Assessments 
All study procedures and assessments are listed in the table in Appendix 1. 
4. GENERAL STATISTICAL CONSIDERATIONS
4.1.   Determination of Sample Size 
The sample size of the Phase I portion of the study is consistent with the standard 3+3 design.  There is 
one dose level above and one below the starting dose, allowing for only one dose escalation or de-
escalation in the study.  Thus, a minimum of 6 patients (assuming, for example, ≥2 DLT on each of levels 
1 and -1) and a maximum of 12 patients (assuming 6 patients accrued to two dose levels) will be enrolled 
into the phase I portion of the study. 
The primary endpoint for the phase II study will be the CR rate, with planned comparison to historical 
controls.  The target CR rate for the ibrutinib-naïve cohort will be 40%, based on a historical rate of 21% 
for single agent ibrutinib, and the target CR rate for the ibrutinib-pretreated cohort will be 23% based on a 
single agent CR rate of 8% for bortezomib.  The goal analysis sample for the phase II study is 31 eligible, 
treated patients in each cohort for a total of 62 eligible, treated patients.  This will provide 86% power for 
the ibrutinib-naïve comparison and 87% power for the ibrutinib-pretreated comparison, allowing for 10% 
one-sided Type I error and using an exact binomial test in each case.  To assure an adequate number of 
eligible, treated patients, up to 36 patients will be enrolled to each arm. This will result in a maximum 
accrual of 84 patients for the full study.  
4.2.   Methodology 
Phase I data will generally be presented in separate tables, listings, and figures from the Phase II data.  
Listings will be sorted by cohort (Phase II only), site, patient number, and, if relevant, visit and date and 
time of assessment.  All listings will include flags to indicate patient-level inclusion/exclusion for each of 
the analysis populations. 
Post-dose safety parameters will be summarized by cohort (ibrutinib-naïve vs. ibrutinib-pretreated) for 
Phase II tables/figures.  All tables will use only data pertaining to the specific population being analyzed.  
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Continuous data will be summarized with the following descriptive statistics: number of observations (n), 
mean, standard deviation (SD), median, minimum, and maximum. Categorical data will be summarized 
with frequencies of patients and associated percentages based on the number of patients in the given 
analysis population.  Percentages will be computed using the number of patients in the relevant analysis 
population as the denominator unless stated otherwise. 
4.3.   Handling of Dropouts or Missing Data 
In the Phase I portion of the study, patients experiencing progression prior to Cycle 2, Day 1 or who are 
non-adherent to the study regimen and/or assessments will be removed from study therapy and replaced 
for the purposes of DLT assessment.  Patients who miss 5 consecutive doses of ibrutinib for reasons 
unrelated to toxicity or who experience an ixazomib dose delay of >72 hours for reasons unrelated to 
toxicity will also be replaced for the purposes of DLT assessment and determination of the MTD/RP2D 
but may continue study therapy at the discretion of the investigator.  All patients replaced for DLT 
assessments will still be included in safety analyses if at least one dose of ibrutinib or ixazomib was 
administered.  Patients who withdraw from the Phase II portion of the study will not be replaced for any 
analyses. 
 
 
If the start date of an adverse event is missing or ambiguous, the event will be assumed to be treatment-
emergent, that is, to have started after the first study treatment administration.  Similarly, if the 
relationship of an adverse event to a certain study treatment is not collected, then the adverse event will 
be assumed to be related to that treatment for inclusion in listings and tables of treatment-related events. 
The start and end dates of all adverse events and their relationships to study treatments will still be listed 
as collected.   
All other cases of missing or invalid data will be treated as missing and will not be imputed.   
4.4.   Interim Analyses and Data Monitoring 
All statistical analyses and data summaries on Phase I data will be completed immediately following the 
last Phase I patient’s study completion.  Analyses on Phase II data will be completed after all Phase II 
patients exit the study.   
PrECOG will convene a data safety monitoring board to review the safety of all enrolled patients and 
ensure compliance with all appropriate guidelines. 
4.5.   Multi-center Studies 
This study will be conducted at a multiple study sites; however, no statistical adjustments or stratification 
is deemed necessary for site effects. 
4.6.   Multiple Comparisons / Multiplicity 
No statistical adjustments will be made for multiplicity considerations.  The primary objective of the 
Phase I portion of the study is to determine the MTD of ixazomib in combination with ibrutinib.  The 
MTD will be determined based upon the set rules of the 3+3 study design, not via statistical 
considerations.  The primary objective of the Phase II portion of the study is to compare the observed CR 
rate to historical single-agent CR rates separately in each of the two cohorts.  No adjustment for 


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multiplicity will be made as the power calculations for the hypothesis tests to evaluate CR rate in each of 
the two cohorts did not adjust for multiplicity.   
4.7.   Analysis Populations 
This section is designed to identify the characteristics that are necessary for inclusion in particular 
populations defined for the purpose of analysis.  All analyses described in this document will be executed 
on either the Safety Population, Modified Intent-to-Treat (mITT) Population, or Maximum Tolerated 
Dose Efficacy (MTDE) Population. 
4.7.1.   Safety Population 
The Safety Population is defined as all patients who received at least one dose of any study treatment – 
ibrutinib or ixazomib.  Phase I patients replaced for the DLT assessment due to protocol non-compliance, 
progression before the beginning of Cycle 2, or sufficiently long dose delays not caused by a toxicity are 
still included in the Safety Population if at least one dose of ixazomib or ibrutinib was administered.  All 
summaries and analyses of safety data, including dose compliance and toxicity, will be completed using 
the Safety Population.   
4.7.2.   Modified Intent-to-Treat (mITT) Population 
The mITT Population will consist of all patients in the Safety Population who met all study eligibility 
criteria.  All non-safety primary and secondary endpoints will be analyzed on the mITT population. 
4.7.3.   Maximum Tolerated Dose Efficacy (MTDE) Population 
The MTDE Population is defined as all patients in the mITT Population from both phases whose starting 
dose level is the maximum tolerated dose as determined by the Phase I toxicity data.  This population will 
be used for a secondary endpoint analysis of overall response rate (ORR) at the maximum tolerated dose. 
5.   STUDY POPULATION CHARACTERISTICS 
5.1.   Patient Accountability and Patient Disposition 
The number of patients registered, included in each analysis population, completing the study, and 
discontinuing treatment will be tabulated by phase, and within Phase II, by cohort and in aggregate (Table 
14.1.1).  Patients discontinuing treatment will be categorized by reason for discontinuation.   
5.2.   Demographics and Baseline Characteristics 
Demographic data (age, sex, and race) and screening characteristics (ECOG performance status, prior 
ibrutinib exposure, presence/absence of gastrointestinal involvement and/or splenomegaly, MIPI score 
and interpretation, and Ann Arbor staging – including presence/absence of B symptoms) will be listed for 
all patients (Phase I: Listing 16.2.4.1; Phase II: Listing 16.2.4.2).  These data, in addition to ethnicity, 
height, weight, prior fluorescence in-situ hybridization [FISH] testing for t(11;14) and/or del(17p), prior 
exposure to high dose cytarabine, proteasome inhibitors, and/or radiation therapy, and the nature of any 
prior bone marrow transplant will be summarized for the Safety Population and the mITT Population 
(Phase I: Table 14.1.2.1; Phase II: Table 14.1.2.2).  The summary for Phase II will be stratified by cohort 
within analysis population.  Descriptive statistics (n, mean, standard deviation, median, minimum, and 


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maximum for numerical variables, count and percentage for categorical variables) will be presented 
where applicable. 
6.   SAFETY ANALYSIS 
The post-baseline safety assessments in this study include adverse event assessments and dose 
compliance.  Separate listings will be produced for Phase I data versus Phase II data.  All safety data 
listings will be sorted by cohort (Phase II only), site, and patient number.   
All summary statistics for safety data will be subset to the Safety Population.   
6.1.   Adverse Events 
Treatment-emergent adverse events (TEAEs) are defined as events which were not present at baseline or 
worsened in severity following the patient’s first dosing with study treatment.  Where the start date of an 
adverse event is missing or ambiguous, the event will be assumed to be treatment-emergent.  Similarly, 
treatment-emergent adverse events for which the relationship to either of the study treatments was not 
collected will be assumed to be treatment-related for inclusion in listings and tables of treatment-related 
adverse events.  Nevertheless, the start and end dates of adverse events and their relationships to study 
treatments will still be listed as collected.    
The number of patients who experience TEAEs will be summarized separately by phase.  These 
summaries will also be subdivided in the same table by seriousness, CTCAE v4.0 toxicity grade, 
outcome, relation to each of the two study medications, and whether or not the event necessitated a dose 
modification (i.e., a reduction in dose, delay in dosing, or withdrawal of one or both study treatments) or 
study discontinuation (Phase I: Table 14.3.1.1.1; Phase II: Table 14.3.1.1.2).  In the Phase I summary, the 
number and percent of patients who experienced a dose-limiting toxicity will also be included.  The Phase 
II summary will be stratified by cohort.  
Treatment-related AEs with CTCAE v4.0 toxicity grade of three or greater will be summarized by system 
organ class and preferred term using MedDRA version 21.0 (Phase I: Table 14.3.1.2.1; Phase II: Table 
14.3.1.2.2).  The Phase II summary will be stratified by cohort.  An event will be considered to be 
treatment-related if it is assessed by the investigator as related, probably related, or possibly related to 
either of the study treatments.  Each table will summarize the number of patients who experience such 
events, ordering the system organ classes, and preferred terms within each system organ class, by 
descending incidence rate.  A patient will be counted at most once for each preferred term and once for 
each system organ class, regardless of the number of relevant TEAEs experienced for a given category.  
The Phase II table will also include a 90% Clopper-Pearson exact two-sided binomial confidence interval 
for the observed incidence rate of each system organ class and preferred term, and also for the overall 
total incidence rate across all system organ classes and preferred terms.   
Treatment-emergent AEs will be summarized by system organ class and preferred term using MedDRA 
version 21.0 (Phase I: Table 14.3.1.3.1; Phase II: Table 14.3.1.3.2).  The Phase II summary will be 
stratified by cohort.  Both tables will summarize the number of patients who experience such events, 
ordering the system organ classes, and preferred terms within each system organ class, by descending 
incidence rate.  A patient will be counted at most once for each preferred term and once for each system 
organ class, regardless of the number of relevant TEAEs experienced for a given category.  Statistics will 
be limited to counts and percentages in both tables; confidence intervals on incidence rates will not be 
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By-patient listings will present all treatment-emergent AEs (Phase I: Listing 16.2.7.1.1; Phase II: Listing 
16.2.7.1.2), and all treatment-related AEs with toxicity grade of three or greater (Phase I: Listing 
16.2.7.2.1; Phase II: Listing 16.2.7.2.2).  These listings will include MedDRA (version 21.0) system 
organ class and preferred term, the date of the start and end of each event, the AE duration in days, 
relationship to and action taken with each of the two study treatments, event outcome, toxicity grade, any 
criteria met for classification as a serious adverse event, and whether or not the event is a dose-limiting 
toxicity (Phase I only).  A separate listing will present these same details for the set of all dose-limiting 
toxicities observed in Phase I (Listing 16.2.7.3.1). 
6.2.   Study Drug Administration and Dose Compliance 
Details of study drug administration and dose compliance will be summarized in one table for each phase.  
The number and percentage of patients who received either study drug will be tabulated by cycle in order 
to show for each given cycle number how many patients received at least that many cycles of treatment.  
Also, the number of ibrutinib dose reductions and ixazomib dose reductions across all cycles will be 
summarized by patient counts and percentages.  Descriptive statistics (n, mean, standard deviation, 
median, minimum, and maximum) will be used to summarize the number of scheduled doses missed per 
cycle for ixazomib and for ibrutinib and the duration in months of patient exposure to study treatment.  
The Phase I summary will be stratified by starting dose level; that is, level 1, 0, or -1 (Table 14.3.4.1).  
The Phase II summary will be stratified by cohort (Table 14.3.4.2).   
7.   EFFICACY ANALYSIS 
The efficacy analyses are designed to evaluate separately for each cohort the primary Phase II endpoint of 
CR rate according to the Lugano criteria and also to evaluate the secondary endpoints of overall response 
rate, overall survival, and time to disease progression in each phase of the study.  All efficacy endpoints 
are evaluated on the Modified Intent-to-Treat (mITT) Population; however, the secondary endpoint of 
overall response rate is also evaluated on the Maximum Tolerated Dose Efficacy (MTDE) Population, 
which combines mITT patients from both phases but subsets the Phase I patients to only those whose 
starting dose was the maximum tolerated dose as determined by the Phase I toxicity data. 
7.1.   Primary and Secondary Efficacy Endpoint Analyses 
The primary endpoint in the Phase II portion of the study is the complete response (CR) rate in 
ibrutinib-naïve and ibrutinib-pretreated patients within the first 12 months of study treatment.  This 
proportion will be computed by cohort for the Phase II patients in the mITT Population and presented 
along with the Clopper-Pearson exact 1-sided 90% confidence bound of the proportion, expressed as a 
percent (Table 14.2.1).  The same table will show the proportion of Phase II patients in the mITT 
Population whose best overall disease response during the 12 months after starting treatment with 
ixazomib and ibrutinib is a complete response (CR), a partial response (PR), stable disease (SD), 
progressive disease (PD), and unevaluable (Un).  The disease response option of ‘unevaluable (Un)’ is not 
a collected value on the CRF but will be used in analysis for patients who do not have a valid disease 
response assessment during the given period for any reason, including termination of study treatment 
prior to a patient’s first on-treatment disease response assessment.   
The historical single-agent CR rate for ibrutinib in relapsed/refractory MCL is 21%, thus the combination 
therapy will be considered to show evidence of superiority to ibrutinib monotherapy in ibrutinib-naïve 
patients if the lower bound of a 1-sided 90% Clopper-Pearson exact confidence interval is > 21% in the 
ibrutinib-naïve cohort (Cohort A).  The implied hypothesis test is designed to have 86% power if there are 


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31 patients in the ibrutinib-naïve cohort of Phase II, given an alternative hypothesis of a CR rate of 40% 
for the combination therapy. 
The single agent CR rate for bortezomib was previously reported as 8%, thus the combination therapy 
will be considered to show evidence of superiority to a combination therapy of ibrutinib and bortezomib 
in ibrutinib-pretreated patients if the lower bound of a 1-sided 90% Clopper-Pearson exact confidence 
interval is > 8% in the ibrutinib-pretreated cohort (Cohort B).  The implied hypothesis test is designed to 
have 87% power if there are 31 patients in the ibrutinib-pretreated cohort of Phase II, given an alternative 
hypothesis of a CR rate of 23% for the combination therapy of ixazomib and ibrutinib.   
One of the secondary endpoints of both study phases is the Overall Response Rate across all post-
baseline disease response assessments.  Overall Response Rate is defined as the proportion of patients 
who achieved a partial response (PR) or complete response (CR) at any disease response assessment over 
the course of the study.  The Overall Response Rate will be computed separately for each phase of the 
mITT Population (Phase I: Table 14.2.2.1; Phase II: Table 14.2.2.2).  The Phase II analysis will be 
stratified by cohort and will present a two-sided 90% Clopper-Pearson exact confidence interval of the 
Overall Response Rate expressed as a percent.  Both the Phase I and Phase II tables will also present the 
best overall disease response, i.e., CR, PR, SD, PD or Un, across all post-baseline study assessments and 
a summary of the duration of the response in months among the patients who attained a PR or CR at any 
time post-baseline.  The response duration will be modeled using the Kaplan-Meier product-limit method 
for each phase.  Response duration is defined as time from the documentation of best response of CR or 
PR until disease progression or death.  Patients alive and without progression will be censored at the date 
of last disease assessment.  The number and percent of patients in the mITT Population who died or 
whose disease progressed on study and the number of patients censored will be summarized along with 
the Kaplan-Meier median response duration times and corresponding 90% confidence intervals.  The 90% 
confidence intervals will be computed using Greenwood’s formula. 
Overall Response Rate will also be assessed on the Maximum Tolerated Dose Efficacy (MTDE) 
Population; that is, the set of all eligible, treated patients in either study phase whose starting dose is the 
maximum tolerated dose as determined from the Phase I toxicity data (Table 14.2.2.3).  The table will be 
stratified by prior ibrutinib status – i.e., ibrutinib-naïve versus ibrutinib-pretreated – and will present a 
two-sided 90% Clopper-Pearson exact confidence interval of the Overall Response Rate expressed as a 
percent.  A summary of best disease response across all post-baseline study assessments and Kaplan-
Meier product-limit estimates of median response duration will be included in the same table.   
Patient-level response duration will be shown graphically by cohort for Phase II patients in the mITT 
Population via swimmer plots (Figure 14.2.7).  Each plot will have one horizontal bar per patient showing 
treatment duration in months.  Notations will be included for start and end of response.   
The secondary endpoints of progression-free survival (PFS) and overall survival (OS) will be modeled 
using the Kaplan-Meier product-limit method for each study phase.  Progression-free survival represents 
the time from the patient’s enrollment in the study until either death or disease progression, whichever 
occurs first.  Censoring for progression-free survival occurs at the date that disease response was last 
adequately assessed as a part of study procedures.  Overall survival represents the time from the patient’s 
enrollment in the study until death from any cause.  Censoring for overall survival occurs at the date of 
last contact with the patient as a part of on-treatment procedures or follow-up assessments.  The Kaplan-
Meier survival curves for progression-free survival and overall survival will be presented for the mITT 
Population in Figures 14.2.5.1 and 14.2.6.1, respectively, for Phase I patients, and in Figures 14.2.5.2 and 
14.2.6.2, respectively, for Phase II patients.  The number of patients remaining in the risk set at each 3-


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month timepoint and the number of patients censored at the beginning/end of each 3-month interval will 
be listed below each figure.  The Kaplan-Meier median survival times and corresponding 90% confidence 
intervals will also be provided for each survival curve.  The 90% confidence intervals will be computed 
using Greenwood’s formula.  The Phase II figures will include a separate survival curve and separate 
median estimates and risk set and censoring subject counts for each cohort.   
The assessment results for disease response (Phase I: Listing 16.2.6.1.1; Phase II: Listing 16.2.6.1.2) and 
target lesion size (Phase I: Listing 16.2.6.2.1; Phase II: Listing 16.2.6.2.2) will be listed by cohort (Phase 
II only), site, patient, visit, time point, and date of assessment.  The listing of target lesion assessments 
will have one row per target lesion and will indicate the length of the tumor in its two longest 
perpendicular dimensions and also the product of these two perpendicular measurements.   
The target lesion, non-target lesion, and overall disease responses (CR, PR, SD, PD, or Unevaluable) will 
be summarized on the mITT Population for each assessment along with the best target, non-target, and 
overall response observed across all post-baseline study assessments (Phase I: Table 14.2.3.1; Phase II: 
Table 14.2.3.2).  The Phase II table will be stratified by cohort.  The best target lesion response will also 
be shown graphically (Phase I: Figure 14.2.4.1; Phase II: Figure 14.2.4.2).  The figure represents each 
patient’s maximum percent decrease in the sum over all target lesions of the product of each lesion’s two 
largest perpendicular diameters (SPD) as a vertical bar in a waterfall plot.  The bars will be colored 
according to the patient’s best overall disease response over both treatment phases.  Three colors will be 
used to distinguish complete responses (CR) from partial responses (PR) and stable or progressive disease 
(SD/PD).  The Phase II figure will include two plots – one per cohort. 
8.   SUMMARY OF CHANGES FROM PROTOCOL-SPECIFIED ANALYSES 
There are no changes to the planned primary and secondary endpoint analyses described in version 1.0 of 
the clinical trial protocol dated September 20, 2017.   
9.   REPORTING CONVENTIONS  
The mean and median will be displayed to one decimal place greater than the original value, and the 
standard deviation will be displayed to two decimal places greater than the original value. All statistical 
programming and analyses will be performed using SAS® Release 9.2 or later (SAS Institute Inc., Cary, 
North Carolina, USA). 
The following standards will be used in the data presentation: 
• 
The filenames for each individual listing, table, or figure will include both the unique number 
assigned to the particular listing, table, or figure in the accompanying mock TLF document and a 
brief description of the contents of the output (i.e., a shortened form of the title). 
• 
Percentages presented in in-text tables should be rounded to one decimal using the SAS rounding 
function. If “%” is part of the column heading, do not repeat the “%” sign in the body of the table. 
Unless specified otherwise, “%” should reflect the total population of the treatment group/cohort. Any 
deviation from that should be part of the footnote. For 0 counts, the corresponding percentage should 
be left blank, as should 0/0. 
• 
SD should be the default for representing scale, unless standard error has been specified. Standard 
deviation should be abbreviated as “SD”, and presented below the mean value. The SD should have 


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one additional decimal place beyond that of the mean (e.g., mean has one decimal place, SD should 
have two). 
• 
If the table or listing is too long to display on one page, the additional (treatment group/cohort) 
columns will be continued on the following pages. 
• 
“N” will represent the entire treatment group/cohort for the population and phase(s) being analyzed, 
while “n” will represent a subset of “N”. For tables with population designated as a row heading, “N” 
should be used (i.e., tables where all participant data is not available for every variable within a 
treatment/memory status group). As a guideline, if the number is used in a denominator, it should be 
presented as “N”. If the number is used in the numerator, it should be presented as an “n”. 
• 
The heading should consist of four lines. Line 1: Sponsor identifier. Line 2: Protocol identifier. Line 
3: blank line. Line 4: Table/Appendix number Table Title – Population. The title for in-text tables 
should begin with the Table/Appendix number. The footer will include a line noting whether the 
table, listing, or figure is draft or final and blinded or unblinded (i.e., ‘Unblinded Draft’, ‘Blinded 
Final’, etc.).  
• 
All data listings will be sorted by cohort (Phase II only), site, patient number, visit, and date/time (as 
applicable). 
• 
The date format for all dates is DDMMMYYYY.  
• 
If no data are collected for use in the tables and listings, then a table and/or listing will be created 
stating that no data are available. 
• 
A solid line should appear both above and below the column headings of a table. A solid line should 
appear at the end of the table or at the bottom of each page if the table extends to more than one page. 
Footnotes should start after the bottom solid line. 
 
10.   REFERENCES 
1. SAS Institute, Inc., SAS® Version 9.2 software, Cary, NC. 
2. ICH Guidance for Industry: E9 Statistical Principles for Clinical Trials, 1998. 
3. ICH Guidance for Industry: E3 Structure and Contents for Clinical Study Report, 1996.


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APPENDIX 1.  STUDY PROCEDURES AND ASSESSMENTS 
 


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* Scheduled Visits: +/-3 day window is allowed for scheduled ixazomib therapy, required tests and/or visits except as otherwise noted. Delay due to holidays, 
weekends, bad weather or other unforeseen circumstances will be permitted.  
 
1. 
Record date of diagnosis and stage. 
2. 
CBC with differential and platelet count which includes WBC, ANC, Platelets, Hemoglobin, and Hematocrit required prior to each dose of chemotherapy. 


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Phase I: Days 1, 8, 15 and 22 of Cycle 1; Days 1 and 15 of Cycle 2 and Cycle 3 (patients with ANC <1000 and/or platelets <100,000/mm3 on Day 15 
should have blood counts done on Day 22 for Cycle 2 and 3 only); and Day 1 of subsequent cycles.  
Phase II: Days 1, 8 and 15 of Cycle 1, then Day 1 of subsequent cycles.  
Results known prior to treatment administration. Patients experiencing cytopenias should have additional labs drawn as clinically indicated at the 
discretion of the treating physician.  
3. 
Albumin, BUN/creatinine, uric acid, sodium, potassium, chloride, glucose, calcium, alkaline phosphatase, AST, ALT, total bilirubin, and total protein.  
NOTE: Patients with a history of hepatitis B or C must have a negative peripheral blood Polymerase Chain Reaction (PCR) and may not be positive for 
Hepatitis B surface antigen.  
4. 
25(OH) Vitamin D level.  
5. 
Required for sexually active females of child-bearing potential.  
6. 
PET/CT may be substituted for CT Chest/Abdomen/Pelvis at the discretion of the investigator, but if this occurs, the CT portion must include IV contrast 
unless otherwise contraindicated due to allergy or impaired renal function.  
7. 
Bone Marrow Biopsy to include: Aspirate and core biopsy morphologic evaluation and flow cytometry. Bone marrow biopsy will be repeated at the time of 
suspected CR for patients with involvement at the time of enrollment. Optional bone marrow biopsies and aspirates will be performed as clinically 
indicated at the end of therapy and/or time of progression.  
8. 
Bone marrow samples will be sent for conventional cytogenetics, FISH for t(11;14) and FISH for del(17p) [conventional cytogenetics, FISH for t(11;14) 
and FISH for del(17p) may also be done on tumor tissue samples (nodal or extranodal) in lieu of or in addition to bone marrow review].  
9. 
Pathologists at the participating site must review available tissue samples to confirm the diagnosis of MCL. If a pathology review has already been 
completed in the routine care of the patient, then additional review is not required. All patients should have an assessment of Ki67 performed on available 
tissue. Tissue used for pathology review should ideally be from the time of relapse, but pre-treated tissue can be used if that is the only available sample.  
10. Research samples shall be obtained at the time of screening/study entry, after cycle 3, at time of suspected CR, and at the end of therapy or time of 
progression. Refer to Section 13 for details.  
Screening/Study Entry  
Peripheral Blood: Two 6 mL in EDTA tubes  
Bone Marrow: One 10 mL in EDTA tube  
FFPE: Block preferred or 1 H&E slide plus 10 unstained slides  
After Cycle 3 (+/- 5 days of Cycle 4, Day 1)  
Peripheral Blood: Two 6 mL in EDTA tubes  
At time of Suspected CR  
Peripheral Blood: Two 6 mL in EDTA tubes  
End of Therapy/At Time of Progression (within 45 days of last dose of study medication)  
Peripheral Blood: Two 6 mL in EDTA tubes  
NOTE: No bone marrow biopsy/aspirate or tissue biopsy should be performed solely for the purposes of obtaining research samples. 
11. Patients will receive ixazomib orally on days 1, 8, and 15 of each 28-day cycle (1 cycle=28 days) [Section 6.1.1 for dosing administration]. Ixazomib shall 
be administered in the clinic during Cycle 1. For subsequent cycles, ixazomib doses on Days 8 and 15 can be administered at home. Ixazomib Medication 
Diary will be reviewed for compliance and collected every cycle after Cycle 1 (Appendix III of protocol). Ibrutinib shall be administered orally daily on days 
1-28 [Section 6.1.2 of protocol for dosing administration]. Ibrutinib Medication Diary will be reviewed for compliance and collected every cycle (Appendix 
IV of protocol). See Section 6.2 of protocol for Phase I and Section 6.3 for Phase II dosing instructions and Section 6.5 for dose delays/modifications.  


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12. While on treatment, patients shall undergo CT chest/abdomen/pelvis (or PET/CT or MRI as clinically indicated per investigator discretion) after cycles 3, 
6, 9, 12 and subsequently every 6 months while on study therapy. Scans should be performed during the 7 days preceding the following cycle (i.e., within 
7 days of Cycle 4, Day 1). Patients with suspected CR should undergo PET/CT to confirm this. This can be done within 21 days of the restaging 
CT that initially demonstrates potential CR.  
13. Thirty (30) days +/- 7 days after last dose of study therapy. If patient is removed from treatment for reason(s) other than progression, follow with regular 
tumor assessments per standard of care until progression or start of new treatment. Once a patient has initiated a new therapy, no further study-related 
imaging assessments for this study are required.  
14. Patients will be followed for adverse events for 30 days after their last dose of study medication. However, an adverse event occurring at any time after 
discontinuation of study therapy that is felt to be at least possibly related to study therapy should be recorded.  
15. There are no study-related visits required after the end of treatment visit. However, as available to the participating investigators, survival status every 6-
12 months for participating patients should be updated and recorded. In addition, the first subsequent therapy shall be reported. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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DOCUMENT HISTORY 
 
Version Date 
Modified By 
Summary of Changes 
 
 
 
 
 
 
 
 
 
 
 
 
 

Prot_000.pdf: 
PrECOG Protocol Number: PrE0404 
Date: 8/21/2020 
 
 
 
PrECOG Protocol Number: PrE0404 
A Phase I/II Study of Ixazomib and Ibrutinib in 
Relapsed/Refractory Mantle Cell Lymphoma 
 
NCT#: 
NCT03323151 
IND #: 
Exempt 
Protocol Version Number: 
3.0 
Version Date: 
8/21/2020 
 


PrECOG Protocol Number: PrE0404 
Confidential 
Date: 8/21/2020 
 
 
 
PrECOG Protocol Number: PrE0404 
A Phase I/II Study of Ixazomib and Ibrutinib in 
Relapsed/Refractory Mantle Cell Lymphoma 
STUDY CHAIR: 
Jonathon B. Cohen, MD 
STUDY CO-CHAIRS: 
 
 
ECOG-ACRIN LYMPHOMA COMMITTEE CHAIR: 
 
STATISTICIAN: 
 
PRECOG STUDY SITE CONTACT: 
Carolyn Andrews, RN 
MEDICAL MONITOR: 
 
(Internal Use Only) Takeda US Ref. ID Number: X16077 
 
 
IND #: 
Exempt 
Version Number: 
3.0 
Version Date: 
8/21/2020 
 
 
Release/Revision History 
Version 1.0: 9/20/2017 
Released to Sites 
Version 2.0: 12/17/2019 
Released to Sites 
Version 3.0: 8/21/2020 
Released to Sites 
 
This protocol contains information that is confidential and proprietary 


PrECOG Protocol Number: PrE0404 
Confidential 
Date: 8/21/2020 
 
2 
Table of Contents 
List of Abbreviations ....................................................................................................................................8 
1. 
Introduction- Background and Rationale ........................................................................................ 12 
1.1 
Mantle Cell Lymphoma – Disease Overview ............................................................................. 12 
1.2 
Background/Rationale ................................................................................................................ 12 
1.3 
Ixazomib (MLN9708) .................................................................................................................. 14 
1.3.1 
Preclinical Experience ................................................................................................. 14 
1.3.2 
Clinical Experience ...................................................................................................... 14 
1.3.3 
Pharmacokinetics and Drug Metabolism ..................................................................... 15 
1.3.4 
Clinical Trial Experience Using the Oral Formulation of Ixazomib .............................. 15 
1.3.5 
Overview of the Oral Formulation of Ixazomib ............................................................ 16 
1.3.6 
Clinical Trial Experience with Ixazomib in NHL28 ........................................................ 16 
1.4 
Ibrutinib ...................................................................................................................................... 17 
1.4.1 
Toxicity32 ...................................................................................................................... 17 
1.5 
Summary of Rationale for Proposed Study ............................................................................... 18 
1.5.1 
Rationale ...................................................................................................................... 18 
1.5.2 
Rationale for the Study Design and Treatment Plan ................................................... 19 
2. 
Study Objectives ................................................................................................................................ 20 
2.1 
Primary Objective ....................................................................................................................... 20 
2.1.1 
Phase I ......................................................................................................................... 20 
2.1.2 
Phase II ........................................................................................................................ 20 
2.2 
Secondary Objectives ................................................................................................................ 20 
2.2.1 
Phase I ......................................................................................................................... 20 
2.2.2 
Phase II ........................................................................................................................ 20 
2.3 
Exploratory Objectives ............................................................................................................... 20 
3. 
Selection of Patients .......................................................................................................................... 21 
4. 
Registration Procedures .................................................................................................................... 25 
4.1 
Ethics ......................................................................................................................................... 25 
4.2 
Regulatory Requirements .......................................................................................................... 25 
4.3 
Phase I and II Patient Registration ............................................................................................ 25 
4.4 
Research Bone Marrow, Tissue and Blood Samples ................................................................ 26 
5. 
Study Design ...................................................................................................................................... 27 
5.1 
Phase I ....................................................................................................................................... 27 
5.2 
Phase II ...................................................................................................................................... 27 
6. 
Treatment Plan ................................................................................................................................... 29 
6.1 
Overview .................................................................................................................................... 29 
6.1.1 
Ixazomib Administration .............................................................................................. 29 
6.1.2 
Ibrutinib Administration ................................................................................................ 29 
6.2 
Phase I Treatment Administration ............................................................................................. 29 
6.2.1 
DLT Assessment ......................................................................................................... 30 
6.3 
Phase II Treatment Administration ............................................................................................ 31 
6.4 
Criteria to Begin a New Cycle of Therapy .................................................................................. 32 
6.5 
Dose Delays & Modifications ..................................................................................................... 32 
6.5.1 
Dose Reductions/Modifications for Ixazomib and Ibrutinib ......................................... 33 


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6.5.2 
Additional Dose Reductions/Modifications for Ibrutinib ............................................... 36 
6.6 
Concurrent Therapies ................................................................................................................ 37 
6.6.1 
Required and/or Permitted .......................................................................................... 37 
6.6.2 
Not Permitted ............................................................................................................... 37 
7. 
Study Duration and Discontinuation of Therapy ............................................................................ 39 
7.1 
Study Duration ........................................................................................................................... 39 
7.2 
Duration of Follow-Up ................................................................................................................ 39 
7.3 
Criteria for Removal from Study Treatment ............................................................................... 39 
8. 
Adverse Event Reporting .................................................................................................................. 41 
8.1 
Collection of Safety Information ................................................................................................. 41 
8.2 
Handling of Serious Adverse Events (SAEs) ............................................................................. 42 
8.2.1 
SAE Definitions ............................................................................................................ 42 
8.3 
SAE Reporting Requirements .................................................................................................... 42 
8.3.1 
Product Complaints or Medication Errors .................................................................... 43 
8.4 
Reporting of Other Second Primary Cancers ............................................................................ 43 
8.5 
Procedures in Case of Pregnancy ............................................................................................. 44 
9. 
Measurement of Effect ....................................................................................................................... 45 
9.1 
Scheduled Restaging Studies .................................................................................................... 45 
9.2 
Complete Response (CR) .......................................................................................................... 45 
9.3 
Partial Response (PR) ............................................................................................................... 45 
9.4 
No Response/Stable Disease (SD) ........................................................................................... 46 
9.5 
Progressive Disease (PD).......................................................................................................... 46 
9.6 
Criteria for PET/CT Reporting .................................................................................................... 47 
10. Study Parameters ............................................................................................................................... 48 
11. Drug Formulation and Procurement ................................................................................................ 52 
11.1 Ixazomib36 .................................................................................................................................. 52 
11.1.1 
Other Names ............................................................................................................... 52 
11.1.2 
Classification................................................................................................................ 52 
11.1.3 
Storage and Stability ................................................................................................... 52 
11.1.4 
Dose Specifics ............................................................................................................. 52 
11.1.5 
Route of Administration ............................................................................................... 53 
11.1.6 
Drug Interactions ......................................................................................................... 53 
11.1.7 
Agent Availability ......................................................................................................... 53 
11.1.8 
Agent Ordering ............................................................................................................ 53 
11.1.9 
Agent Accountability .................................................................................................... 53 
11.1.10 Side Effects.................................................................................................................. 54 
11.2 Ibrutinib37 .................................................................................................................................... 56 
11.2.1 
Other Names ............................................................................................................... 56 
11.2.2 
Classification................................................................................................................ 56 
11.2.3 
Mode of Action ............................................................................................................. 56 
11.2.4 
Storage and Stability ................................................................................................... 56 
11.2.5 
Dose Specifics ............................................................................................................. 56 
11.2.6 
Route of Administration ............................................................................................... 56 
11.2.7 
Drug Interactions ......................................................................................................... 56 
11.2.8 
Availability .................................................................................................................... 57 


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11.2.9 
Side Effects.................................................................................................................. 57 
11.2.10 Nursing/Patient Implications ........................................................................................ 58 
12. Statistical Considerations ................................................................................................................. 59 
12.1 Study Design & Sample Size Considerations ............................................................................ 59 
12.1.1 
Phase I ......................................................................................................................... 59 
12.1.2 
Phase II ........................................................................................................................ 60 
12.2 Phase II 60 
12.2.1 
Primary Objectives ...................................................................................................... 60 
12.2.2 
Secondary Objectives .................................................................................................. 61 
12.3 Planned Analyses ...................................................................................................................... 61 
12.3.1 
Toxicity Monitoring Plan .............................................................................................. 61 
12.3.2 
Analyses of Correlative Studies................................................................................... 62 
13. Laboratory and Pathology Correlative Studies ............................................................................... 63 
13.1 Correlative Studies ..................................................................................................................... 63 
13.1.1 
Overview ...................................................................................................................... 63 
13.1.2 
Methodology ................................................................................................................ 63 
13.1.3 
Sample Collection ........................................................................................................ 64 
13.1.4 
Research Samples Processing and Shipment ............................................................ 64 
14. Administrative .................................................................................................................................... 67 
14.1 Protocol Compliance .................................................................................................................. 67 
14.2 Institutional Review Board (IRB) ................................................................................................ 67 
14.3 Informed Consent Procedures ................................................................................................... 67 
14.4 Safety Communication ............................................................................................................... 68 
14.5 Monitoring .................................................................................................................................. 68 
14.6 Study Records ........................................................................................................................... 68 
14.7 Electronic Case Report Form (eCRF) Information .................................................................... 69 
14.8 Records Retention ..................................................................................................................... 69 
15. References .......................................................................................................................................... 70 
Appendix I 
ECOG Performance Status ....................................................................................... 73 
Appendix II: 
NYHA Classification .................................................................................................. 74 
Appendix III: 
Ixazomib Medication Diary ....................................................................................... 75 
Appendix IV: 
Ibrutinib Medication Diary ........................................................................................ 76 
Appendix V: 
Investigator’s Statement ........................................................................................... 78 
 
 
 


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5 
PrECOG STUDY SITE CONTACT 
MEDICAL MONITOR 
Carolyn Andrews, RN 
Project Manager 
PrECOG, LLC 
1818 Market Street 
Suite 3000 
Philadelphia, PA 19103 
Phone: 215-789-7001 
Email: candrews@precogllc.org 
 
985 Old Eagle School Road 
Suite 510 
Wayne, PA 19087 
During normal business hours 
(8:30 am-5:00 pm EST): 
Phone: 610-354-0404 
After normal business hours: 
Phone: 484-574-2367 
Email: 
 
SAE Email: PrE0404SAE@qdservices.com 
 


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6 
Brief Protocol Synopsis 
See Protocol Document Sections for complete details 
Study Schema 
Phase I 
 
 
 
 
 
 
 
 
 
 
Phase I: Treatment should begin within 10 working days of registration. 
Phase I: Dose Limiting Toxicity (DLT) will be assessed through Cycle 1. Refer to Section 6.2.1 for details. 
Phase I Accrual: Maximum of 12 patients. 
Three patients were enrolled to Dose Level 1 with no DLTs during the 28 day assessment period. Nine 
patients were enrolled to Dose Level 2, five of the nine patients completed the 28 day assessment period 
with no DLTs, and one patient experienced a Grade 3 lung infection that was considered a DLT. Three of 
the nine patients were not evaluable for DLT and were replaced. One patient was inadvertently given 
neulasta prior to receiving Cycle 2, Day 1 therapy; another patient unintentionally took Day 15 ixazomib on 
Day 9; and one patient forgot to take ibrutinib the last 8 days of Cycle 1 unrelated to any toxicities. Phase I 
was completed November 25, 2019. Dose Level 2 is the recommended Phase 2 dose. 
 
 
Dose Level 
Ixazomib 
Days 1, 8, 15 of 
a 28 Day Cycle 
Ibrutinib 
Days 1-28 of a 
28 Day Cycle 
-1 
3 mg 
420 mg 
1 
Starting Dose 
3 mg 
560 mg 
2 
4 mg 
560 mg 
Open to Ibrutinib-
Naïve and Selected 
Pretreated Patients 


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Phase II 
 
 
 
 
 
 
 
 
RP2D: 
Recommended Phase 2 Dose 
BTK: 
Bruton’s Tyrosine Kinase 
Phase II: 
Treatment should begin within 10 working days of registration. 
Phase II Accrual Goal: 
Maximum of 72 patients enrolled for 62 eligible, treated patients. August 7, 2020: 
Cohort A will continue to enroll patients (see below) and enrollment to Cohort B 
is closed. 
Cohort A: 31 eligible, treated patients will be accrued (see below). 
Cohort B: 31 eligible, treated patients will be accrued. Closed to enrollment August 7, 2020. Two 
patients enrolled. 
August 7, 2020: Phase II opened December 17, 2019 with Cohort A: BTK-naïve or Cohort B: BTK-
pretreated. 
Enrollment to Cohort A: BTK-naïve will continue. We plan to reach our original accrual goal of 36 BTK-
naïve subjects treated at the established Dose Level 2 for 31 eligible, treated patients. The Phase I BTK-
naïve patients treated at Dose Level 2 will be included in the 36 patient total. Seventeen additional BTK-
naïve patients will be enrolled to complete this cohort. 
Enrollment to Cohort B: BTK-pretreated will close. To date, only two patients have enrolled in Cohort B. 
Ixazomib 
Days 1, 8, 15 of a 
28 Day Cycle 
Ibrutinib 
Days 1-28 of a 
28 Day Cycle 
4 mg 
560 mg 
Dosed at RP2D 
Cohort A: BTK-Naive 
Cohort B: BTK-Pretreated: 
Closed to Enrollment 8/7/2020 


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List of Abbreviations 
Abbreviation 
Term 
5-HT3 
5-Hydroxytryptamine 3 Serotonin Receptor 
ADL 
Activities of Daily Living 
ADME 
Absorption, Distribution, Metabolism, and Excretion 
AE 
Adverse Event 
AL 
Light-Chain Amyloidosis 
ALT 
Alanine Aminotransferase 
ANC 
Absolute Neutrophil Count 
ASCO 
American Society of Clinical Oncology 
ASCT 
Autologous Stem Cell Transplant 
AST 
Aspartate Aminotransferase 
AUC 
Area Under the Plasma Concentration versus Time Curve 
BCR 
B-Cell Receptor 
BCRP 
Breast Cancer Resistance Protein 
BM 
Bone Marrow 
BSA 
Body Surface Area 
BTK 
Bruton’s Tyrosine Kinase 
BUN 
Blood Urea Nitrogen 
CBC 
Complete Blood Count 
CFR 
Code of Federal Regulations 
CI 
Confidence Interval 
Cmax 
Maximum (peak) Concentration 
CNS 
Central Nervous System 
CR 
Complete Response 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
Cytochrome P450 
DDI 
Drug-Drug Interaction 
DLT 
Dose-Limiting Toxicity 
DRESS 
Drug Reaction with Eosinophilia and Systemic Symptoms 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 


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Abbreviation 
Term 
EDC 
Electronic Data Capture 
FDA 
Food and Drug Administration 
FDG 
Fluorodeoxyglucose 
FFPE 
Formalin-Fixed, Paraffin-Embedded 
FISH 
Fluorescence In Situ Hybridization 
GCP 
Good Clinical Practice 
G-CSF 
Granulocyte Colony Stimulating Factor 
GI 
Gastrointestinal 
GM-CSF 
Granulocyte Macrophage-Colony Stimulating Factor 
GVHD 
Graft-Versus-Host Disease 
HIPAA 
Health Information Portability and Accountability Act 
HIV 
Human Immunodeficiency Virus 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IHC 
ImmunoHistoChemistry 
IND 
Investigational New Drug 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IV 
Intravenous; Intravenously 
KPS 
Karnofsky Performance Status 
LDH 
Lactate Dehydrogenase 
LenDex 
Lenalidomide plus Dexamethasone 
MCL 
Mantle Cell Lymphoma 
MedDRA 
Medical Dictionary for Regulatory Activities 
mL 
Milliliter 
MM 
Multiple Myeloma 
MRI 
Magnetic Resonance Imaging 
MRP2 
Multidrug Resistance Associated Protein 2 
MTD 
Maximum Tolerated Dose 
N 
Number 
NCDB 
National Cancer Data Base 
NCI 
National Cancer Institute 


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Abbreviation 
Term 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse 
Events 
NDMM 
Newly Diagnosed Multiple Myeloma 
NEC 
Not Elsewhere Classified 
NHL 
Non-Hodgkin’s Lymphoma 
NIH 
National Institutes of Health 
ORR 
Overall Response Rate 
OS 
Overall Survival 
PBMC 
Peripheral Blood Mononuclear Cell 
PCR 
Polymerase Chain Reaction 
PD 
Progressive Disease (disease progression) 
PET 
Positron Emission Tomography 
PFS 
Progression Free Survival 
Pgp 
P-Glycoprotein 
PK 
Pharmacokinetic(s) 
PML 
Progressive Multifocal Leukoencephalopathy 
PO 
per os; By Mouth (orally) 
PR 
Partial Response 
PT 
Partial Thromboplastin Time 
RevDex 
Revlimid plus Dexamethasone 
RP2D 
Recommended Phase 2 Dose 
RRAL 
Relapsed and/or Refractory Systemic Light Chain (AL) Amyloidosis 
RRMM 
Relapsed and/or Refractory Multiple Myeloma 
SAE 
Serious Adverse Event 
SD 
Stable Disease 
SPD 
Sum of the Product of the Diameters 
SRM 
Study Reference Manual 
TEAE 
Treatment-Emergent Adverse Event 
TEN 
Toxic Epidermal Necrolysis 
Tmax 
Single-Dose Time to Reach Maximum (peak) Concentration 
TNFα 
Tumor Necrosis Factor-alpha 
TTP 
Thrombotic Thrombocytopenic Purpura 
ULN 
Upper Limit of the Normal Range 


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Abbreviation 
Term 
US 
United States 
WBC 
White Blood Cell 
 


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1. 
Introduction- Background and Rationale 
1.1 
Mantle Cell Lymphoma – Disease Overview 
Mantle cell lymphoma (MCL) is a rare subtype of non-Hodgkin lymphoma that is considered 
incurable with conventional therapy. The disease is identified through a characteristic 
chromosomal translocation [i.e., t(11;14)] which results in overexpression of cyclin D1. 
While patients who receive aggressive induction 
therapy followed by autologous stem cell 
transplant (ASCT) can have a prolonged overall 
survival (OS), ASCT is not considered curative 
and the OS for all diagnosed patients has not 
changed over the past several years (Figure 1). 
Current approaches to induction therapy for fit 
patients 
includes 
aggressive 
inpatient 
chemotherapy regimens followed by ASCT, 
which can result in responses of 5-8 years in 
many patients and prolonged OS.1-3 
For relapsed patients, ibrutinib, lenalidomide, 
and bortezomib are all Food and Drug 
Administration 
(FDA)-approved 
options, 
although these do not represent curative 
approaches.4-6 While ibrutinib has a high overall 
response rate (ORR) of 67% in heavily pre-
treated patients, the 2-year progression-free 
survival (PFS) is only 31%.7 Those patients who 
progress on ibrutinib have a very poor prognosis, 
with an OS of 8 months.8 Novel approaches are 
required to improve outcomes for patients with 
relapsed/refractory MCL, and to improve the 
remission duration for patients completing their 
initial therapy. 
1.2 
Background/Rationale 
Proteasome inhibition remains an integral approach to the management of MCL. The single 
agent ORR of bortezomib in the relapsed/refractory setting is 33%, including 8% complete 
response (CR) rate, and the median duration of response is roughly 9 months. However, 
among patients achieving a CR, the median time to progression is 14.6 months, suggesting 
that a subset of patients can have prolonged responses.6 Bortezomib has also been studied 
in the post-transplant maintenance setting, where the 5-year PFS for patients treated on 
CALGB 50403 was 73%, compared to 52% for patients treated on the prior trial (CALGB 
59909) where bortezomib was omitted (p=0.0006).3,9 Bortezomib has also been evaluated 
in the front-line setting and as part of the conditioning regimen for patients undergoing 
ASCT.10,11 Despite the activity in MCL, bortezomib is associated with toxicities, most notably 
peripheral neuropathy, which occurred at grade 3 or higher in 13% of patients enrolled on 
the single agent study.6 
While bortezomib and proteasome inhibition represents an effective therapy for a subset of 
patients, the novel Bruton’s tyrosine kinase (BTK) inhibitor, ibrutinib has an even higher 
ORR of 68% and appears to be well-tolerated.4 Ibrutinib is not curative and better outcomes 
are possible through novel drug combinations. Through combinational drug screening in 
pre-clinical models, promising agents with synergistic cytotoxicity have been identified. In a 
collaborative effort between the University of Virginia and MD Anderson, we have evaluated 
drugs with targets close to BTK in the B-Cell Receptor (BCR) pathway (proximal) as well as 
drugs with targets far from BTK or not clearly in the BCR pathway (distal) (Figure 2).12 
Figure 1. Overall survival (OS) of newly diagnosed 
patients with mantle cell lymphoma in the United 
States, based on time of diagnosis. Source: National 
Cancer Data Base (NCDB). 


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The initial drug screen identified drugs distal to BTK, specifically ABT-199 and proteasome 
inhibitors, as promising agents with synergistic cytotoxicity and apoptosis with ibrutinib. In 
pre-clinical models, there is significant synergy between proteasome inhibitors and ibrutinib 
in both direct cytotoxicity (Figure 3a) and apoptosis induction (Figure 3b). Proteasome 
inhibitor and ibrutinib combination also had an improved survival in a mouse-human 
xenograft model (Figure 4).12 
 
 
 
 
The orally available proteasome inhibitor, ixazomib, is currently under investigation in 
lymphoma and multiple myeloma. Ixazomib citrate (MLN9708) is immediately converted to 
its active metabolite, Ixazomib (MLN2238), upon ingestion, resulting in inhibition of TNFα-
induced activation of NFκB. In WSU-DLCL2 tumor-bearing mice, MLN2238 generated a 
stronger anti-tumor activity and greater apoptotic response (measured by levels of cleaved 
caspase-3) compared to bortezomib. In a murine disseminated lymphoma model (NOD-
SCID mice inoculated with OCI-Ly7-Luc cells) anti-tumor activity of MLN2238 was better 
Figure 2. Hierarchical 
clustering of % synergy 
by cytotoxicity. 
Figure 3. % cytotoxicity of 
ibrutinib and carfilzomib in MCL 
cell lines and patient samples. 
Figure 4. OS in xenograft model. 


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than bortezomib, where median OS was 54 days for mice exposed to MLN2238 compared 
to 33 days for vehicle controls (p=0.05). Median OS was not significantly different for 
bortezomib-treated mice compared to those exposed to vehicle controls (p>0.99).13 In a 
subsequent experiment evaluating in vivo activity of ixazomib in OCI-Ly10 tumor-bearing 
SCID mice, the anti-tumor activity (treated vs. control; T/C) of ixazomib was improved (T/C 
= 0.37) compared to bortezomib (T/C = 0.68) in this model based on a human cell line of 
activated-B-cell like diffuse large B-cell lymphoma. In vivo anti-tumor activity was also 
demonstrated in PHTX22L tumor-bearing NOD-SCID mice (T/C for ixazomib 0.14, p<0.01), 
while bortezomib did not demonstrate significant anti-tumor activity.14 
Based on these pre-clinical findings in murine models, ixazomib has been evaluated in early 
phase clinical trials. In a phase I study of the IV formulation of ixazomib in 
relapsed/refractory Non-Hodgkin’s Lymphoma (NHL), 30 patients were treated at 8 dose 
levels, including 10 at the maximum tolerated dose (MTD) of 2.34 mg/m2 on days 1, 8, and 
15. Five of twenty-six patients responded, with durations ranging from 6-33 months. Ten 
percent of patients discontinued due to an adverse event, and the most common adverse 
events were neutropenia, gastrointestinal (GI) toxicity, and acute renal failure secondary to 
GI toxicity.15 Ixazomib has also been evaluated alone and combined with other agents in 
multiple myeloma, where the oral formulation has a MTD of 2.97 mg/m2 on days 1, 8, and 
15 of 28 day cycles. Notably, there were no instances of grade 3-4 peripheral neuropathy 
in a single agent phase I study of weekly ixazomib.16 An additional phase I study of twice-
weekly ixazomib in multiple myeloma found an MTD of 2.0 mg/m2 on days 1, 4, 8, and 11 
of a 21 day cycle, with only 11% of patients experiencing peripheral neuropathy and no 
cases of grade 3-4 neuropathy.17 Ixazomib is also being investigated in combination with 
dexamethasone and lenalidomide in relapsed myeloma.18 It continues to be investigated in 
ongoing studies alone and in combination in both lymphoma and multiple myeloma, 
including one study combining ixazomib with lenalidomide for post-transplant maintenance 
in multiple myeloma (NCT01718743) and combination studies are planned in lymphoma. 
1.3 
Ixazomib (MLN9708) 
1.3.1 
Preclinical Experience 
Please refer to the current Ixazomib Investigator’s Brochure (IB). 
1.3.2 
Clinical Experience 
Ixazomib has been evaluated as an oral single agent in phase 1, phase 1/2 and 
phase 2 studies in multiple myeloma (MM), systemic light-chain amyloidosis (AL), 
solid tumors, and lymphoma. In addition, Phase I studies are completed in patients 
with renal or hepatic impairment to evaluate the effect on food on ixazomib 
pharmacokinetics (PK), to evaluate drug-drug interactions (DDI’s), and to 
characterize ixazomib absorption, distribution, metabolism, and excretion (ADME) 
have been conducted. Phase 3 trials in RRMM, newly diagnosed multiple 
myeloma (NDMM), and relapsed or refractory systemic light-chain amyloidosis 
(RRAL amyloidosis) are underway. As of 27 March 2017, data are available from 
941 patients who have received at least 1 dose of either the IV or oral ixazomib 
formulations across the clinical development program; in addition, 2682 patients 
have enrolled in 7 phase 3 clinical trials: 
• 
Double-blind, placebo-controlled Global Study C16010 and Study C16010 
China continuation study (CCS) of ixazomib versus placebo in combination 
with LenDex in patients with RRMM 
• 
Double-blind, placebo-controlled Study C16014 and Study C16014 South 
Korea extension study (KES) of ixazomib versus placebo in combination with 
LenDex in patients with NDMM 
 


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• 
Double-blind, placebo-controlled Study C16019 of ixazomib versus placebo as 
maintenance in patients with NDMM 
• 
Open-label Study C16011 of ixazomib and dexamethasone versus physician’s 
choice of a dexamethasone-containing regimen in patients with AL amyloidosis 
Regardless, of the route of administration, in the twice-weekly dosing schedule 
ixazomib is given on Days 1, 4, 8, and 11 of a 21-day cycle, and in the weekly 
dosing schedule ixazomib is given on Days 1, 8, and 15 of a 28-day cycle 
(approved schedule). 
In 2015, FDA approval was received for ixazomib (NINLARO®) in combination with 
lenalidomide and dexamethasone for the treatment of patients with multiple 
myeloma who have received at least one prior therapy. 
Adverse events (AEs) observed to date (as of 27 March 2017) are generally 
reversible, are manageable with standard medical interventions, and are dose 
dependent. The type of AEs 
are generally consistent across the patient 
populations treated to date, though some AEs may be more common either due to 
the patient population or the regimen being studied (e.g., thrombocytopenia is more 
common with weekly single-agent ixazomib in RRMM than in RRAL amyloidosis; 
thrombocytopenia is more common with weekly ixazomib + LenDex in RRMM than 
ixazomib + LenDex in NDMM; myelosuppression is more common overall when 
ixazomib is combined with MelPred; nausea is common across studies; and 
diarrhea is more common with weekly ixazomib + LenDex than with single-agent 
ixazomib). Such differences may illustrate effects of the disease or prior therapy on 
the body (e.g., on the bone marrow) as well as the side effect profile of the agents 
in a combination regimen. 
The most commonly observed (≥ 30% incidence) treatment-emergent AEs 
(TEAEs) from pooled data across clinical studies with oral ixazomib include 
nausea and diarrhea (43% each), fatigue (39%), rash (all terms; 36%), and 
vomiting (33%). The frequency of rash is noted in an aggregate because it is 
characterized in different ways; however, it is less common when considering 
individual preferred terms. 
Additional detailed information regarding the clinical experience of ixazomib may be 
found in the IB, including information on the IV formulation. 
1.3.3 
Pharmacokinetics and Drug Metabolism 
After oral dosing, absorption of ixazomib is rapid with a median first time to 
maximum observed plasma concentration (Tmax) of approximately 1 hour post dose. 
The plasma exposure (AUC) of ixazomib increases in a dose-proportional manner 
over a dose range of 0.2 to 10.6 mg based on population PK analysis.19 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 taken on an empty 
stomach (at least 2 hours after food or 1 hour before food). 
Detailed information regarding pharmacokinetics and drug metabolism is available 
in the IB. 
1.3.4 
Clinical Trial Experience Using the Oral Formulation of Ixazomib 
As of the clinical data cutoff of 27 March 2017, there are 16 ongoing oncology clinical 
studies of ixazomib, and 9 completed studies. 
These patients have been treated with different doses of ixazomib either as a single-
agent treatment or in combination with currently clinically available treatments. 


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Information regarding the ongoing studies, patient populations, and doses 
investigated is included in the IB. 
Ixazomib is currently FDA-approved for the treatment of relapsed multiple myeloma 
in combination with lenalidomide and dexamethasone. The FDA-approved dose is 
4 mg on days 1, 8, and 15 of a 28-day cycle. 
1.3.5 
Overview of the Oral Formulation of Ixazomib 
The emerging safety profile indicates that ixazomib is generally well tolerated. The 
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. 
In the 4 ongoing studies (C16003, C16004, C16007, and C16009) investigating 
single-agent oral ixazomib in patients with differing malignancies (multiple 
myeloma, AL amyloidosis, non-hematologic cancers, and lymphoma), a total of 259 
patients have been treated as of 27 March 2017. 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 
provided in the latest IB. 
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 tumors20, non-
Hodgkin’s disease, Hodgkin’s disease21, RRMM22,23, relapsed or refractory 
systemic light chain amyloidosis [RRAL]24, and NDMM25,26,27) to date. 
Though additional data are needed to characterize the clinical benefit of this drug, 
the emerging data supports the ongoing development of ixazomib. 
1.3.6 
Clinical Trial Experience with Ixazomib in NHL28 
Ixazomib was evaluated in IV form in a dose-escalation study for nearly all 
lymphoma subtypes. Patients received an IV bolus on days 1, 8, and 15 of a 28-
day cycle for up to 12 months. Thirty patients received therapy, including 2 patients 
with MCL. The majority of patients had follicular lymphoma (n=11), diffuse large b-
cell lymphoma (n=5) and peripheral T-cell lymphoma (n=4). Four DLT’s were 
identified, including neutropenia (n=2), acute renal failure (n=1) and one patient with 
fatigue, nausea, vomiting, and diarrhea. Ultimately, 2.34 mg/m2 was determined to 
be the MTD using the IV formulation. Additional grade ≥3 drug-related toxicities 
included neutropenia (n=6), thrombocytopenia (n=4), diarrhea (n=3), and 
dehydration, lymphopenia, renal failure, and skin disorders (n=2). 
Five of 26 evaluable patients experienced a complete or partial response, including 
3 with follicular lymphoma and 1 patient with peripheral T-cell lymphoma. Six 
additional patients (including a MCL patient) had stable disease lasting a median of 
3.6 months. 
A study of oral ixazomib in relapsed/refractory follicular lymphoma has recently 
been completed (NCT01939899). 
 


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1.4 
Ibrutinib 
The Bruton’s tyrosine kinase inhibitor (BTK) ibrutinib (Imbruvica®) was FDA approved for 
the management of previously treated MCL in 2013 based on the results of a single agent 
phase II study. The FDA-approved dose for MCL is 560 mg once daily. In the pivotal phase 
II study, which incorporated bortezomib-pretreated and -naïve patients, the ORR was 67%, 
a significant improvement over previously reported single-agent response rates for 
bortezomib and lenalidomide.4-6 In addition to this response rate, the median duration of 
response is 17.5 months. Additional therapy options, including combination therapy and 
novel treatments are currently under investigation. In addition to single agent studies, 
ibrutinib has been evaluated in combination in MCL. In a phase Ib/II study of ibrutinib, 
rituximab, and bendamustine, the ORR for the patients with MCL (n=17) was 94%.29 When 
combined with rituximab alone in relapsed/refractory MCL, the ORR (n=45) is 87%, while 
100% of patients with a Ki67 <50% responded.30 
Despite the promising results with single agent ibrutinib, resistance mechanisms are 
emerging, including most notably, the C481S mutation of BTK.31 In a recent update of long-
term follow-up for the phase II study, the 2-year PFS was only 31%, indicating that a 
substantial portion of treated patients will progress within the first 2 years.7 Patients who 
progress on ibrutinib have demonstrated aggressive disease behavior and shortened 
overall survival.8 
1.4.1 
Toxicity32 
Ibrutinib-related toxicity continues to be better understood with prolonged follow-up. 
While most patients tolerate prolonged therapy, several associated toxicities have 
emerged, which are described below based on the package insert. While many are 
manageable, these toxicities must be monitored and addressed for all patients who 
are receiving prolonged therapy. 
1.4.1.1 
Hemorrhage 
Fatal bleeding events have occurred in patients treated with ibrutinib. 
Grade 
3 
or 
higher 
bleeding 
events 
(subdural 
hematoma, 
gastrointestinal bleeding, hematuria and post procedural hemorrhage) 
have occurred in up to 6% of patients. Bleeding events of any grade, 
including bruising and petechiae, occurred in approximately half of 
patients treated with ibrutinib. The mechanism for the bleeding events 
is not well understood. Ibrutinib may increase the risk of hemorrhage in 
patients receiving antiplatelet or anticoagulant therapies. Consider the 
benefit-risk of withholding ibrutinib for at least 3 to 7 days pre and post-
surgery depending upon the type of surgery and the risk of bleeding. 
1.4.1.2 
Infections 
Fatal and non-fatal infections have occurred with ibrutinib therapy. 
Grade 3 or greater infections occurred in 14% to 26% of patients. 
Cases of progressive multifocal leukoencephalopathy (PML) have 
occurred in patients treated with ibrutinib. Monitor patients for fever and 
infections and evaluate promptly. 
1.4.1.3 
Cytopenias 
Treatment-emergent Grade 3 or 4 cytopenias including neutropenia 
(range, 19 to 29%), thrombocytopenia (range, 5 to 17%), and anemia 
(range, 0 to 9%) occurred in patients treated with ibrutinib. 
 


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1.4.1.4 
Atrial Fibrillation 
Atrial fibrillation and atrial flutter (range, 6 to 9%) have occurred in 
patients treated with ibrutinib, particularly in patients with cardiac risk 
factors, acute infections, and a previous history of atrial fibrillation. 
Periodically monitor patients clinically for atrial fibrillation. Patients who 
develop arrhythmic symptoms (e.g., palpitations, lightheadedness) or 
new onset dyspnea should have an ECG performed. If atrial fibrillation 
persists, consider the risks and benefits of ibrutinib treatment and dose 
modification. 
1.4.1.5 
Second Primary Malignancies 
Other malignancies (range, 5 to 14%) including non-skin carcinomas 
(range, 1 to 3%) have occurred in patients treated with ibrutinib. The 
most frequent second primary malignancy was non-melanoma skin 
cancer (range, 4 to 11 %). 
1.4.1.6 
Tumor Lysis Syndrome 
Tumor lysis syndrome has been reported with ibrutinib therapy. Monitor 
patients closely and take appropriate precautions in patients at risk for 
tumor lysis syndrome (e.g. high tumor burden). 
In the recently published long-term follow-up for patients with MCL 
treated with single agent ibrutinib, the following recurrent serious 
adverse events were reported: 
Table 1-1 
Ibrutinib: Recurrent Serious Adverse Events 
Total (N=111) 
SAE*, n (%) 
Any Grade 
Grade 3-4 
Grade 5 
Disease Progression 
11 (10%) 
3 (3%) 
8 (7%) 
Pneumonia 
8 (7%) 
7 (6%) 
1 (1%) 
Atrial Fibrillation 
7 (6%) 
6 (5%) 
0 
Urinary Tract Infection 
4 (4%) 
3 (3%) 
0 
Febrile Neutropenia 
3 (3%) 
3 (3%) 
0 
Abdominal Pain 
3 (3%) 
3 (3%) 
0 
Acute Renal Failure 
3 (3%) 
2 (2%) 
1 (1%) 
Subdural hematoma 
3 (3%) 
2 (2%) 
0 
Pyrexia 
3 (3%) 
1 (1%) 
0 
Confusional State 
3 (3%) 
1 (1%) 
0 
1.5 
Summary of Rationale for Proposed Study 
1.5.1 
Rationale 
Single agent therapy for patients with relapsed MCL can result in responses that 
are durable for some patients but is not curative. With continued follow-up, it is 
evident that most patients will relapse within 2 years. As a result, we plan to build 
upon the successes of recently identified novel therapies by investigating a novel, 
all oral combination of ixazomib and ibrutinib. These agents appear to have synergy 
in pre-clinical assessments, as ibrutinib appears to result in increased cell death for 
MCL cells that are previously bortezomib-resistant when they are exposed to the 
combination.33 
While bortezomib is effective as a single agent in several settings in MCL, it is 
associated with dose-limiting peripheral neuropathy and also requires serial 
injections. Ixazomib is available orally and appears to have decreased peripheral 


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19 
neuropathy, allowing for an all oral therapy for patients with relapsed MCL. As a 
result, we will proceed with a phase I/II study of ixazomib and ibrutinib in 
combination for relapsed/refractory mantle cell lymphoma. The phase I portion of 
the study will be designed to identify the appropriate dose of ixazomib when 
combined with ibrutinib in this setting, and the phase II portion of the study will 
assess the efficacy of this combination. 
1.5.2 
Rationale for the Study Design and Treatment Plan 
We have elected to enroll both BTK-pretreated and BTK-naïve patients for this 
study. For the phase I portion of the study, which is focused primarily on safety and 
tolerability, all patients will be enrolled regardless of prior ibrutinib exposure. 
However, we will require ibrutinib pre-treated patients to satisfy specific criteria 
(Eligibility Criteria 3.4) in order to avoid rapid progression during the first cycle of 
therapy which would make dose limiting toxicity assessment challenging. 
Phase I Summary: Three patients were enrolled to Dose Level 1 with no DLTs 
during the 28 day assessment period. Nine patients were enrolled to Dose Level 2, 
five of the nine patients completed the 28 day assessment period with no DLTs. 
One patient experienced a grade 3 lung infection that was considered a DLT. Three 
of the nine patients were not evaluable for DLT and were replaced. One patient was 
inadvertently given neulasta prior to receiving Cycle 2, Day 1 therapy; another 
patient unintentionally took Day 15 ixazomib on Day 9; and one patient forgot to 
take ibrutinib the last 8 days of Cycle 1 unrelated to any toxicities. The Phase I 
portion of the study was completed November 25, 2019. Dose Level 2 is the 
recommended Phase 2 dose with ixazomib 4 mg on Days 1, 8 and 15 of a 28 day 
cycle and ibrutinib 560 mg on Days 1-28 of a 28 day cycle. 
For the phase II portion of the study, we have developed two dosing cohorts (BTK-
pretreated and BTK-naïve), so that we can assess the efficacy of this combination 
in both settings. Based on the preclinical evidence of synergy, it is our hope and 
expectation that patients who have previously progressed on single agent ibrutinib 
or other BTK inhibitor will still achieve benefit when they receive the combination. 
Efficacy will be assessed separately for each cohort, with success determined 
based on historical cohorts. For BTK-pretreated patients, we will use the previously 
reported CR rate for bortezomib, while for BTK-naïve patients we will compare our 
results to the previously reported single agent activity of ibrutinib, using CR rate as 
the primary endpoint. 
August 7, 2020: Phase II opened December 17, 2019 with Cohort A: BTK-naïve 
or Cohort B: BTK-pretreated. 
Enrollment to Cohort A: BTK-naïve will continue. We plan to reach our original 
accrual goal of 36 BTK-naïve subjects treated at the established Dose Level 2 for 
31 eligible, treated patients. The Phase I BTK-naïve patients treated at Dose Level 
2 will be included in the 36 patient total. Seventeen additional BTK-naïve patients 
will be enrolled to complete this cohort. 
Enrollment to Cohort B: BTK-pretreated will close. To date, only two patients 
have enrolled in Cohort B. 


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2. 
Study Objectives 
2.1 
Primary Objective 
2.1.1 
Phase I 
To determine the maximum tolerated dose (MTD) of ixazomib in combination with 
ibrutinib in patients with relapsed/refractory mantle cell lymphoma (MCL). 
2.1.2 
Phase II 
To determine the complete response (CR) rate of ixazomib in combination with 
ibrutinib in relapsed/refractory MCL in BTK-naïve patients. 
2.2 
Secondary Objectives 
2.2.1 
Phase I 
• 
To evaluate regimen-related toxicities for the combination of ixazomib and 
ibrutinib in relapsed/refractory MCL. 
• 
To evaluate preliminary evidence of efficacy by describing the overall response 
rate (ORR) for the combination. 
• 
To evaluate evidence of efficacy by describing the median progression-free 
(PFS) and overall survival (OS) for patients treated with this combination. 
2.2.2 
Phase II 
• 
To evaluate the ORR of the combination of ixazomib and ibrutinib. 
• 
To evaluate PFS and OS for patients treated with the combination. 
• 
To further evaluate regimen-related toxicity for patients treated with ixazomib 
and ibrutinib. 
2.3 
Exploratory Objectives 
 
 
 
 
 
 
 
 
 
 
 
 


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3. 
Selection of Patients 
Each of the criteria in the checklist that follows must be met in order for a patient to be considered 
eligible for this study. Use the checklist to confirm a patient’s eligibility. For each patient, this 
checklist must be photocopied, completed and maintained in the patient’s chart. 
In calculating days of tests and measurements, the day a test or measurement is done is 
considered Day 0. Therefore, if a test is done on a Monday, the Monday four weeks later 
would be considered Day 28. 
PrECOG Patient No. 
 
 
Patient’s Initials ( F, M, L) 
 
 
Physician Signature and Date 
 
NOTE: PrECOG does not allow waivers to any protocol specified criteria. All eligibility criteria listed 
in Section 3 must be met, without exception. The registration of individuals who do not meet 
all criteria listed in Section 3 can result in the participant being censored from the analysis 
of the study, and a major protocol violation. All questions regarding clarification of eligibility 
criteria must be directed to the Medical Monitor or PrECOG Study Contact. 
NOTE: Institutions may use the eligibility checklist as source documentation if it has been reviewed, 
signed, and dated prior to registration by the treating physician. 
3.1 
Patients must have relapsed or refractory, pathologically proven mantle cell lymphoma. 
Patients must have a current or prior tissue sample that is IHC positive for cyclin D 1 or that 
is positive by FISH or cytogenetics for t(11;14). 
Date of Relapse/Refractory MCL: _______________ 
3.2 
Patients must have been refractory to and/or relapsed/progressed after at least 1 prior 
therapy. 
Date of Last Therapy: _______________ 
3.3 
Prior autologous or allogeneic transplant are allowed. Patients may not have active grade 
II-IV acute GVHD or moderate/severe chronic GVHD by NIH criteria and may not require 
immunosuppressive medications and/or corticosteroids for the management of acute or 
chronic GVHD. 
3.4 
Phase I: Prior proteasome inhibitor and/or Bruton’s tyrosine kinase inhibitors are allowed 
but patients may not have been exposed to the combination of proteasome inhibitor and 
BTK inhibitor. Patients who have progressed on ibrutinib that are felt to be at high risk for 
rapid progression on this study shall not be eligible for the phase I portion of the study. 
NOTE: Ibrutinib pre-treated patients must meet all eligibility criteria AND must have 
discontinued prior ibrutinib at least 3 months prior to starting study therapy. 
Pretreated with ibrutinib:  Yes  
 No 
If yes, does patient meet criteria above:  Yes  No 
PHASE I COMPLETED NOVEMBER 25, 2019. 
Phase II: Prior proteasome inhibitors allowed. 
(Please note prior to Version 3.0 of the protocol prior proteasome inhibitor and/or Bruton’s 
tyrosine kinase inhibitors were allowed but patients could not have been exposed to the 
combination of proteasome inhibitor and BTK inhibitor). 
3.5 
Age ≥ 18 years. 
_____
_____
_____
_____
_____ 


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3.6 
ECOG performance status of 0-2 (Appendix I). 
3.7 
Ability to understand and willingness to sign IRB-approved informed consent. 
3.8 
Willing to provide archived tumor tissue, bone marrow (if sufficient bone marrow and tumor 
tissue are available) and blood samples for research (Section 13.0). 
3.9 
Adequate organ function as measured by the following criteria, obtained ≤ 2 weeks prior to 
registration: 
• 
Absolute Neutrophil Count (ANC) ≥ 750/mm3 
ANC: __________________ 
Date of Test: ____________ 
• 
Platelets ˃50,000/mm3 
Platelets: _______________ 
Date of Test: ____________ 
NOTE: Platelet transfusions are not allowed within 3 days before registration to meet 
eligibility criteria. 
• 
Serum Creatinine ≤ 2x Upper Limit Normal (ULN) 
Serum Creatinine: ________ 
ULN: ________ 
Date of Test: ___________ 
• 
ALT and AST ≤ 3x ULN 
ALT: _________ Institution ULN: ________ Date of Test: __________ 
AST: _________ Institution ULN: ________ Date of Test: __________ 
• 
Total Bilirubin ≤ 1.5x ULN (in the absence of previously diagnosed Gilbert’s disease) 
Total Bilirubin: ___________ 
ULN: ________ 
Date of Test: ___________ 
3.10 
Patients must not have received systemic treatment for MCL for at least 14 days prior to 
enrollment, except for steroids which may be used to manage acute symptoms related to 
disease up to 48 hours prior to starting study therapy. Radiation therapy must be concluded 
at least 14 days prior to enrollment. 
3.11 
Women must not be pregnant or breastfeeding since we do not know the effects of ixazomib 
and ibrutinib on the fetus or breastfeeding child. All sexually active females of childbearing 
potential (not surgically sterilized and between menarche and 1 year post menopause) must 
have a blood test to rule out pregnancy within 2 weeks prior to registration. 
Is the patient a woman of childbearing potential? _____________________ (yes/no) 
If yes, Date of Test: _______________ Results: ____________________________ 
3.12 
Sexually active women of child-bearing potential with a non-sterilized male partner and 
sexually active men must agree to use 2 methods of adequate contraception (hormonal plus 
barrier or 2 barrier forms) OR abstinence prior to study entry, for the duration of study 
participation, and for 3 months following last dose of study drugs. 
NOTE: Should a woman become pregnant or suspect she is pregnant while participating in 
this study, she should inform her treating physician immediately. 
3.13 
Patients must have resolved all prior non-hematologic toxicities assessed as related to prior 
therapy to ≤ grade 1. 
3.14 
Patients must have measurable disease (i.e., ≥ 1.5 cm in largest diameter) by conventional 
imaging modalities. Patients with extranodal involvement as the only measurable site of 
disease must have a largest diameter greater than ≥ 1.0 cm and must be attributable to 
active lymphoma in the opinion of the investigator. 
_____
_____
_____
_____ 
_____ 
_____ 
_____ 
_____ 
_____


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3.15 
Patients may not have current/active Central Nervous System (CNS) involvement with 
mantle cell lymphoma (patients with prior CNS involvement are eligible as long as they have 
had no evidence of active CNS disease for at least 6 months). Patients without clinical 
evidence of CNS involvement do not require CNS assessment at screening. 
3.16 
Patients may not have another malignancy that could interfere with the evaluation of safety 
or efficacy of this combination. Patients with a prior malignancy will be allowed without study 
chair approval in the following circumstances: 
1) Not currently active and diagnosed at least 3 years prior to the date of enrollment. 
2) Non-invasive diseases such as low risk cervical cancer or any cancer in situ. 
3) Localized disease in which chemotherapy would not be indicated (such as Stage I 
colon, lung, prostate or breast cancer). Patients with other malignancies not meeting 
these criteria must be discussed with PrECOG prior to enrollment. 
3.17 
Patients requiring long-term anticoagulation must be managed on an anticoagulant besides 
warfarin. Patients who require warfarin are not eligible. 
3.18 
Patients with a clinically significant bleeding episode as judged by the investigator within 3 
months of registration are not eligible, except patients who suffer bleeding due to trauma. 
3.19 
Patients may not have had major surgery within 14 days, or minor surgery within 3 days, 
before registration. 
3.20 
Patients may not have any active infection requiring oral or intravenous antimicrobial 
therapy at the time of therapy initiation. Patients with a recent self-limited infection that has 
clinically resolved may complete a prescribed course of antimicrobial therapy after study 
initiation as long as they are asymptomatic with no clinical evidence of infection for at least 
7 days prior to treatment. Patients with a recent serious (grade ≥ 3) infection requiring 
hospitalization must have completed all antimicrobial therapy within 14 days of therapy 
initiation. 
3.21 
Patients may not have evidence of uncontrolled cardiovascular conditions, including 
uncontrolled hypertension, uncontrolled cardiac arrhythmias, symptomatic congestive heart 
failure (NYHA class III or higher [Appendix II]), unstable angina, or myocardial infarction 
within the past 6 months. Patients with a history of any significant cardiovascular disease 
that has been controlled for at least 14 days before registration are allowed (except for 
patients who have had a myocardial infarction within 6 months). 
3.22 
No systemic treatment, within 14 days before the first dose of ibrutinib with moderate or 
strong inhibitors of CYP3A (Strong Inhibitors: ketoconazole, itraconazole, voriconazole, 
posaconazole, clarithromycin, and telithromycin; Moderate Inhibitors: fluconazole, 
darunavir, erythromycin, diltiazem, atazanavir, aprepitant, amprenavir, fosamprenavir, 
crizotinib, imatinib, verapamil, ciprofloxacin, grapefruit juice products, and Seville oranges) 
or strong CYP3A inducers for ibrutinib and ixazomib (carbamazepine, rifampin, phenytoin, 
St. John’s wort). Refer to Section 11.2.7 for additional excluded medications and 
information. 
3.23 
Patients with ongoing or active systemic infection, active hepatitis B or C virus infection, or 
known Human Immunodeficiency Virus (HIV) positive are not eligible. Testing is not required 
in absence of clinical suspicion. 
3.24 
Patients with a history of hepatitis B or C must have a negative peripheral blood Polymerase 
Chain Reaction (PCR) and may not be positive for Hepatitis B surface antigen. Patients with 
cirrhosis or other evidence of liver damage due to Hepatitis B or C are not eligible. 
3.25 
Patients with any serious medical or psychiatric illness that could, in the investigator’s 
opinion, potentially interfere with the completion of the treatment according to the protocol 
are not eligible. 
_____ 
_____ 
_____ 
_____ 
_____ 
_____ 
_____ 
_____ 
_____ 
_____ 
_____ 


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3.26 
Patients with a known allergy to any of the study medications, their analogues, or excipients 
in the various formulations of any agent are not eligible. 
3.27 
Patients with known GI disease or prior GI procedure that could interfere with the oral 
absorption or tolerance of ixazomib or ibrutinib including difficulty swallowing are not eligible. 
3.28 
Patients with ≥ Grade 2 peripheral neuropathy, or Grade 1 peripheral neuropathy with pain 
on clinical examination during the screening period are not eligible. 
3.29 
Patients may not participate in any other therapeutic clinical trials, including those with other 
investigational agents not included in this trial throughout the duration of this study. 
3.30 
As ibrutinib will not be provided by the study, the patient must be able to obtain ibrutinib 
through other means (i.e., commercially or through patient assistance programs). This must 
be confirmed prior to registration. 
_____ 
_____ 
_____ 
_____ 
_____ 


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4. 
Registration Procedures 
4.1 
Ethics 
This study will be conducted in accordance with the ethical principles that have their origin 
in the current Declaration of Helsinki and will be consistent with applicable US regulatory 
requirements and International Conference on Harmonization/Good Clinical Practice 
(ICH/GCP). 
The study will be conducted in compliance with the protocol. The protocol and any 
amendments and the patient informed consent will receive Institutional Review Board (IRB) 
approval prior to initiation of the study. 
Freely given written informed consent must be obtained from every patient or their legally 
acceptable representative prior to clinical trial participation, including informed consent for 
any screening procedures conducted to establish patient eligibility for the trial. 
Study personnel involved in conducting this trial will be qualified by education, training, and 
experience to perform their respective task(s). This trial will not use the services of 
investigators or study personnel where sanctions have been invoked or where there has 
been scientific misconduct or fraud (e.g., loss of medical licensure, debarment). 
Investigators are responsible for the conduct of the study at their study site. 
4.2 
Regulatory Requirements 
Before a site may enter patients, protocol-specific regulatory and other documents must be 
submitted to PrECOG as noted in study materials. Detailed information regarding document 
submission and control is provided to each site in separate study materials. 
Once required documents are received, reviewed, and approved by PrECOG or their 
representative, a Study Reference Manual (SRM) will be forwarded to the site. Any changes 
to site regulatory documents must be submitted by the investigator to the responsible party 
in a timely manner. Initial study drug shipment will not occur until the regulatory packet is 
complete. No patients will begin protocol therapy without formal registration as per the 
process below. 
4.3 
Phase I and II Patient Registration 
Patients must meet all of the eligibility requirements listed in Section 3 prior to registration. 
Treatment should begin ≤ 10 working days from study entry (date of registration). 
An eligibility checklist is included in Section 3. A confirmation of eligibility assessment by 
the investigator and/or site will be performed during the registration process. 
Phase I Registration – Prior to discussing protocol entry with the patient AND prior to 
registering in the electronic data capture (eDC) system, call the assigned PrECOG Project 
Manager to ensure that a place on the protocol is open to the patient. An Enrollment 
Approval Form must be completed prior to registration. 
Upon determination that a subject meets eligibility criteria, the subject will be registered in 
the study by site personnel via an electronic data capture (eDC) system. Confirmation of 
registration will be displayed in the eDC system. Detailed registration procedures and study 
contacts will be outlined in the SRM. 
The phase II portion will be conducted using the dose and schedule selected from the phase 
I portion of the study. Before proceeding to phase II, the protocol will be amended to specify 
the final dose selected from phase I. Patients that participate in phase I will not be eligible 
to participate in phase II. 
Phase II Registration – After it is verified by the site that the patient meets all eligibility 
criteria, registration will occur by entering the patient in the eDC system. 


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Full information regarding registration procedures and guidelines can be found in the SRM 
provided to your site. Correspondence regarding patient registration must be kept in the 
study records. 
Patients must not start protocol treatment prior to registration. 
4.4 
Research Bone Marrow, Tissue and Blood Samples 
Mandatory bone marrow and tumor tissue samples are required at baseline (if sufficient 
bone marrow and tumor tissue are available, submission is mandatory). 
Mandatory peripheral blood samples will also be collected. 
NOTE: No bone marrow biopsy/aspirate or tissue biopsy should be performed solely for the 
purposes of obtaining research samples. 
Time points for bone marrow, tissue and blood samples are outlined in the study parameters 
(Section 10) and specific requirements are outlined in the correlative section of this protocol 
(Section 13) and the lab manual. 
 


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5. 
Study Design 
5.1 
Phase I 
The phase I portion of the study will accrue patients in a standard 3+3 design with the 
primary objective of determining the maximum tolerate dose (MTD)/recommended phase 2 
dose (RP2D) of this combination in MCL. Both ibrutinib-pretreated and ibrutinib-naïve 
patients will be enrolled. Planned dose levels are described below. There will be no dose 
escalation above Dose Level 2. If dose level 1 is too toxic, we will de-escalate to dose level 
(-1). There shall be no dose reductions below dose level (-1). 
 
 
 
 
 
 
 
 
 
 
 
NOTE: For the phase I portion of the study, ibrutinib pre-treated patients must meet 
all eligibility criteria AND must have discontinued prior ibrutinib at least 3 
months prior to starting study therapy. 
Three patients were enrolled to Dose Level 1 with no DLTs during the 28 day assessment 
period. Nine patients were enrolled to Dose Level 2. Five of the nine patients completed the 
28 day assessment period with no DLTs, and one patient experienced a Grade 3 lung 
infection that was considered a DLT. Three of the nine patients were not evaluable for DLT 
and were replaced. One patient was inadvertently given neulasta prior to receiving Cycle 2, 
Day 1 therapy; another patient unintentionally took Day 15 ixazomib on Day 9; and one 
patient forgot to take ibrutinib the last 8 days of Cycle 1 unrelated to any toxicities. Phase I 
was completed November 25, 2019. Dose Level 2 is the recommended Phase 2 dose. 
5.2 
Phase II 
Once dose escalation and de-escalation has completed with determination of the 
MTD/RP2D (Phase I completed November 25, 2019), the phase II portion of the study will 
begin. Patients will be enrolled to two cohorts, based on prior BTK inhibitor treatment: BTK-
pretreated and BTK-naïve (see below). Patients will be treated until disease progression or 
until unacceptable toxicity, with dose modifications and delays as described in Section 6.5. 
August 7, 2020: Phase II opened December 17, 2019 with Cohort A: BTK-naïve or Cohort 
B: BTK-pretreated. 
Enrollment to Cohort A: BTK-naïve will continue. We plan to reach our original accrual 
goal of 36 BTK-naïve subjects treated at the established Dose Level 2 for 31 eligible, treated 
patients. The Phase I BTK-naïve patients treated at Dose Level 2 will be included in the 36 
patient total. Seventeen additional BTK-naïve patients will be enrolled to complete this 
cohort. 
Enrollment to Cohort B: BTK-pretreated will close. To date, only two patients have 
enrolled in Cohort B. 
Dose Level 
Ixazomib 
Days 1, 8, 15 of 
a 28 Day Cycle 
Ibrutinib 
Days 1-28 of a 
28 Day Cycle 
-1  
3 mg 
420 mg 
1 
Starting Dose 
3 mg 
560 mg 
2  
4 mg 
560 mg 
Open to Ibrutinib Naïve 
and Selected Pretreated 
Patients 


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28 
 
 
 
 
 
 
 
 
Ixazomib 
Days 1, 8, 15 of a 
28 Day Cycle 
Ibrutinib 
Days 1-28 of a 28 
Day Cycle 
4 mg 
560 mg 
Dosed at RP2D 
Cohort A: BTK-Naive 
Cohort B: BTK-Pretreated: 
Closed to Enrollment 8/7/2020 


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6. 
Treatment Plan 
6.1 
Overview 
This study shall be divided into phase I and phase II components. The phase I portion of 
the study shall be designed to evaluate the safety and tolerability of the combination of 
ibrutinib and ixazomib in relapsed/refractory MCL and to identify the MTD/RP2D. The phase 
II portion of the study will evaluate the efficacy of this combination. 
6.1.1 
Ixazomib Administration 
Ixazomib will be administered orally. Patients should be instructed to swallow 
ixazomib capsules whole, with water, and not to break, chew, or open the capsules. 
Ixazomib should be taken on an empty stomach (no food or drink) at least 1 hour 
before or at least 2 hours after food. Each capsule should be swallowed separately 
with a sip of water. A total of approximately 8 ounces (240 mL) of water should be 
taken with the capsules. A Medication Diary will be provided to the patient to record 
each date and dose of ixazomib after Cycle 1 (Appendix III). 
Missed doses can be taken as soon as the patient remembers if the next scheduled 
dose is ≥ 72 hours for all cycles aside from Cycle 1 of the phase 1 study. Patients 
with dose delays in Phase I, Cycle 1 shall be managed as described below in 
Section 6.2 and Section 6.2.1. 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 on Cycle 2 and beyond of the phase I study and those enrolled on the 
phase II study shall not make up any ixazomib doses that are delayed >72 hours 
due to toxicity. 
6.1.2 
Ibrutinib Administration 
Ibrutinib will be administered orally. Doses should be taken at the same time each 
day without regard to food or drink (except as noted in Section 6.6.2). Ibrutinib 
should be swallowed whole with water and the tablets should not be opened, 
broken, or chewed. A Medication Diary will be provided to the patient to record each 
date and dose of ibrutinib (Appendix IV). 
If a dose of ibrutinib is not taken at the scheduled time, it can be taken as soon as 
possible up to 8 hours after the scheduled time on the same day with a return to the 
normal schedule the following day. If a patient does not take a dose within 8 hours 
of the scheduled time, that day’s dose will be skipped. Extra capsules of ibrutinib 
should not be taken to make up for the 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. 
6.2 
Phase I Treatment Administration 
Patients will be enrolled to the phase I study through a standard 3 + 3 design. Eligible 
patients will include ibrutinib-naïve patients as well as selected ibrutinib-pretreated patients. 
Given the focus of the phase I study on safety/tolerability, patients who have progressed on 
ibrutinib that are felt to be at high risk for rapid progression on this study shall not be eligible 
for the phase I portion of the study (Eligibility Criteria 3.4). This exclusion of rapid 
progressors is designed to decrease the risk of having to replace multiple patients due to 
progression during the dose-limiting toxicity (DLT) assessment period. 
Dose escalation shall occur according to Table 6-1. The first three patients shall be accrued 
to Dose Level 1 (3 mg ixazomib and 560 mg ibrutinib). Patients shall take ibrutinib 
continuously once daily of a 28 day cycle. Ixazomib will be administered orally on days 1, 8, 
and 15 of a 28 day cycle. Patients shall continue therapy until progression or unacceptable 
toxicity. 


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The MTD/RP2D shall be defined as the highest dose level where 0 or 1 out of 6 patients 
experiences a DLT. The first 3 patients will be accrued to Dose Level 1. If 0 of the first 3 
patients enrolled experience a DLT, then the following cohort of 3 patients will be accrued 
to the next highest dose level. If 1 of the first 3 patients experience a DLT, then an additional 
3 patients will be accrued at the current dose level. If 2 or 3 of the first 6 patients experience 
a DLT, then that dose level shall be considered too toxic and dosing will occur at Dose Level 
(-1). If 2 or 3 patients experience a DLT at Dose Level (-1), the regimen will be considered 
too toxic and the trial will end. If Dose Level 2 proves safe (0 or 1 DLT’s out of 3 patients), 
then an additional 3 patients shall be accrued to Dose Level 2. If 0-1 out of 6 total patients 
treated at Dose Level 2 experience a DLT, then that dose level shall be considered the 
RP2D and the phase 1 study shall end. There shall be no dose escalation above Dose Level 
2. If 2 or 3 patients in Dose Level 2 experience a DLT, then that dose level shall be 
considered too toxic and Dose Level 1 shall be considered the RP2D as long as 0 or 1 out 
of 6 patients experiences a DLT. 
Patients may delay therapy (ibrutinib and/or ixazomib) up to 1 week in Phase I, Cycle 1. In 
this case, subsequent doses of ixazomib must be >72 hours from the prior dose. As a result, 
for Phase I, Cycle 1 only, patients who delay a dose due to toxicity may delay subsequent 
doses up to 1 week to allow for at least a 3 day period between doses of ixazomib. 
Patients on Phase I, Cycle 2 and subsequent cycles shall not make up any ixazomib doses 
that are delayed >72 hours due to toxicity (missed doses can be taken as soon as the patient 
remembers if the next scheduled dose is 72 hours or more away). 
For Cycle 1, patients should receive all ixazomib doses in clinic after a provider assessment. 
For all subsequent cycles, patients are only required to be seen in clinic on day 1 of the 
cycle (NOTE: Cycle 2 and Cycle 3, Day 15 (and Day 22, if applicable) mandatory blood 
counts can be done locally). 
Three patients were enrolled to Dose Level 1 with no DLTs during the 28 day assessment 
period. Nine patients were enrolled to Dose Level 2. Five of the nine patients completed the 
28 day assessment period with no DLTs, and one patient experienced a Grade 3 lung 
infection that was considered a DLT. Three of the nine patients were not evaluable for DLT 
and were replaced. One patient was inadvertently given neulasta prior to receiving Cycle 2, 
Day 1 therapy; another patient unintentionally took Day 15 ixazomib on Day 9; and one 
patient forgot to take ibrutinib the last 8 days of Cycle 1 unrelated to any toxicities. Phase I 
was completed November 25, 2019. Dose Level 2 is the recommended Phase 2 dose. 
6.2.1 
DLT Assessment 
Patients shall be assessed for DLT through the conclusion of Cycle 1 (i.e., prior to 
Cycle 2, Day 1). Patients experiencing progression or who are non-adherent to the 
study regimen and/or assessments will be removed from study therapy and 
replaced for the purposes of DLT assessment. Patients who miss 5 consecutive 
Table 6-1 Dose Levels for Phase I Study 
Dose Level 
Ixazomib 
Days 1, 8, 15 of 
a 28 Day Cycle 
Ibrutinib 
Days 1-28 of a 
28 Day Cycle 
-1  
3 mg 
420 mg 
1 
Starting Dose 
3 mg 
560 mg 
2  
4 mg 
560 mg 


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doses of ibrutinib for reasons unrelated to toxicity OR who experience a dose delay 
of ixazomib of >72 hours for reasons unrelated to toxicity will not be considered 
DLT’s. These patients shall be replaced for the purposes of DLT assessment and 
determination of the MTD/RP2D but may continue study therapy at the discretion 
of the investigator. DLT shall be defined according to Table 6-2. Patients who 
experience a DLT, may continue on study therapy. DLTs shall be managed 
according to Section 6.5 detailing dose modifications/delays and patient can re-start 
therapy once they meet criteria noted in Section 6.4. 
Table 6-2 
Dose Limiting Toxicities for Phase I 
 
Any toxicity-related dose delay >7 days of ibrutinib or ixazomib or 
inability to complete 3 doses of ixazomib within the first cycle due 
to toxicity shall constitute a DLT. A delay of >7 days of the start of 
Cycle 2 due to toxicity shall also constitute a DLT. 
Grade 3 
Non-Hematologic Toxicity aside from Grade 3 diarrhea, nausea, 
or vomiting which resolve within 48 hours of supportive care. 
Grade 3 
Thrombocytopenia with significant bleeding (defined as acute 
bleeding requiring a transfusion and/or hospitalization). 
Grade 4 
Thrombocytopenia 
Grade 4 
Febrile Neutropenia lasting longer than 7 days. To meet criteria for 
DLT, patients must remain febrile and neutropenic for >7 days. If 
a patient remains neutropenic but the fever resolves within 7 days, 
it shall not constitute a DLT. 
Grade 4 
Non-Hematologic Toxicity 
Grade 5 
Any Toxicity 
6.3 
Phase II Treatment Administration 
Once the MTD/RP2D is determined, the phase I portion of the study shall end and the phase 
II portion shall begin (Phase I completed November 25, 2019). For the phase II portion of 
the study, patients will be divided into two cohorts: BTK-pretreated and BTK-naïve. All 
patients who have received one dose of ibrutinib or any BTK inhibitor or more shall be 
assigned to the BTK-pretreated cohort. August 7, 2020: BTK-pretreated cohort closed. 
Patients shall receive therapy at the RP2D: Ibrutinib 560 mg and Ixazomib 4 mg, with 
ibrutinib administered continuously daily and ixazomib administered on days 1, 8, and 15 of 
a 28 day cycle. Patients shall continue therapy until they have evidence of progression or 
unacceptable toxicity or withdrawal of consent. 
Patients shall not make up any ixazomib doses that are delayed >72 hours due to toxicity 
(missed doses can be taken as soon as the patient remembers if the next scheduled dose 
is 72 hours or more away). 
For Cycle 1, patients should receive day 1 and day 15 ixazomib doses in clinic after a 
provider assessment. For Cycle 2-7, patients are only required to be seen in clinic on day 1 
of the cycle. 
If patients continue on study therapy after Cycle 6, patients are required to be seen in clinic 
every 12 weeks (Day 1 of every 3 cycles) starting with Cycle 7. 
 


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6.4 
Criteria to Begin a New Cycle of Therapy 
Prior to starting a new cycle of treatment (Cycle 2 onwards), all of the following criteria must 
be met: 
• 
ANC must be ≥ 1000/mm3 (>750/mm3 if documented bone marrow involvement at study 
entry [Cycle 2 only]). 
• 
Platelet count must be ≥ 75,000/mm3 (>50,000/mm3 if documented bone marrow 
involvement [Cycle 2 only]). 
NOTE: Patients with marrow involvement at study entry may start Cycle 2 with decreased 
ANC/platelet counts as documented above. For all other cycles, the standard 
criteria to start a new cycle apply. 
• 
All other non-hematologic toxicity (except for alopecia, fatigue, and electrolyte/glucose 
abnormalities that are immediately reversible and/or not felt to be clinically significant) 
deemed at least possibly related to study therapy must have resolved to ≤ Grade 1 or 
to the patient’s baseline condition. Study therapy related fatigue must be resolved to ≤ 
Grade 2. 
Patients failing to meet these criteria may be delayed for up to 3 weeks (21 days) and should 
be restarted at adjusted dose levels as described below. Growth factors, platelet and blood 
transfusions may be used per institutional practice for all cycles except Cycle 1 of the phase 
1 study (unless patient experiences a DLT). 
6.5 
Dose Delays & Modifications 
All toxicities should be graded according to the National Cancer Institute (NCI) 
Common Terminology Criteria for Adverse Events Version 5.0 (CTCAE V5.0). A copy 
of 
the 
CTCAE 
V5.0 
can 
be 
downloaded 
from 
the 
CTEP 
website 
(http://www.ctep.cancer.gov). 
A +/-3 day window is allowed for scheduled ixazomib therapy, required tests and/or visits 
except as otherwise noted. Delays due to holidays, weekends, bad weather or other 
unforeseen circumstances will be permitted. 
Patients who experience a dose delay during Cycle 1 of the phase 1 study shall be managed 
as described above in Section 6.2 and Section 6.2.1. If a patient experiences a DLT and 
continues on study therapy, follow the dose delays & modifications guidelines as noted in 
this section. Phase I completed November 25, 2019. 
Patients on Cycle 2 and beyond of the phase I study and those enrolled on the phase II 
study shall not make up any ixazomib doses that are delayed >3 days due to toxicity. Missed 
doses can be taken as soon as the patient remembers if the next scheduled dose is 72 
hours or more away, otherwise the dose shall be considered skipped and shall not be made 
up. 
NOTE: It is the intent of this protocol to preserve the full labeled dosing of ibrutinib 
whenever possible. With the exception of the specified toxicities noted in 
Section 6.5.2, ibrutinib should be continued at full dose and on schedule for 
all patients, regardless of ixazomib delays or modifications. Patients who are 
unable to tolerate ixazomib at any dose level due to toxicity shall be removed 
from study therapy, except in cases of potential overlapping toxicity in which 
case the dose of ibrutinib may be reduced by one dose level (Table 6-6).


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6.5.1 
Dose Reductions/Modifications for Ixazomib and Ibrutinib 
Table 6-3 
Ixazomib and Ibrutinib Dose Adjustments for Hematologic Toxicities 
Criteria 
Action on Ixazomib 
Action on Ibrutinib 
Within-Cycle Dose Modifications 
 
 
• If platelet count ≤ 30 × 109/L or ANC ≤ 0.50 × 109/L on 
an ixazomib dosing day (other than Day 1). 
• Ixazomib dose should be withheld. 
• Complete blood count (CBC) with differential 
should be repeated at least twice weekly (with 
2 days between CBC’s) until ANC and/or 
platelet counts have exceeded the pre-
specified values (Section 6.4) required to 
initiate a treatment cycle on at least 2 
occasions. 
• Upon recovery, ixazomib may be reinitiated 
with 1 dose level reduction (Table 6-5). 
• If no recovery after reduction of ixazomib to 
2.3 mg, then reduce ibrutinib to 420 mg dose. 
• If no recovery on the 420 mg dose, then 
discontinue study therapy. 
Dose Modifications for Subsequent Treatment Cycles 
 
 
• 
Delay of >2 weeks in the start of a subsequent cycle due 
to lack of toxicity recovery (Section 6.4). 
• 
ANC ≤ 750 × 109/L and/or platelet count ≤ 50 × 109/L 
(except for Cycle 1 and Cycle 2; Section 6.4). 
• 
NOTE: Patients requiring delay of ≤ 2 weeks before 
starting a cycle do not require a dose reduction unless 
a delay has been required on more than 1 cycle, in 
which case the ixazomib dose should be decreased by 
one level (Table 6-5). 
• Hold ixazomib until resolution as per criteria 
in Section 6.4. 
• Upon recovery, reduce ixazomib 1 dose level 
(Table 6-5). 
• The maximum delay before treatment should 
be discontinued will be 3 weeks or at the 
discretion of the principal investigator. 
• If no recovery after reduction of ixazomib to 
2.3 mg, then reduce ibrutinib to 420 mg dose. 
• If no recovery on the 420 mg dose, then 
discontinue study therapy. 
6.5.1.1 
Hematologic Guidelines for Subsequent Treatment Cycles with Ixazomib 
• 
For hematologic toxicity that occurs during a cycle but recover in time for the start of the next cycle: 
o 
If dose was reduced within the cycle, start the next cycle at that same dose. 
o 
If due to toxicity timing, i.e., after Day 15 dosing thus a dose reduction was not required at that point in 
the cycle, reduce ixazomib by 1 dose level at the start of that cycle if the severity of the hematologic 
toxicity would have otherwise mandated a dose reduction. 
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 6-4 
Ixazomib and Ibrutinib Treatment Modification (Delays, Reductions, and Discontinuations) Due to Non-Hematologic 
Adverse Events 
Adverse Event (Severity) 
Action on Ixazomib 
Action on Ibrutinib 
Further Considerations 
Peripheral Neuropathy 
 
 
 
• Grade 1 peripheral neuropathy (PN) 
without pain 
• No action. 
• NONE 
Grade 1 signs and symptoms: 
asymptomatic; without pain or loss 
of function; clinical or diagnostic 
observations only.34 
• Grade 2 peripheral neuropathy or 
Grade 1 PN with pain 
• Hold ixazomib until resolution to 
Grade ≤ 1 without pain or 
baseline. 
• NONE 
Grade 2 signs and symptoms: 
Moderate 
symptoms; 
limiting 
instrumental activities of daily living 
(ADL).34 
• New 
or 
worsening 
Grade 
2 
peripheral neuropathy with pain or 
Grade 3 
• Hold ixazomib until resolution to 
Grade ≤ 1 without pain or 
baseline. 
• Reduce ixazomib to next lower 
dose upon recovery 
(Table 6-5). 
• NONE 
Grade 3 signs and symptoms: 
severe symptoms; limiting self-care 
ADL; assistive device indicated.34 
• New 
or 
worsening 
Grade 
4 
peripheral neuropathy 
• Discontinue ixazomib. 
• NONE 
 
Grade 2 Non-Hematologic Toxicity 
that was Grade ≤ 1 at baseline. 
• Day 1 of cycle: Hold ixazomib 
until resolution to Grade ≤ 1 or 
baseline (except for alopecia, 
fatigue and electrolyte/glucose 
abnormalities 
that 
are 
immediately reversible and/or 
not 
felt 
to 
be 
clinically 
significant). 
Day 8 and/or 15 of cycle: No 
change. 
• NONE 
Study therapy related to fatigue 
must be resolved to ≤ Grade 2 to 
continue treatment. 


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Table 6-4 
Ixazomib and Ibrutinib Treatment Modification (Delays, Reductions, and Discontinuations) Due to Non-Hematologic 
Adverse Events 
Adverse Event (Severity) 
Action on Ixazomib 
Action on Ibrutinib 
Further Considerations 
Grade 3 Non-Hematologic Toxicity 
• Hold ixazomib until resolution to 
Grade ≤ 1 or baseline. 
• NONE 
See 
Section 
6.5.2 
for 
dose 
reductions/modifications 
for 
toxicities related to ibrutinib. 
• If not recovered to ≤ Grade 1 or 
baseline within 2 weeks 
• Reduce ixazomib to next lower 
dose upon return to ≤ Grade 1 
or baseline (Table 6-5). 
• NONE 
 
• Subsequent recurrence Grade 3 
that does not recover to ≤ Grade 1 
or baseline within 2 weeks 
• Hold ixazomib until resolution to 
Grade <1 or baseline. 
• Reduce ixazomib to next lower 
dose (Table 6-5). 
• NONE 
Monitor closely, take appropriate 
medical precautions, and provide 
appropriate symptomatic care. 
• Subsequent recurrence of Grade 3 
toxicity that does not recover to 
≤ Grade 1 despite treatment at 
lowest dose level of ixazomib (GI 
toxicities ONLY) 
• Continue ixazomib at lowest 
dose 
• For 
GI 
toxicities 
ONLY 
(nausea, 
vomiting, 
or 
diarrhea) reduce dose of 
ibrutinib to 420 mg daily. 
In this setting, ibrutinib shall not be 
reduced below 420 mg daily. If a 
patient 
cannot 
tolerate 
the 
combination of ixazomib 2.3 mg and 
ibrutinib 420 mg, they shall be 
removed from study therapy. 
Grade 4 Non-Hematologic Toxicity 
• Consider permanently 
discontinuing ixazomib. 
• Discuss with PrECOG and 
principal investigator. 
• If it is felt to be of potential 
clinical 
benefit 
to 
reinitiate 
therapy, patients should be 
managed per the Grade 3 non-
hematologic toxicity guidelines 
above. 
• 
NONE 
See 
Section 
6.5.2 
for 
dose 
reductions/modifications 
for 
toxicities related to ibrutinib. 
Exceptions are cases in which the 
investigator determines the patient 
is obtaining a clinical benefit. 
Patients who experience a recurrent 
grade 4 non-hematologic toxicity 
shall be permanently removed from 
study therapy. 
Patients requiring a delay of 2 weeks or less before starting a cycle do not require a dose reduction unless a delay has been 
required on more than 1 cycle, in which case the ixazomib dose should be decreased by one level (Table 6-5). 
The maximum delay before treatment should be discontinued will be 3 weeks or at the discretion of the principal investigator. 
Once ixazomib is reduced for any toxicity, the dose may not be re-escalated. If it is ultimately determined that therapy 
with ixazomib is no longer safe, the patient will be removed from the study. 


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Table 6-5 
Recommended Dose Modifications for Ixazomib 
6.5.2 
Additional Dose Reductions/Modifications for Ibrutinib 
The following toxicities shall be considered related to ibrutinib and shall result in 
ibrutinib dose delay/modification per Table 6-6: 
• 
Grade ≥ 3 Hemorrhage 
• 
Grade ≥ 3 Hypertension 
• 
Grade ≥ 3 Atrial Fibrillation 
• 
Grade ≥ 3 Arthralgias 
If a patient experiences any of these events, they should hold ibrutinib until recovery 
to grade ≤ 1 (or baseline) and subsequently shall modify the dose of ibrutinib as 
specified below in Table 6-6. The occurrence of any of these events does not 
require a dose adjustment/delay of ixazomib if the investigator feels that continued 
therapy is appropriate and concomitant toxicities do not require a dose 
delay/modification of ixazomib. 
If at any time a patient experiences any grade ≥ 3 non-hematologic toxicity deemed 
at least possibly related to ibrutinib, the investigator should consider holding 
ibrutinib until the toxicity has resolved to grade ≤ 1 (or baseline). If upon resolution 
the toxicity is still felt to be at least possibly related to ibrutinib, patients should be 
restarted on ibrutinib according to the instructions in Table 6-6. An investigator may, 
at any time, permanently discontinue ibrutinib if they feel it is no longer safe to 
continue ibrutinib therapy. In this case, a patient may continue on ixazomib if felt to 
be benefitting from treatment. Any patient requiring discontinuation of ixazomib will 
be removed from study therapy. 
Table 6-6: Dose Modifications for Ibrutinib 
Occurrence 
Action for Ibrutinib 
First 
Withhold ibrutinib until recover to grade ≤1 or baseline; 
may restart at original dose level. 
Second 
Withhold ibrutinib until recover to grade ≤1 or baseline; 
may restart at 420 mg/day. 
Third 
Withhold ibrutinib until recover to grade ≤1 or baseline; 
may restart at 280 mg/day (only for above ≥ Grade 3 
toxicities). 
Fourth 
Discontinue ibrutinib. 
Once a dose reduction of ibrutinib has occurred, there shall be no re-escalation of 
the ibrutinib dose in future cycles. Patients requiring discontinuation of ibrutinib may 
remain on study therapy with ixazomib alone if they are felt to be receiving clinical 
benefit and are otherwise eligible to continue study therapy. Patients requiring 
discontinuation of ixazomib will be removed from the study. 
 
Starting Dose 
Modification 
Dose Level 
4.0 mg 
3.0 mg 
Dose Level 
3.0 mg 
2.3 mg 
Dose Level 
2.3 mg 
Remove from study 


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All toxicities (including ibrutinib-specific toxicities) shall be managed with 
appropriate supportive care and expert consultation as indicated. Patients may 
remain on study therapy if these are able to be medically managed and resolve to 
grade ≤ 1 with therapy. Anti-platelet therapy or anti-coagulation is allowed for 
patients experiencing atrial fibrillation as long as Warfarin is not used. 
6.6 
Concurrent Therapies 
6.6.1 
Required and/or Permitted 
The following medications and procedures are permitted during the study: 
• 
Antiemetics, including 5-HT3 serotonin receptor antagonists, may be used at 
the discretion of the investigator. 
• 
Loperamide or other antidiarrheal should be used for symptomatic diarrhea at 
discretion of the investigator. The dose and regimen will be according to 
institutional guidelines. IV fluids should be given to prevent volume depletion. 
• 
Growth factors (e.g., granulocyte colony stimulating factor [G-CSF], granulocyte 
macrophage-colony stimulating factor [GM-CSF], recombinant erythropoietin) 
are permitted except for Cycle 1 of the phase 1 study (unless patient 
experiences a DLT). Their use should follow ASCO guidelines and/or 
institutional practice. 
• 
Patients should be transfused with red cells and platelets as clinically indicated 
and according to institutional guidelines. However, transfusions may not be 
used to satisfy inclusion criteria for study entry. 
• 
Antiviral therapy such as acyclovir may be administered if medically 
appropriate. 
• 
Patients who experience worsening neuropathy from baseline may be observed 
for recovery, and have dose reductions/delays as indicated in the protocol, and 
any supportive therapy or intervention may be initiated as appropriate at the 
discretion of the investigator. 
• 
Supportive measures consistent with optimal patient care may be given 
throughout the study. 
6.6.2 
Not Permitted 
Strong CYP3A inducers should be avoided during treatment with ixazomib and/or 
ibrutinib: 
• 
Avoid concomitant administration with strong CYP3A inducers (such as 
rifampin, phenytoin, carbamazepine, and St. John’s Wort). 
Systemic treatment with any of the above metabolizing enzyme inducers should be 
avoided, unless there is no appropriate alternative medication for the patient’s use 
(Rationale: If there were to be a drug-drug interaction with an inducer, ixazomib 
and/or ibrutinib exposure would be decreased; therefore, there would be a reduced 
chance of an AE. However, there may be less chance for an antitumor effect, but 
that is not an absolute reason to be taken off ixazomib and/or ibrutinib). 
Strong or moderate CYP3A inhibitors should be avoided during treatment with 
ibrutinib: 
• 
Concomitant use of strong CYP3A inhibitors which would be taken chronically 
(e.g., ritonavir, indinavir, nelfinavir, saquinavir, boceprevir, telaprevir, 
nefazodone) is not recommended. 
• 
For strong CYP3A inhibitors used short-term (e.g., antifungals and antibiotics for 
7 days or less, e.g., ketoconazole, itraconazole, voriconazole, posaconazole, 


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clarithromycin, telithromycin) consider interrupting ibrutinib therapy during the 
duration of inhibitor use. 
• 
Reduce ibrutinib to 140 mg if a moderate CYP3A inhibitor must be used (e.g., 
fluconazole, darunavir, erythromycin, diltiazem, atazanavir, aprepitant, 
amprenavir, fosamprenavir, crizotinib, imatinib, verapamil, and ciprofloxacin). 
• 
Avoid grapefruit and Seville oranges during ibrutinib treatment, as these contain 
moderate inhibitors of CYP3A. 
Patients taking concomitant strong or moderate CYP3A4 inhibitors should be 
monitored more closely for signs of ibrutinib toxicity. 
The following procedures are prohibited during the study. 
• 
Any antineoplastic treatment with activity against lymphoma, other than study 
drugs. This includes corticosteroids which should not be used with the intent to 
treat the underlying lymphoma for a patient who has initiated study therapy. 
Corticosteroid use as an anti-emetic or for other non-malignant etiologies may 
be used but should be limited to the smallest dose and duration required and 
should be documented. 
• 
Radiation therapy (note that, in general, the requirement for local radiation 
therapy indicates disease progression). 
• 
Platelet transfusions to help patients meet eligibility criteria are not allowed 
within 3 days prior to study drug dosing for any dosing day. 
• 
Major surgery will be allowed as clinically indicated with a 7 day interruption of 
ibrutinib. Minor surgery will be allowed with a 3 day interruption of ibrutinib. 
Ixazomib does not have to be discontinued for surgery but one dose may be 
missed if the patient is unable to take the dose due to the surgery (or if the 
treating investigator feels it is in the patient’s best interest to miss the dose). If 
more than one dose of ixazomib will need to be missed, this should be 
discussed with PrECOG. 
 
 


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7. 
Study Duration and Discontinuation of Therapy 
7.1 
Study Duration 
Patients will receive protocol therapy unless: 
1. Disease progression per LUGANO criteria or clinical progression. 
2. Toxicities considered unacceptable by either the patient or the investigator, despite 
optimal supportive care and dose modifications. 
3. Any requirement to discontinue ixazomib based on dose modification guidelines in 
Section 6.5.1. 
4. Development of an inter-current illness that prevents further administration of study 
treatment. 
5. Extraordinary Medical Circumstances: If at any time the constraints of this protocol are 
detrimental to the patient's health, protocol treatment should be discontinued. 
6. Patient withdraws consent or is unable to comply with study procedures. 
7.2 
Duration of Follow-Up 
Patients will be followed for adverse events for 30 days after their last dose of study 
medication. However, if a patient experiences an adverse event >30 days after their last 
dose of study medication that is felt to be, in the opinion of the investigator, possibly, 
probably or definitely related to study therapy, the adverse event should be reported. 
If a patient is removed from treatment for reason(s) other than progression, follow with 
regular tumor assessments per standard of care until progression or start of new treatment. 
For patients who are registered but do not receive any protocol therapy, baseline and follow-
up information per Section 10 will be collected. 
7.3 
Criteria for Removal from Study Treatment 
A genuine effort will be made to determine the reason(s) why a patient fails to return for the 
necessary visits or is discontinued from the trial, should this occur. It will be documented 
whether or not each patient completed the clinical study. If for any patient study treatment 
or observations were discontinued, the reason will be recorded on the appropriate electronic 
case report form. Reasons that a patient may discontinue treatment in a clinical study are 
considered to constitute one of the following: 
1. Recurrence of disease or documented progression of disease (with the exception of 
progressive lymphocytosis without any other evidence of disease progression). 
2. Intercurrent illness that prevents further administration of treatment per investigator 
discretion. 
3. Unacceptable adverse events and/or occurrence of dose limiting toxicity. 
4. Treatment interruption of more than 3 weeks. 
5. Investigator and/or patient discontinue chemotherapy. 
6. Pregnancy. 
7. Develops a second malignancy (except for non-melanoma skin cancer or cervical 
carcinoma in-situ) that requires treatment, which would interfere with this study. 
8. The patient may choose to withdraw from the study at any time for any reason. 
9. General or specific changes in the patient's condition that render the patient 
unacceptable for further treatment in the judgment of the investigator. 


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10. Severe non-compliance to protocol as judged by the investigator. 
11. Lost to follow-up. 
12. Death. 
13. Closure of study by PrECOG. 
Any patient who receives at least one dose of ixazomib or ibrutinib will be included in the 
safety analysis. Patients who discontinue study treatment early should be followed for 
response assessments, if possible. Follow-up will continue per Section 10, as applicable. 


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8. 
Adverse Event Reporting 
8.1 
Collection of Safety Information 
Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of 
a pre-existing medical condition in a patient administered a medicinal product in a clinical 
investigation and which does not necessarily have a causal relationship with this treatment. 
An AE can therefore be any unfavorable and unintended sign (e.g., including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a product 
(investigational or marketed), whether or not considered related to the product 
(investigational or marketed). 
After informed consent, but prior to initiation of study treatment (ixazomib and ibrutinib), only 
AEs/SAEs caused by a protocol-mandated intervention will be collected (e.g., SAEs related 
to invasive procedures such as biopsies). After the initiation of study treatment, all identified 
AEs and SAEs must be recorded and described on the appropriate page of the electronic 
Case Report Form (eCRF). If known, the diagnosis of the underlying illness or disorder 
should be recorded, rather than individual symptoms. The following information should be 
documented for all AEs: date of onset and resolution, severity of the event; the investigator’s 
opinion of the relationship to investigational product (see definitions below); treatment 
required for the AE treatment required for the AE; cause of the event (if known); and 
information regarding resolution/outcome. 
Only clinically significant laboratory abnormalities that require active management will be 
recorded as AEs or SAEs on the eCRF (e.g., abnormalities that require study drug dose 
modification, discontinuation of study treatment, more-frequent follow-up assessments, 
further diagnostic investigation, etc.). 
If the clinically significant laboratory abnormality is a sign of a disease or syndrome (e.g., 
alkaline phosphatase and bilirubin 5x the ULN associated with cholecystitis), only the 
diagnosis (e.g., cholecystitis) needs to be recorded on the Adverse Event eCRF. 
If the clinically significant laboratory abnormality is not a sign of a disease or syndrome, the 
abnormality itself should be recorded as an AE or SAE on the eCRF. If the laboratory 
abnormality can be characterized by a precise clinical term, the clinical term should be 
recorded as the AE or SAE. For example, an elevated serum potassium level of 7.0 mEq/L 
should be recorded as “hyperkalemia”. 
Observations of the same clinically significant laboratory abnormality from visit to visit 
should not be repeatedly recorded as AEs or SAEs on the eCRF unless their severity, 
seriousness, or etiology changes. 
Severity 
The categories and definitions of severity used for clinical trials AEs are defined in the NCI’s 
Common Terminology Criteria (CTCAE) V5.0 (http://www.ctep.cancer.gov). 
Attribution 
The following categories and definitions of causal relationship or attribution to study drug 
should be used to assess Adverse Events: 
• Definite: There is a reasonable causal relationship between the study drug and the event. 
The event response to withdrawal of study drug (dechallenge) and recurs with 
rechallenge, if clinically feasible. 
• Probable: There is a reasonable causal relationship between the study drug and the 
event. The event responds to dechallenge. Rechallenge is not required. 
• Possible: There is a reasonable causal relationship between the study drug and the 
event. Dechallenge information is lacking or unclear. 
• Unlikely: There is doubtful causal relationship between the study drug and the event. 


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• Unrelated: There is clearly not a causal relationship between the study drug and the 
event or there is a causal relationship between another drug, concurrent disease, or 
circumstances and the event. 
Categories ‘definite’, ‘probable’ and ‘possible’ are considered study drug related. Categories 
‘unlikely’ and ‘unrelated’ are considered not study drug-related. 
The development of a new cancer should be regarded as an AE. New cancers are those 
that are not the primary reason for administration of study treatment and have been 
identified after inclusion of the patient into the clinical study. 
AEs related to ibrutinib and ixazomib should be followed for 30 days after last dose 
of study therapy until ≤ grade 1 or stabilization, and reported as SAEs if they become 
serious. Any AE’s (serious or not) that occur more than 30 days after the last dose of 
study therapy but that are deemed to be at least possibly related to study therapy 
shall be reported. 
8.2 
Handling of Serious Adverse Events (SAEs) 
8.2.1 
SAE Definitions 
A serious AE is any untoward medical occurrence occurring after initiation of study 
treatment or that at any dose: 
• 
results in death, 
• 
is life-threatening (defined as an event in which the study patient was at risk of 
death at the time of the event; it does not refer to an event which hypothetically 
might have caused death if it were more severe), 
• 
requires inpatient hospitalization or causes prolongation of existing 
hospitalization, 
• 
results in persistent or significant disability/incapacity, 
• 
is a congenital anomaly/birth defect, 
• 
is an important medical event (defined as a medical event(s) that may not be 
immediately life-threatening or result in death or hospitalization but, based upon 
appropriate medical and scientific judgment, may jeopardize the patient or may 
require intervention (e.g., medical, surgical) to prevent one of the other serious 
outcomes listed in the definition above). 
Examples of such events include, but are not limited to, intensive treatment in an 
emergency room or at home for allergic bronchospasm; blood dyscrasias or 
convulsions that do not result in hospitalization. 
8.3 
SAE Reporting Requirements 
Serious adverse events (SAE) are defined above. The investigator should inform PrECOG 
of any SAE within 24 hours of being aware of the event. The date of awareness should be 
noted on the report. This must be documented on the PrECOG SAE form. This form must 
be completed and supplied to PrECOG within 24 hours/1 business day at the latest on the 
following working day. The initial report must be as complete as possible, including details 
of the current illness and (serious) adverse event, and an assessment of the causal 
relationship between the event and the investigational product(s). Information not available 
at the time of the initial report (e.g., an end date for the adverse event or laboratory values 
received after the report) must be documented on a follow-up PrECOG SAE report form. A 
final report to document resolution of the SAE is required. The investigator is responsible 
for following all SAEs until resolution, until the subject returns to baseline status, or until the 
condition has stabilized with the expectation that it will remain chronic, even if this extends 
beyond study participation. A copy of the transmission confirmation of the SAE report to 
PrECOG should be attached to the SAE and retained with the patient records. 


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SAEs should be scanned and emailed to PrE0404SAE@qdservices.com as per the 
instructions found in study materials provided to the investigator site. 
 
Medical Monitor 
During normal business hours 
(8:30 am-5:00 pm EST): 
Phone: 610-354-0404 
After normal business hours: 
Phone: 484-574-2367 
Email:
 
Manager, Clinical Safety 
During normal business hours 
(8:30 am-5:00 pm EST): 
Phone: 610-354-0404 
After normal business hours: 
Cell: 484-574-2367 
PrECOG will notify Takeda Pharmacovigilance (or designee) of all SAE’s within 24 hours of 
PrECOG’s & Investigator’s Awareness Date as discussed above. Relevant follow-up 
information will be provided to Takeda as soon as it becomes available. 
Investigators should also report event(s) to their IRB as required. 
Collection of complete information concerning SAEs is extremely important. Full 
descriptions of each event will be followed. Thus, follow-up information which becomes 
available as the SAE evolves, as well as supporting documentation (e.g., hospital discharge 
summaries and autopsy reports), should be collected subsequently, if not available at the 
time of the initial report, and immediately sent using the same procedure as the initial SAE 
report. 
All SAEs, regardless of causality, must be collected which occur within 30 days of last dose 
of study treatment. This includes all deaths within 30 days of last dose of ixazomib and 
ibrutinib regardless of attribution. In addition, the Investigator should notify PrECOG or 
designee of any SAE that may occur after this time period which they believe to be definitely, 
probably or possibly related to investigational product. 
NOTE: After study closure, study-drug related SAEs should be reported voluntarily by the 
treating physician to the manufacturer. 
Serious adverse event reporting to regulatory authorities and all participating investigators 
will be conducted by PrECOG (or designee) in accordance with 21CFR312.32, local 
requirements and international regulations, as appropriate. FDA reporting requirement 
timelines will be followed. PrECOG will also concurrently forward any such reports to 
Takeda. 
8.3.1 
Product Complaints or Medication Errors 
A medication error is a preventable event that involves an identifiable patient and 
that leads to inappropriate medication use, which may result in patient harm. While 
overdoses and under doses constitute medication errors, doses missed 
inadvertently by a patient do not. Individuals who identify a potential medication 
error situation should immediately contact PrECOG and report the event. 
Product complaints and medication errors in and of themselves are not AEs. If a 
product complaint or medication error results in an SAE, an SAE form should be 
completed and sent to PrECOG. 
8.4 
Reporting of Other Second Primary Cancers 
New cancers are those that are not the primary reason for administration of study treatment 
and have been identified after inclusion of the patient into the clinical study. 
All cases of new primary cancers that occur during or after protocol treatment must be 
reported to PrECOG on a Second Primary Cancer form within 30 days of diagnosis, 
regardless of relationship to protocol treatment. Secondary primary malignancies should 
also be reported as a SAE. The SAE form is not for use for reporting recurrence or 


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development of metastatic disease. A copy of the pathology report, if applicable, should be 
sent, if available. 
NOTE: Once data regarding survival and remission status are no longer required by the 
protocol, no follow-up data should be submitted. 
8.5 
Procedures in Case of Pregnancy 
Prior to study enrollment, women of childbearing potential (WOCBP) and male patients with 
a female partner of childbearing potential must be advised of the importance of avoiding 
pregnancy during trial participation and the potential risk factors for an unintentional 
pregnancy, documented in the informed consent. In addition, all WOCBP should be 
instructed to contact the Investigator immediately if they suspect they might be pregnant 
(e.g., missed or late menstrual period) at any time during study participation. 
Pregnancy of a female patient or the female partner of a male patient occurring while the 
patient is receiving study drug or within 3 months after the patient’s last dose of study drug 
will be reported to PrECOG on a Pregnancy Form within 24 hours of the investigator’s 
knowledge of the pregnancy. 
All reports of congenital abnormalities/birth defects and spontaneous miscarriages should 
also be reported and handled as SAEs. Elective abortions without complications should not 
be handled as AEs. 
The outcome of all pregnancies (spontaneous miscarriage, elective termination, normal 
birth including health of the newborn or congenital abnormality) must be followed and 
documented on the Pregnancy Form even if the subject was discontinued from the study 
treatment. Should pregnancy occur during a subject’s participation, the subject will 
immediately be discontinued from the treatment and followed per protocol. 
The study-specific Pregnancy Form can be found in the Study Reference Manual. 


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9. 
Measurement of Effect 
LUGANO Classification 
All disease response evaluation shall occur according to the Lugano classification35. 
9.1 
Scheduled Restaging Studies 
All patients shall complete a PET/CT at the time of study enrollment. Thereafter, restaging 
shall include CT chest/abdomen/pelvis after cycles 3, 6, 9, and 12, and then every 6 months 
while on study therapy. PET/CT or MRI may be substituted for CT at the discretion of the 
treating investigator, especially in cases where lesions are not readily noted on CT. Patients 
who discontinue study therapy for reasons other than disease progression shall have CT’s 
performed every 6 months until progression and/or initiation of a new therapy. 
All patients with suspected CR based on routine restaging should have a PET/CT 
performed to confirm CR. 
9.2 
Complete Response (CR) 
In order to satisfy the criteria for a complete response, patients who undergo CT scan only 
must meet the following criteria: 
• 
Target nodes/nodal masses must regress to ≤1.5 cm in longest transverse diameter. 
• 
No extralymphatic sites of disease. 
• 
Absent non-measured lesions. 
• 
All organ enlargement must be regressed to normal. 
• 
No new lesions. 
• 
Bone marrow must be normal by morphology (must be evaluated at the time of 
suspected CR in patients with a positive bone marrow at enrollment). 
Patients undergoing a PET/CT must meet the following criteria: 
• 
Deauville score of 1, 2 or 3 on the 5-point scale. 
• 
No new lesions. 
• 
No evidence of FDG avid disease in the bone marrow. 
NOTE: ALL PATIENTS WITH SUSPECTED CR WHO HAD BONE MARROW 
INVOLVEMENT AT SCREENING MUST UNDERGO A BONE MARROW BIOPSY 
TO CONFIRM RESPONSE. 
9.3 
Partial Response (PR) 
Patients undergoing a CT must meet the following criteria for PR: 
• 
≥ 50% decrease in the sum of the product of the diameters (SPD) of up to 6 target 
measurable nodes and extranodal sites. 
• 
Lesions too small to measure on CT should be considered 5 mm x 5 mm as the default 
value. 
• 
Lesions that are no longer visible should be considered 0 mm x 0 mm. 
• 
Non-measured lesions should be absent/normal or regressed, but without increase. 
• 
Spleen, if previously enlarged, must have regressed by >50% in length beyond normal. 
Patients undergoing PET/CT must meet the following criteria for PR: 
• 
Deauville score of 4 or 5 with reduced uptake compared to baseline and residual 
masses of any size. 
 
 


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• 
Bone marrow with residual uptake higher than uptake in normal marrow but reduced 
compared to baseline (diffuse uptake compatible with reactive changes from 
chemotherapy is allowed). If there are persistent focal changes in the marrow in the 
context of a nodal response, consideration should be given to further evaluation with 
MRI or biopsy or an interval scan. 
9.4 
No Response/Stable Disease (SD) 
Patients undergoing CT must meet the following criteria for SD/No response: 
• 
<50% decrease from baseline in SPD of up to 6 dominant, measurable nodes and 
extranodal sites; no criteria for progressive disease are met. 
• 
No increase of non-measured lesions or organ enlargement consistent with 
progression. 
Patients undergoing PET/CT must meet the following criteria for SD/No response: 
• 
Deauville score of 4 or 5 with no significant change in FDG uptake from baseline at 
interim or end of treatment. 
• 
No change in FDG activity of bone marrow from baseline. 
9.5 
Progressive Disease (PD) 
Patients undergoing CT must meet one of the following criteria for PD: 
• 
An individual node/lesion must be abnormal with the following: 
o 
Longest diameter >1.5 cm and 
o 
Increase by ≥ 50% from the cross product of the longest diameter and perpendicular 
diameter nadir and 
o 
Increase in the longest diameter or shortest diameter from nadir: 
 
0.5 cm for lesions ≤ 2 cm 
 
1.0 cm for lesions >2cm 
• 
For patients with splenomegaly, the splenic length must increase by >50% of the extent 
of its prior increase above baseline. If no prior splenomegaly, it must increase by at 
least 2 cm from baseline. 
• 
New or recurrent splenomegaly. 
• 
New or clear progression of pre-existing non-measured lesions. 
• 
Regrowth of previously resolved lesions. 
• 
A new node >1.5 cm in any axis. 
• 
A new extranodal site >1.0 cm in any axis; if <1.0 cm in any axis, its presence must be 
unequivocal and must be attributable to lymphoma. 
• 
Assessable disease of any size unequivocally attributable to lymphoma. 
• 
New or recurrent bone marrow involvement. 
Patients undergoing PET/CT must meet one of the following criteria for PD: 
• 
Deauville score of 4 or 5 with an increase in intensity of uptake from baseline. 
• 
New FDG-avid foci consistent with lymphoma (If uncertain regarding the etiology of a 
new lesion, biopsy or interval scan may be considered). 
NOTE: Patients with isolated lymphocytosis shall not constitute progression in the absence 
of other findings. 
 


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9.6 
Criteria for PET/CT Reporting  
Patients who undergo PET/CT as part of their interim, on-treatment, and end of treatment 
staging assessments should be assessed according to the following scoring system. 
1. No uptake above background. 
2. Uptake ≤ mediastinum. 
3. Uptake >mediastinum but ≤ liver. 
4. Uptake moderately greater than liver. 
5. Uptake markedly higher than liver and/or new lesions. 
X 
New areas of uptake unlikely to be related to lymphoma. 
For further information regarding the Deauville scoring system, please refer to Barrington et al, J 
Clin Oncol 201435. 


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10. 
Study Parameters 
1. All pre-study scans should be done ≤ 4 weeks prior to registration. 
2. All other pre-study assessments should be done ≤ 2 weeks prior to registration. 
Procedures 
Screening 
Cycle 1* 
(1 cycle=28 Days) 
Cycle 2-Cycle 6* 
Cycle 7 and 
Subsequent 
Cycles12* 
Every 3 
Cycles* 
Off 
Treatment14 
Follow-
Up16 
Day 1 
+/- 1 
day 
Day 8 
+/- 1 
day 
Day 15 
+/- 1 
day 
Day 22 
Day 1 
+/- 3 
days 
Day 8 
+/- 3 
days 
Day 15 
+/- 3 
days 
Day 22 
BREAK 
Day 1 
Every 12 
Weeks 
Written Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Disease Characteristics1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/Surgical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Assessment of Baseline 
Signs & Symptoms 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Exam including 
Weight 
X 
X 
 
X 
 
X 
 
 
 
X12 
 
X 
 
Vital Signs 
(Temperature, Pulse, 
Blood Pressure) 
X 
X 
 
X 
 
X 
 
 
 
X12 
 
X 
 
Performance Status 
X 
X 
 
 
 
X 
 
 
 
X12 
 
X 
 
CBC/Differential/Platelets2 
X 
X 
 
X 
X 
X2 
 
X2 
 
X2 
 
X 
 
Chemistry3 
X 
X 
 
X 
 
X3 
 
 
 
X3 
 
X 
 
PT/INR 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Lactate Dehydrogenase 
(LDH) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Vitamin D Level4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Peripheral Blood Flow 
Cytometry 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Pregnancy Test5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
PET/CT 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Chest/Abdomen/Pelvic 
MRI or CT6 
 
 
 
 
 
 
 
 
 
 
X13 
X 
 
Bone Marrow Aspirate 
and Biopsy7 
X 
 
 
 
 
 
 
 
 
 
 
X7 
 


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Procedures 
Screening 
Cycle 1* 
(1 cycle=28 Days) 
Cycle 2-Cycle 6* 
Cycle 7 and 
Subsequent 
Cycles12* 
Every 3 
Cycles* 
Off 
Treatment14 
Follow-
Up16 
Day 1 
+/- 1 
day 
Day 8 
+/- 1 
day 
Day 15 
+/- 1 
day 
Day 22 
Day 1 
+/- 3 
days 
Day 8 
+/- 3 
days 
Day 15 
+/- 3 
days 
Day 22 
BREAK 
Day 1 
Every 12 
Weeks 
Bone Marrow 
Conventional 
Cytogenetics and FISH8 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Pathology Review with 
Ki67 Assessment9 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Research Specimens10 
 
X10 
 
 
 
 
 
 
 
 
X10 
X10 
 
Treatment 
Administration11 
 
X 
X11 
X 
 
X11 
X11 
X11 
 
X11 
 
 
 
Concomitant Medication 
Review 
X 
X 
 
X 
 
X 
 
 
 
X12 
 
X 
 
Adverse Events 
Assessment 
 
X 
 
X 
 
X 
 
 
 
X12 
 
X15 
 
Survival Status 
 
 
 
 
 
 
 
 
 
 
 
 
X 
* 
Scheduled Visits: +/-3 day window is allowed for scheduled ixazomib therapy, required tests and/or visits except as otherwise noted. Delay due to holidays, 
weekends, bad weather or other unforeseen circumstances will be permitted. 
1 
Record date of diagnosis and stage. 
2 
CBC with differential and platelet count which includes WBC, ANC, Platelets, Hemoglobin, and Hematocrit required as noted below. 
Phase I: 
Days 1, 8, 15 and 22 of Cycle 1; Days 1 and 15 of Cycle 2 and Cycle 3 (patients with ANC <1000 and/or platelets <100,000/mm3 on Day 15 should 
have blood counts done on Day 22 for Cycle 2 and 3 only); and Day 1 of subsequent cycles. Phase I completed November 25, 2019. 
Phase II: Days 1 and 15 of Cycle 1 for which a clinic visit is required. Patients will be required to be seen in clinic on Day 1 of Cycles 2-7, then every 3 cycles 
thereafter. Labs are only required on the days patients are seen in clinic. 
Results known prior to treatment administration. Patients experiencing cytopenias should have additional labs drawn as clinically indicated at the discretion 
of the treating physician. 
3 
Albumin, BUN/creatinine, uric acid, sodium, potassium, chloride, glucose, calcium, alkaline phosphatase, AST, ALT, total bilirubin, and total protein. Days 1 
and 15 of Cycle 1 for which a clinic visit is required. Patients will be required to be seen in clinic on Day 1 of Cycles 2-7, then every 3 cycles thereafter. Labs 
are only required on the days patients are seen in clinic. 
NOTE: Patients with a history of hepatitis B or C must have a negative peripheral blood Polymerase Chain Reaction (PCR) and may not be positive for 
Hepatitis B surface antigen. 
 


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4 
25(OH) Vitamin D level. 
5 
Required for sexually active females of child-bearing potential. 
6 
PET/CT may be substituted for CT Chest/Abdomen/Pelvis at the discretion of the investigator. 
7 
Bone Marrow Biopsy to include: Aspirate and core biopsy morphologic evaluation and flow cytometry. Bone marrow biopsy will be repeated at the time of 
suspected CR for patients with involvement at the time of enrollment. Optional bone marrow biopsies and aspirates will be performed as clinically indicated 
at the end of therapy and/or time of progression. 
8 
Bone marrow samples will be sent for conventional cytogenetics, FISH for t(11;14) and FISH for del(17p) [conventional cytogenetics, FISH for t(11;14) and 
FISH for del(17p) may also be done on tumor tissue samples (nodal or extranodal) in lieu of or in addition to bone marrow review]. 
9 
Pathologists at the participating site must review available tissue samples to confirm the diagnosis of MCL. If a pathology review has already been completed 
in the routine care of the patient, then additional review is not required. All patients should have an assessment of Ki67 performed on available tissue. Tissue 
used for pathology review should ideally be from the time of relapse but pre-treated tissue can be used if that is the only available sample. 
10 Research samples shall be obtained at the time of screening/study entry, after cycle 3, at time of suspected CR, and at the end of therapy or time of 
progression. Refer to Section 13 for details. 
Screening/Study Entry 
Peripheral Blood: Two 6 mL in EDTA tubes 
Bone Marrow: One 10 mL in EDTA tube 
FFPE: Block preferred or 1 H&E slide plus 10 unstained slides 
After Cycle 3 (up to 5 days before Cycle 4, Day 1) 
Peripheral Blood: Two 6 mL in EDTA tubes 
At time of Suspected CR 
Peripheral Blood: Two 6 mL in EDTA tubes 
End of Therapy/At Time of Progression (within 45 days of last dose of study medication) 
Peripheral Blood: Two 6 mL in EDTA tubes 
NOTE: If sufficient bone marrow and tumor tissue are available, submission is mandatory). No bone marrow biopsy/aspirate or tissue biopsy should be 
performed solely for the purposes of obtaining research samples. 
11 Patients will receive ixazomib orally on days 1, 8, and 15 of each 28 day cycle (1 cycle=28 days) [Section 6.1.1 for dosing administration]. Ixazomib shall be 
administered in the clinic on Cycle 1, Day 1 and Cycle 1, Day 15 (Day 8 can be administered at home). For subsequent cycles, ixazomib doses on Days 8 
and 15 can be administered at home. Ixazomib Medication Diary will be reviewed for compliance and collected every cycle after Cycle 1 (Appendix III). Ibrutinib 
shall be administered orally daily on days 1-28 [Section 6.1.2 for dosing administration]. Ibrutinib Medication Diary will be reviewed for compliance and 
collected every cycle (Appendix IV). See Section 6.2 for Phase I and Section 6.3 for Phase II dosing instructions and Section 6.5 for dose delays/modifications. 
NOTE: If patient continues on study therapy after Cycle 6, the visit schedule may be increased to every 3 cycles starting with Cycle 7 and study medication 
will be dispensed for 3 cycles. Medication Diaries will be collected every 3 cycles when patient returns to clinic. 
12 If patient continues on study therapy after Cycle 6, the visit schedule may be increased from 4 to 12 weeks starting with Cycle 7 while receiving study therapy 
(Scan schedule will remain unchanged, see footnote 13). Physical exam with weight, vital signs, performance status, blood work, concomitant medication 
review and adverse events assessment will be performed every 12 weeks (Day 1 of every 3 cycles). 
 


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13 While on treatment, patients shall undergo CT chest/abdomen/pelvis (or PET/CT or MRI as clinically indicated per investigator discretion) after cycles 3, 6, 9, 
12 and subsequently every 6 months while on study therapy. Scans should be performed during the 7 days preceding the following cycle (i.e., within 7 days 
of Cycle 4, Day 1). Patients with suspected CR should undergo PET/CT to confirm this. This can be done within 21 days of the restaging CT that 
initially demonstrates potential CR. 
14 Thirty (30) days +/- 7 days after last dose of study therapy. If patient is removed from treatment for reason(s) other than progression, follow with regular tumor 
assessments per standard of care until progression or start of new treatment. Once a patient has initiated a new therapy, no further study-related imaging 
assessments for this study are required. 
15 Patients will be followed for adverse events for 30 days after their last dose of study medication. However, an adverse event occurring at any time after 
discontinuation of study therapy that is felt to be at least possibly related to study therapy should be recorded. 
16 There are no study-related visits required after the end of treatment visit. However, as available to the participating investigators, survival status every 6-12 
months for participating patients should be updated and recorded. In addition, the first subsequent therapy shall be reported. 
 


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11. 
Drug Formulation and Procurement 
11.1 
Ixazomib36 
11.1.1 Other Names 
Ixazomib is also referred to as MLN9708 or MLN2238. 
11.1.2 Classification  
Ixazomib is an oral proteasome inhibitor. 
11.1.3 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; do not store above 86°F (30°C); do not freeze. Ensure that the drug 
is used before the retest expiry date provided. 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. 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 
(starting with Cycle 7, may receive 3 cycles at a time). Patients should be instructed 
not to store the medication above 86°F (30°C); do not freeze for the duration of each 
cycle. Patients should be instructed to return their empty blister packs to the 
investigative site, rather than discarding them. Reconciliation will occur accordingly 
when the patient returns for their next cycle of take-home medication. Any extreme in 
temperature should be reported as an excursion and should be dealt with on a case-
by-case basis. 
Because ixazomib is an investigational agent, it should be handled with due care. 
Patients should be instructed not to chew, break, or open capsules. In case of contact 
with broken capsules, raising dust should be avoided during the clean-up operation. 
The product may be harmful by inhalation, ingestion, or skin absorption. Gloves and 
protective clothing should be worn during cleanup and return of broken capsules and 
powder to minimize skin contact. 
The area should be ventilated and the site washed with soap and water after material 
pick-up is complete. The material should be disposed of as hazardous medical waste 
in compliance with federal, state, and local regulations. 
In case of contact with the powder (e.g., from a broken capsule), skin should be 
washed immediately with soap and copious amounts of water for at least 15 minutes. 
In case of contact with the eyes, copious amounts of water should be used to flush the 
eyes for at least 15 minutes. Medical personnel should be notified. Patients are to be 
instructed on proper storage, accountability, and administration of ixazomib, including 
that ixazomib is to be taken as intact capsules. 
11.1.4 Dose Specifics 
Ixazomib is dispensed in a 4-week supply (starting with Cycle 7, may be dispensed in 
12-week supply). The capsules will be individually packaged using cold-form foil-foil 
blisters that are in child-resistant carton. There will be 3 capsules in each wallet/carton. 
Patients will take one capsule on days 1, 8, and 15 of each cycle. 
Refer to Section 6.5.1 and Table 6-3, Table 6-4 and Table 6-5 for Dose Delays and 
Modifications details. 


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11.1.5 Route of Administration 
Ixazomib will be administered orally. Patients should be instructed to swallow ixazomib 
capsules whole, with water, and not to break, chew, or open the capsules. Ixazomib 
should be taken on an empty stomach (no food or drink) at least 1 hour before or at 
least 2 hours after food. Each capsule should be swallowed separately with a sip of 
water. A total of approximately 8 ounces (240 mL) of water should be taken with the 
capsules. 
Missed doses can be taken as soon as the patient remembers if the next scheduled 
dose is 72 hours or more away for all cycles aside from Cycle 1 of the phase 1 portion 
of the study. Patients with dose delays in Cycle 1 shall be managed as described in 
Section 6.2. A double dose should not be taken to make up for a missed dose. If the 
patient vomits after taking a dose, the patient should not repeat the dose but should 
resume dosing at the time of the next scheduled dose. 
Ixazomib Medication Diary will be reviewed for compliance and collected every cycle 
for Cycle 1-Cycle 6 (Appendix III). Starting with Cycle 7, Ixazomib Medication Diary 
will be reviewed and collected every 3 cycles. 
11.1.6 Drug Interactions 
Avoid concomitant administration of ixazomib with strong CYP3A inducers (such as 
rifampin, phenytoin, carbamazepine, and St. John’s Wort). 
11.1.7 Agent Availability 
Ixazomib capsules will be supplied by Takeda Pharmaceuticals. 
The ixazomib drug product is provided in strengths of 4.0-, 3.0-, and 2.3-mg capsules 
as the active boronic acid. The different dose strengths are differentiated by both 
capsule size and color as described below: 
Dose Strength 
Capsule Size 
Capsule Color 
4.0 mg 
Size 4 
Ivory 
3.0 mg 
Size 3 
Light gray 
2.3 mg 
Size 2 
Light pink 
The initial supply of ixazomib will be sent directly to the site upon site activation. As 
needed, ixazomib may be requested by the principal investigator (or their authorized 
designees) at each participating institution. The investigator, or a responsible party 
designated by the investigator, must maintain a careful record of the receipt, 
disposition, and return/destruction (site’s drug destruction policy must be reviewed and 
approved by PrECOG before any study drug can be destroyed at a site) of ixazomib. 
11.1.8 Agent Ordering 
PrECOG will be responsible for ordering drug for re-supply to the site. Requests for 
shipments of ixazomib will be coordinated between PrECOG and Takeda. 
11.1.9 Agent Accountability 
lxazomib will be stored in a secure location. Only authorized pharmacy and study staff 
will have access to this agent. Drug accountability will be performed by PrECOG. 
 


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11.1.10 Side Effects 
Adverse drug reactions such as thrombocytopenia, diarrhea, fatigue, nausea, 
vomiting, and rash have been associated with ixazomib treatment. Management 
guidelines regarding these events are outlined below. Further details of management 
of ixazomib AEs are described in the ixazomib IB. 
11.1.10.1 
Prophylaxis Against Risk of Reactivation of Herpes Infection 
Patients may be at an increased risk of infection including reactivation of 
herpes zoster and herpes simplex viruses. Antiviral therapy such as 
acyclovir, valacyclovir, or other antivirals may be initiated as clinically 
indicated.  
11.1.10.2 
Nausea and/or Vomiting 
Standard anti-emetics including 5-hydroxytryptamine 3 serotonin receptor 
antagonists are recommended for emesis if it occurs once treatment is 
initiated; prophylactic anti-emetics may also be considered at the 
physician’s discretion. Dexamethasone should not be administered as an 
anti-emetic. Fluid deficit should be corrected before initiation of study drug 
and during treatment. 
11.1.10.3 
Diarrhea 
Prophylactic antidiarrheals will not be used in this protocol. However, 
diarrhea should be managed according to clinical practice, including the 
administration of antidiarrheals once infectious causes are excluded. Fluid 
intake should be maintained to avoid dehydration. Fluid deficit should be 
corrected before initiation of treatment and during treatment. 
11.1.10.4 
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 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 (Table 6-4). 
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). Rare risks are Stevens-
Johnson Syndrome, a severe and potentially life-threatening rash with 
skin peeling and mouth sores, toxic epidermal necrolysis (TEN) and drug 


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reaction with eosinophilia and systemic symptoms (DRESS syndrome) 
which should be managed symptomatically according to standard medical 
practice. Punch biopsies for histopathological analysis are encouraged at 
the discretion of the investigator. 
11.1.10.5 
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 (Table 
6-3). 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. 
11.1.10.6 
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. Ixazomib administration should be modified as noted as 
per dose modification recommendations in the protocol when neutropenia 
occurs (Table 6-3). Therapy can be reinitiated at a reduced level upon 
recovery of ANCs. 
11.1.10.7 
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. 
11.1.10.8 
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. 
11.1.10.9 
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 


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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. 
11.1.10.10 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. 
11.2 
Ibrutinib37 
11.2.1 Other Names 
Additional names for ibrutinib include Imbruvica® and PCI-32765. 
11.2.2 Classification 
Ibrutinib is an oral inhibitor of Bruton’s tyrosine kinase. Ibrutinib is approved for the 
treatment of patients with Mantle Cell Lymphoma and will be obtained 
commercially. 
11.2.3 Mode of Action 
Ibrutinib is a small-molecule inhibitor of BTK. Ibrutinib forms a covalent bond with 
cysteine residue in the BTK active site, leading to inhibition of BTK enzymatic activity. 
BTK is a signaling molecule of the B-cell antigen receptor (BCR) and cytokine receptor 
pathways. BTK’s role in signaling through the B-cell surface receptors results in 
activation of pathways necessary for B-cell trafficking, chemotaxis, and adhesion. 
Nonclinical studies show that ibrutinib inhibits malignant B-cell proliferation and survival 
in vivo as well as cell migration and substrate adhesion in vitro. 
11.2.4 Storage and Stability 
Ibrutinib is provided as white opaque 140 mg capsules marked with “ibr 140 mg” in 
black ink. Bottles should be stored at room temperature 20°-25°C (68°-77°F). 
Excursions are permitted between 15°C and 30°C (59°F to 86°F). 
11.2.5 Dose Specifics 
Ibrutinib shall be obtained through available commercial pharmacies. Patients should 
take the dose as prescribed by the treating investigator, with a maximum dose of 
560 mg (4 tablets). Doses should be taken at the same time each day. Ibrutinib should 
be swallowed whole with water and the tablets should not be opened, broken, or 
chewed. If a dose of ibrutinib is not taken at the scheduled time, it can be taken as 
soon as possible on the same day with a return to the normal schedule the following 
day. Extra capsules of ibrutinib should not be taken to make up for the missed dose. 
Refer to Section 6.5.2 and Table 6-6 for Dose Delays and Modifications details. 
11.2.6 Route of Administration 
Ibrutinib shall be consumed orally, with the full capsules swallowed for each dosing. 
Ibrutinib Medication Diary will be reviewed for compliance and collected every cycle for 
Cycle 1-6 [Appendix IV]. Starting with Cycle 7, Ibrutinib Medication Diary will be 
reviewed and collected every 3 cycles. 
11.2.7 Drug Interactions 
Ibrutinib is primarily metabolized by cytochrome P450 enzyme 3A. 


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11.2.7.1 
CYP3A Inhibitors 
Concomitant use of strong CYP3A inhibitors which would be taken 
chronically (e.g., ritonavir, indinavir, nelfinavir, saquinavir, boceprevir, 
telaprevir, nefazodone) is not recommended. For short-term use 
(treatment for 7 days or less) of strong CYP3A inhibitors (e.g., antifungals 
and antibiotics such as ketoconazole, itraconazole, voriconazole, 
posaconazole, clarithromycin, telithromycin) consider interrupting ibrutinib 
until the CYP3A inhibitor is no longer needed. Reduce ibrutinib to 140 mg 
if a moderate CYP3A inhibitor must be used (e.g., fluconazole, darunavir, 
erythromycin, 
diltiazem, 
atazanavir, 
aprepitant, 
amprenavir, 
fosamprenavir, crizotinib, imatinib, verapamil, and ciprofloxacin). 
Patients taking concomitant strong or moderate CYP3A4 inhibitors should 
be monitored more closely for signs of ibrutinib toxicity. 
Avoid grapefruit and Seville oranges during ibrutinib treatment, as these 
contain moderate inhibitors of CYP3A. 
11.2.7.2 
CYP3A Inducers 
Administration of ibrutinib with rifampin, a strong CYP3A inducer, 
decreased ibrutinib 
Cmax and AUC by approximately 13- and 10-fold, 
respectively. 
Avoid concomitant use of strong CYP3A inducers (e.g., carbamazepine, 
rifampin, phenytoin and St. John’s Wort). Consider alternative agents 
with less CYP3A induction. 
11.2.8 Availability 
Ibrutinib shall be obtained through commercial or other sources and shall not be 
provided by the study. 
11.2.9 Side Effects 
There are no listed contra-indications for ibrutinib. 
11.2.9.1 
Hemorrhage 
Fatal bleeding events have occurred in patients treated with ibrutinib. 
Grade 3 or higher bleeding events (subdural hematoma, gastrointestinal 
bleeding, hematuria and post procedural hemorrhage) have occurred in 
up to 6% of patients. Bleeding events of any grade, including bruising and 
petechiae, occurred in approximately half of patients treated with ibrutinib. 
The mechanism for the bleeding events is not well understood. 
Ibrutinib may increase the risk of hemorrhage in patients receiving 
antiplatelet or anticoagulant therapies. 
Consider the benefit-risk of withholding ibrutinib for at least 3 to 7 days 
pre and post-surgery depending upon the type of surgery and the risk of 
bleeding. 
11.2.9.2 
Infections 
Fatal and non-fatal infections have occurred with ibrutinib therapy. Grade 
3 or greater infections occurred in 14% to 26% of patients. Cases of 
progressive multifocal leukoencephalopathy (PML) have occurred in 
patients treated with ibrutinib. Monitor patients for fever and infections and 
evaluate promptly. 


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11.2.9.3 
Cytopenias 
Treatment-emergent Grade 3 or 4 cytopenias including neutropenia 
(range, 19 to 29%), thrombocytopenia (range, 5 to 17%), and anemia 
(range, 0 to 9%) occurred in patients treated with ibrutinib. 
11.2.9.4 
Atrial Fibrillation 
Atrial fibrillation and atrial flutter (range, 6 to 9%) have occurred in patients 
treated with ibrutinib, particularly in patients with cardiac risk factors, acute 
infections, and a previous history of atrial fibrillation. Periodically monitor 
patients clinically for atrial fibrillation. Patients who develop arrhythmic 
symptoms (e.g., palpitations, lightheadedness) or new onset dyspnea 
should have an ECG performed. If atrial fibrillation persists, consider the 
risks and benefits of ibrutinib treatment and dose modification. 
11.2.9.5 
Second Primary Malignancies 
Other malignancies (range, 5 to 14%) including non-skin carcinomas 
(range, 1 to 3%) have occurred in patients treated with ibrutinib. The most 
frequent second primary malignancy was non-melanoma skin cancer 
(range, 4 to 11 %). 
11.2.9.6 
Tumor Lysis Syndrome 
Tumor lysis syndrome has been reported with ibrutinib therapy. Monitor 
patients closely and take appropriate precautions in patients at risk for 
tumor lysis syndrome (e.g. high tumor burden). 
11.2.10 Nursing/Patient Implications 
Based on findings in animals, ibrutinib can cause fetal harm when administered to a 
pregnant woman. Ibrutinib caused malformations in rats at exposures 14 times those 
reported in patients with MCL and 20 times those reported in patients with Chronic 
Lymphocytic Leukemia or Waldenström’s Macroglobulinemia, receiving the ibrutinib 
dose of 560 mg per day and 420 mg per day, respectively. Reduced fetal weights were 
observed at lower exposures. Advise women to avoid becoming pregnant while taking 
ibrutinib. If this drug is used during pregnancy or if the patient becomes pregnant while 
taking this drug, the patient should be apprised of the potential hazard to a fetus. 
Women who are nursing are not eligible for this study and any woman who becomes 
pregnant over the course of the study will be removed from study therapy. 
Ibrutinib is a Pregnancy Category D drug. 
Please refer to the commercial package insert for full prescribing information. 


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12. 
Statistical Considerations 
12.1 
Study Design & Sample Size Considerations 
This study will be conducted in two phases: Phase I and Phase II. The phase I portion will 
include dose-escalation and de-escalation designed to identify the RP2D/MTD for the 
combination of ixazomib and ibrutinib for the phase II portion of the study. Based on the 
planned dose escalation and de-escalation described below, we will enroll a minimum of 6 
patients (assuming DLT on levels 1 & -1) and a maximum of 12 patients (assuming 6 patients 
accrued to two dose levels) on the phase I portion of the study. 
Phase I Summary: Three patients were enrolled to Dose Level 1 with no DLTs during the 28 
day assessment period. Nine patients were enrolled to Dose Level 2. Five of the nine patients 
completed the 28 day assessment period with no DLTs. One patient experienced a DLT. Three 
of the nine patients were not evaluable for DLT and were replaced. One patient was 
inadvertently given neulasta prior to receiving Cycle 2, Day 1 therapy; another patient 
unintentionally took Day 15 ixazomib on Day 9; and one patient forgot to take ibrutinib the last 
8 days of Cycle 1 unrelated to any toxicities. Phase I was completed November 25, 2019. 
Dose Level 2 is the recommended Phase 2 dose. 
12.1.1 Phase I 
For the phase I portion of the study, the primary objective will be to evaluate safety 
and toxicity of ixazomib when administered in combination with ibrutinib for patients 
with relapsed/refractory MCL, which we will assess by determining the MTD/RP2D as 
described in Section 6.2.1. We will determine this using a standard 3+3 design. The 
first cohort of 3 patients will be accrued to Dose Level 1 and will start therapy with 
ixazomib and ibrutinib. These 3 patients will be evaluated for a DLT during the first 28-
day cycle, with DLT defined according to Table 6-2. If zero patients experience a DLT, 
the next cohort of 3 will be accrued at the next dose level. If 1 patient experiences a 
DLT, the next cohort of 3 will be accrued at the same dose level to further evaluate 
safety. If 2 or 3 patients experience a DLT, that level will be deemed too toxic and next 
cohort of 3 will be accrued to Dose Level (-1). If Dose Level (-1) proves too toxic, the 
study will end. If 1 or fewer out of 6 patients experience a DLT, then that level will be 
deemed the RP2D and the phase I trial will end. 
 
 
 
 
 
 
 
 
The table below summarizes the probabilities of dose escalation and de-escalation for 
a range of true DLT rates for the combination treatment using the standard 3+3 design. 
 
True DLT Rate 
1% 
5% 
10% 
15% 
20% 
30% 
40% 
50% 
Probability of Dose escalation 
.999 
.973 
.906 
.814 
.709 
.494 
.309 
.172 
Probability of Dose de-escalation 
.001 
.027 
.094 
.186 
.291 
.506 
.691 
.828 
Dose Level 
Ixazomib 
Days 1, 8, 15 of a 
28 Day Cycle 
Ibrutinib 
Days 1-28 of a 
28 Day Cycle 
-1  
3 mg 
420 mg 
1 
Starting Dose 
3 mg 
560 mg 
2  
4 mg 
560 mg 


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12.1.2 Phase II 
For the phase II portion of the study, we will accrue patients to two cohorts (BTK-naïve 
[Cohort A] and BTK-pretreated [Cohort B]) simultaneously. The primary endpoint for 
the phase II study will be the CR rate, with planned comparison to historical controls. 
The target CR rate for the BTK-naïve cohort will be 40%, based on a historical rate of 
21% for single agent ibrutinib, and the target CR rate for the BTK-pretreated cohort 
will be 23% based on a single agent CR rate of 8% for bortezomib. As a result, we will 
accrue 31 eligible, treated patients to each cohort for a total of 62 eligible, treated 
patients for the phase II study. To assure an adequate number of eligible, treated 
patients, up to 36 patients will be enrolled to each arm. 
12.1.2.1 
Administrative Changes: August 7, 2020 
Due to administrative and/or industry sponsor reasons, it was decided that 
enrollment to Cohort B (BTK-pretreated cohort) will be stopped. The total 
number of BTK-pretreated patients enrolled was 2 as of August 7, 2020. 
Enrollment to Cohort A (BTK-naïve cohort) will continue however, and up 
to the full accrual of 36 patients as initially planned. To supplement the 
enrollment of 36 patients in Cohort A, the BTK-naïve patients that were 
treated at the R2PD in Phase I (n=6) will contribute to the 36 patients 
needed for full accrual in Phase II. 
The statistical operating characteristics, and primary endpoint, of the BTK-
naïve cohort remains the same as indicated in Section 12.1.2 above. 
12.2 
Phase II 
12.2.1 Primary Objectives 
Patients will receive oral ixazomib and ibrutinib, in combination, at the RP2D. The 
efficacy of ixazomib and ibrutinib therapy will be assessed using CR rate. The CR rate 
will be the defined as the percentage of patients who achieve a CR (confirmed by BM 
biopsy) within the first 12 months of initiating treatment. Patients who are unevaluable 
or whose CR is not confirmed by BM biopsy will be included in the denominator as 
non-responders when computing the CR rate. Relapse/progression will be defined as 
either frank progression by clinical or laboratory exam (i.e., increased circulating 
monoclonal lymphocytes) or progressive disease by restaging CT, defined according 
to standard criteria.34 Patients with isolated lymphocytosis shall not constitute 
progression in the absence of other findings. 
In order to facilitate rapid accrual and to determine evidence of efficacy in multiple 
clinical settings, patients in the phase II portion of the study will be divided into two 
cohorts. Cohort A will include BTK-naïve patients. Cohort B will include BTK-
pretreated patients. August 7, 2020: BTK-pretreated cohort closed. 
Based on a historical single-agent 21% CR rate of ibrutinib in relapsed/refractory 
MCL4, we would consider a CR rate of 40% for the combination therapy in the BTK-
naïve cohort (Cohort A) to be of interest. To detect an improvement of CR rate to 40% 
from the historical CR rate of 21%, a total of 31 patients will be accrued to Cohort A. 
This design will have 86% power and 10% one-sided Type I error using an exact 
binomial test and the null hypothesis will be rejected if CR is observed in 10 or more 
patients. 
For the BTK-pretreated cohort (Cohort B) a CR rate of 23% will be of interest and a 
CR rate of 8%, based on a previously reported single agent CR rate for bortezomib, 
will not be of interest. To detect an improvement in CR rate to 23% from 8%, a total of 
31 patients will also be accrued to Cohort B. This design will have 87% power and 


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10% one-sided Type I error using an exact binomial test and the null hypothesis will 
be rejected if CR is observed in 5 or more patients. August 7, 2020: BTK-pretreated 
cohort closed. 
12.2.2 Secondary Objectives 
The secondary objectives for phase I and II of this study will include evaluation of 
regimen-related toxicities for the combination of ixazomib and ibrutinib in 
relapsed/refractory MCL; evaluation of the ORR for the drug combination; and to 
evaluate the median PFS and OS for patients treated with the drug combination. 
To describe the ORR for phase I and II, descriptive statistics will be used to compute 
the proportion of patients who achieved complete and partial response to the drug 
combination. A 90% exact binomial confidence interval (CI) around the overall 
response rate estimate from the phase II portion of this study will be computed for 
descriptive purposes. Based on the planned dose escalation and de-escalation, 
between 6 and 12 patients will be accrued to the phase I portion of this study. 
The median PFS and OS will be evaluated using the Kaplan Meier method, separately 
for phase I and II patients. The estimates from the phase I will give preliminary 
information about efficacy which will be further assessed in the phase II patients. The 
patients included in survival efficacy analysis will include eligible and treated patients 
only. 
All enrolled patients who receive treatment, irrespective of eligibility, will be reviewed 
for toxicities attributable to treatment. The phase I assessment of treatment-related 
toxicities of Grade 3 or higher will be described using proportions. In phase II, if 72 
patients (up to 36 in each cohort; August 7, 2020: BTK-pretreated cohort closed.) 
are treated and assuming there is an equal rate of toxicity in both cohorts, the 
maximum width of 90% CI on the proportion of treatment-related grade 3 or higher 
toxicity in both cohorts, combined, will be no wider than 20%. The probability of 
observing at least one rare toxicity (true rate of 5%) is approximately 97.5%. August 
7, 2020: Among 36 treated patients, the maximum 2-sided width of a 90% CI around 
the proportion of treatment related Grade 3 or higher toxicity will be within 29.4% and 
the probability of seeing ≥1 rare toxicity if such toxicity has a true prevalence of 5% for 
example is 84.2%. 
We will also describe and tabulate all adverse events, regardless of treatment 
attribution. 
To assure an adequate number of eligible, treated patients, up to 36 patients will be 
enrolled to each arm. This will result in a maximum accrual of 84 patients for the full 
study (August 7, 2020: BTK-pretreated cohort closed; updated per Section 
12.1.2.1). 
The efficacy assessment population will include all eligible and treated patients while 
the adverse events assessment population will include all treated patients, regardless 
of eligibility. 
12.3 
Planned Analyses 
12.3.1 Toxicity Monitoring Plan 
Toxicity and adverse events for all enrolled patients will be monitored throughout the 
conduct of the study. For the phase I portion of the study, all patients will be evaluated 
for the development of a DLT as defined in Section 6.2.1. Those patients experiencing 
a DLT shall be removed from study therapy and the dosing for subsequent cohorts of 
patients shall be adjusted as described in the protocol. 
 


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All other toxicities or adverse events encountered for all patients from the time of study 
treatment initiation (any toxicities or adverse events related to a protocol-mandated 
intervention after informed consent is signed will also be included) until the withdrawal 
of consent or the patient has been off study therapy for 30 days shall be reported, 
regardless of attribution. We shall review all reported adverse events and shall present 
recurrent adverse events, grade 3-5 adverse events, or other adverse events felt to 
be clinically significant and related to study therapy in tabular form. 
In addition to the planned tabular description of encountered adverse events, PrECOG 
shall convene a data safety monitoring board to review the safety of all enrolled 
patients and ensure compliance with all appropriate guidelines. 
12.3.2 Analyses of Correlative Studies 
 
 
 
 
 
 
 
 
 
 
 
 
 


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13. 
Laboratory and Pathology Correlative Studies 
13.1 
Correlative Studies 
13.1.1 Overview 
In addition to the planned primary assessments of safety/tolerability and efficacy of the 
combination, we will also evaluate several candidate predictive and prognostic 
biomarkers in MCL through analysis of mandatory collected tissue samples, bone 
marrow aspirates, and peripheral blood. In addition, patient samples collected at pre-
specified time points shall be sent to the ECOG-ACRIN Central Biorepository 
Pathology Facility (E-A CBPF) to be stored and used for future study. 
Several of the planned analyses shall take place at the local site under the supervision 
of the treating investigators while others shall be conducted centrally through the use 
of the repository. 
NOTE: If sufficient bone marrow and tumor tissue are available, submission is 
mandatory. No bone marrow biopsy/aspirate or tissue biopsy should be performed 
solely for the purposes of obtaining research samples. 
13.1.2 Methodology 
Local Assays: 
Ki67 Proliferative Index: The Ki67 proliferative index shall be assessed for all tumor 
samples used to confirm the diagnosis of relapsed MCL for the purposes of this study. 
This shall be conducted according to each institutional practice and shall be reported 
as a percentage of cells expressing Ki67. This shall occur at one time point at the time 
of study entry. Patients for whom there is no tissue available to conduct this 
assessment will NOT require repeat biopsies simply for the purposes of conducting 
this assessment. 
Cytogenetic Analyses: Each site shall submit a bone marrow aspirate sample and/or 
a tumor tissue sample (nodal or extranodal) for cytogenetic assessments. These 
assessments shall be conducted locally according to institutional standards. In 
addition to a conventional cytogenetic assessment, samples shall be assessed by 
FISH for t(11;14) and FISH for del(17p). Patients shall require 1 (one) sample (either 
from the bone marrow or from involved tissue) with preference given towards using a 
sample that is known to be involved with MCL. 
Vitamin D Level Assessment: All patients at the time of study enrollment will have a 
25(OH) Vitamin D3 level drawn by peripheral blood draw. This one-time assessment 
will be processed locally. 
Centrally Processed Assays: 
Peripheral blood and involved tissue samples shall be sent to a central lab for future 
use. Planned assessments include the following: 
PSMB1 Allele Frequency: Given the potential association of the PSMB1 P11A (G 
allele) with prolonged PFS and OS in patients treated with bortezomib, we will assess 
the allelic frequency among enrolled patients. All patients will provide a peripheral 
blood sample at the time of enrollment that will be utilized to evaluate allelic frequency. 
This shall be determined using a TaqMan SNP assay. 
BTK Mutational Analysis: All patients will have a mutational analysis of BTK and 
PLC-γ2 performed on involved tissue samples. This will be performed using the 
commercially available NeoGenomics assay and will require Formalin-Fixed, Paraffin-
Embedded (FFPE) tissue or bone marrow from aspirate. 
Future studies: We will collect and store samples for future correlative studies and 
will be incorporated into this protocol as future amendments as they are developed. 


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13.1.3 Sample Collection 
Kits will be supplied for research samples. Instructions will be provided in the kit. 
Planned research assessments and required submissions: 
Screening/Study Entry 
Local, per Institutional Practice 
• 
Ki67 assessment 
• 
Conventional cytogenetics 
• 
FISH for t(11;14) 
• 
FISH for del(17p) 
• 
25(OH) Vitamin D 
Research Samples 
• 
Peripheral Blood: Two 6 mL in EDTA tubes 
• 
BM aspirate: 10 mL in EDTA tube 
• 
Formalin-Fixed, Paraffin-Embedded (FFPE) tissue (block preferred or 1 H&E slide 
plus 10 unstained slides) 
After Cycle 3 
Up to 5 days before Cycle 4, Day 1 
Peripheral Blood: Two 6 mL in EDTA tubes 
Suspected CR 
At Time of Suspected CR 
Peripheral Blood: Two 6 mL in EDTA tubes 
End of Therapy/At Time of Progression 
Within 45 days of last dose of study medication 
• 
Peripheral Blood: Two 6 mL in EDTA tubes 
NOTE: If sufficient bone marrow and tumor tissue are available, submission is 
mandatory. No bone marrow biopsy/aspirate or tissue biopsy should be 
performed solely for the purposes of obtaining research samples. 
13.1.4 Research Samples Processing and Shipment 
Instructions, shipping labels, supplies and address will be provided in the kits. 
All samples collected will be labeled with a unique numeric identifier that will be coded 
for patient privacy protection. 
13.1.4.1 
FFPE Tissue Block or Slide Samples 
Sites should submit FFPE tumor tissue blocks or FFPE slides (2 sections 
per slide) plus H&E slide from a tumor tissue block as noted in Section 
13.1.3. Thickness of the sections should be at 4-5 micron. 
Screening/Study Entry samples should be submitted within 1 month of 
patient registration. 
A copy of the pathology report should be sent when the sample is shipped. 
Samples should be shipped Monday-Thursday. Samples will be shipped 
ambient via overnight courier. 


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13.1.4.2 
Bone Marrow (BM) Samples 
Sites should submit BM samples in EDTA tubes as noted in Section 
13.1.3. 
Store in the freezer at ≤ -70°C or colder until shipped to central lab. 
BM samples should be submitted within 4 months of obtaining, as 
applicable. A copy of the BM report should be sent when the sample is 
shipped. Samples should be shipped Monday-Thursday. Samples must 
be shipped on dry ice via overnight courier. 
13.1.4.3 
Peripheral Blood Samples 
Sites should submit peripheral blood samples in EDTA tubes as noted in 
Section 13.1.3. 
EDTA Tube Processing for Plasma and Buffy Coat 
**Process sample within 30 minutes of collection** 
• 
Gently mix blood sample by inversion 10 times (do not shake). 
• 
Place tube immediately on wet ice for 5 minutes. 
• 
Centrifuge at 1200 RPM for 15 minutes at 4°C. If a refrigerated 
centrifuge is not available, spin sample at room temperature (1200 
RPM for 15 minutes). Immediately place the tube on wet ice after 
centrifugation. 
After centrifugation, the plasma layer will be at the top half of the tube. 
The nucleated cells (WBC) will be in a whitish layer, called the “buffy coat”, 
just under the plasma and above the red blood cells. 
Plasma Preparation: 
• 
Using a transfer pipette take the top two-thirds of the plasma and 
transfer plasma into a 15 ml conical centrifuge tube, be careful not to 
disturb the buffy coat layer in the EDTA tube (NOTE: see below for 
buffy coat processing instructions). Centrifuge the 15 ml conical tube 
at 1200 RPM for 15 minutes at 4°C. If a refrigerated centrifuge is not 
available, spin sample at room temperature (1200 RPM for 15 
minutes). Immediately place the conical tube on wet ice after 
centrifugation. 
• 
Transfer equal amounts of plasma into two (2) properly labeled 
polypropylene tubes for cryopreservation being careful not to disturb 
the small PBMC/pellet. 
• 
Store the two aliquots of plasma samples in the freezer at ≤ -70°C or 
colder until they are shipped to central lab. 
Buffy Coat Preparation: 
• 
From the EDTA tube remove and aliquot the “buffy coat”; be careful 
not to disturb the layer of red blood cells. 
• 
Store the aliquot of cells in two (2) properly labeled polypropylene 
tube for cryopreservation. 
• 
Store the sample in the freezer at ≤ -70°C or colder until it is shipped 
to central lab. 


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Plasma and buffy coat samples should be batched together and shipped 
approximately every 4 months. Individual patients should only be included 
in the shipment if all of their samples have been completed. Samples 
should be shipped Monday-Thursday. Samples must be shipped on dry 
ice via overnight courier. 


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14. 
Administrative 
14.1 
Protocol Compliance 
The study shall be conducted as described in this protocol. All revisions to the protocol must 
be discussed with, and be prepared by PrECOG and/or representatives. The Investigator 
should not implement any deviation or change to the protocol or consent without prior review 
and documented approval from PrECOG and/or representatives and the Institutional Review 
Board (IRB) of an amendment, except where necessary to eliminate an immediate hazard(s) 
to study patients. 
If a deviation or change to the approved protocol is implemented to eliminate an immediate 
hazard(s) prior to obtaining IRB approval, notification will be submitted to the IRB for review 
and approval as soon as possible afterward. Documentation of approval signed by the 
chairperson or designee of the IRB(s) should be in the study records. If PrECOG and/or 
representatives provides an amendment that substantially alters the study design or increases 
the potential risk to the patient; the consent form must be revised and submitted to the IRB(s) 
for review and approval; the revised form must be used to obtain consent from patients 
currently enrolled in the study if they are affected by the Amendment; and the new form must 
be used to obtain consent from new patients prior to study entry. Information as to who 
investigators should send correspondence will be provided in additional study documents. 
14.2 
Institutional Review Board (IRB) 
Before study initiation, the Investigator must have written and dated approval from their 
respective IRB for the protocol, consent form, patient recruitment materials/process and any 
other written information to be provided to patients. The Investigator should also provide the 
IRB with a copy of the Investigator Brochure or product labeling, and any updates. 
The Investigator should provide the IRB with reports, updates, and other information (e.g., 
Safety Updates, amendments, and administrative letters) according to regulatory 
requirements, IRB or study site procedures. 
14.3 
Informed Consent Procedures 
Investigators must ensure that patients who volunteer for clinical trials or their legally 
acceptable representative are clearly and fully informed about the purpose, potential risks and 
other information. 
A protocol specific informed consent form (ICF) template will be provided to sites. Preparation 
of the site-specific consent form is the responsibility of the site Investigator and must include 
all applicable regulatory and IRB requirements, and must adhere to Good Clinical Practices 
(GCP) and to the ethical principles that have their origin in the Declaration of Helsinki. All 
changes to the ICF template will be approved by PrECOG and/or their representatives prior to 
implementation. 
In accordance with the Health Information Portability and Accountability Act (HIPAA), the 
consent process will also include written authorization by patients to release medical 
information to allow PrECOG and/or its agents, regulatory authorities, and the IRB of record at 
the study site for access to patient records and medical information relevant to the study, 
including the medical history. This will be documented in the informed consent form or other 
approved form obtained at the time of informed consent per institutional policies. This form 
should also be submitted to PrECOG and/or its agents for review prior to its implementation. 
The Investigator must provide the patient or legally acceptable representative with a copy of 
the consent form and written information about the study in the language in which the patient 
is most proficient. The language must be non-technical and easily understood. The Investigator 
should allow time necessary for patient or patient's legally acceptable representative to inquire 
about the details of the study, then informed consent must be signed and personally dated by 
the patient or the patient's legally acceptable representative and by the person who conducted 


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the informed consent discussion. The patient or legally acceptable representative should 
receive a copy of the signed informed consent and any other written information provided to 
study patients prior to patient's participation in the trial. The investigator is responsible for 
assuring adequate documentation of this process and for storage and maintenance of the 
original signed consent form for each patient/subject.  
The informed consent and any other information provided to patients or the patient's legally 
acceptable representative, should be revised whenever important new information becomes 
available that is relevant to the patient's consent, and should receive IRB approval prior to use. 
The Investigator, or a person designated by the Investigator should inform the patient or the 
patient's legally acceptable representative of all pertinent aspects of the study and of any new 
information relevant to the patient's willingness to continue participation in the study. This 
communication should be documented in the patient record. During a patient's participation in 
the trial, any updates to the consent form and any updates to the written information will be 
provided to the patient. 
14.4 
Safety Communication 
Investigators will be notified of all AEs that are serious, unexpected, and definitely, probably, 
or possibly related to the investigational product. Upon receiving such notices, the Investigator 
must review and retain the notice with the Investigator Brochure and submit a copy of this 
information to the IRB according to local regulations. The Investigator and IRB will determine 
if the informed consent requires revision. The Investigator should also comply with the IRB 
procedures for reporting any other safety information. All revisions should be submitted to 
PrECOG and/or agents for review. 
14.5 
Monitoring 
Representatives and agents of PrECOG and, as applicable to the study, the manufacturer of 
investigational product must be allowed to visit all study site locations periodically to assess 
the data, quality and study integrity. The purpose of this visit is to review study records and 
directly compare them with source documents and discuss the conduct of the study with the 
Investigator, and verify that the facilities remain acceptable. Monitoring of drug accountability 
will also occur. 
The study may be evaluated by other auditors and government inspectors who must be 
allowed access to electronic Case Report Forms (eCRFs), source documents and other study 
files. The Investigator must notify PrECOG of any scheduled visits by regulatory authorities, 
and submit copies of all reports. Information as to who investigators should notify of an audit 
or where to address questions will be provided in additional study materials. 
14.6 
Study Records 
An Investigator is required to maintain adequate regulatory files with corresponding 
communication and approvals, accurate histories, observations and other data on each 
individual treated. Full details of required regulatory documents will be provided in additional 
study materials. Data reported on the eCRFs must be consistent with the source documents 
as part of the patient record. 
The confidentiality of records that could identify patients must be protected, respecting the 
privacy and confidentiality rules in accordance with the applicable regulatory requirement(s). 
A study specific signature record will be maintained to document signatures and initials of all 
persons at a study site who are authorized to make entries and/or corrections on eCRFs as 
well as document other study-specific roles. 
 


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14.7 
Electronic Case Report Form (eCRF) Information 
Additional information regarding eCRF instructions, timelines for data entry/ submission and 
query completion can be found in supplemental materials provided to the site. Sites will be 
expected to complete eCRFs as per the schedule provided and submit all relevant data as per 
the specified timelines. All items recorded on eCRFs must be found in source documents. 
The completed eCRF must be promptly reviewed, electronically signed, and dated by the 
Principal Investigator. 
Instructions for management of patients who do not receive any protocol therapy: 
If a patient is registered and does not receive any assigned protocol treatment, baseline, 
Serious Adverse Event and follow-up data will still be entered and must be submitted according 
to the eCRF instructions. Document the reason for not starting protocol treatment on the 
appropriate electronic off treatment form. 
14.8 
Records Retention 
FDA Regulations (21CFR 312.62) require clinical investigators to retain all trial-related 
documentation, including source documents for the periods described below for studies 
performed under a US Investigational New Drug (IND): 
• two years after the FDA approves the marketing application, or 
• two years after the FDA disapproves the application for the indication being studied, or 
• two years after the FDA is notified by the sponsor of the discontinuation of trials and that an 
application will not be submitted. 
The Investigator must retain investigational product disposition records, copies of eCRFs (or 
electronic files), and source documents for the maximum period required by applicable 
regulations and guidelines, or Institution procedures, whichever is longer. The Investigator 
must contact PrECOG and/or representatives prior to destroying any records associated with 
the study. 
Information as to who investigators should contact for questions will be provided in additional 
study documents. PrECOG and/or representatives will notify the Investigator when the trial 
records for this study are no longer needed. 
 


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15. 
References 
1. 
Nastoupil LJ, Shenoy PJ, Ambinder A, et al: Intensive chemotherapy and consolidation with high 
dose therapy and autologous stem cell transplant in patients with mantle cell lymphoma. Leuk 
Lymphoma:1-20, 2014. 
2. 
Delarue R, Haioun C, Ribrag V, et al: CHOP and DHAP plus rituximab followed by autologous 
stem cell transplantation in mantle cell lymphoma: a phase 2 study from the Groupe d'Etude des 
Lymphomes de l'Adulte. Blood 121:48-53, 2013. 
3. 
Damon LE, Johnson JL, Niedzwiecki D, et al: Immunochemotherapy and autologous stem-cell 
transplantation for untreated patients with mantle-cell lymphoma: CALGB 59909. J Clin Oncol 
27:6101-8, 2009. 
4. 
Wang ML, Rule S, Martin P, et al: Targeting BTK with Ibrutinib in Relapsed or Refractory Mantle-
Cell Lymphoma. N Engl J Med, 2013. 
5. 
Goy A, Sinha R, Williams ME, et al: Single-Agent Lenalidomide in Patients With Mantle-Cell 
Lymphoma Who Relapsed or Progressed After or Were Refractory to Bortezomib: Phase II MCL-
001 (EMERGE) Study. J Clin Oncol 31:3688-95, 2013. 
6. 
Fisher RI, Bernstein SH, Kahl BS, et al: Multicenter phase II study of bortezomib in patients with 
relapsed or refractory mantle cell lymphoma. J Clin Oncol 24:4867-74, 2006. 
7. 
Wang ML, Blum KA, Martin P, et al: Long-term follow-up of MCL patients treated with single-
agent ibrutinib: Updated safety and efficacy results. Blood, 2015. 
8. 
Cheah CY, Chihara D, Romaguera JE, et al: Patients with mantle cell lymphoma failing ibrutinib 
are unlikely to respond to salvage chemotherapy and have poor outcomes. Ann Oncol 26:1175-
9, 2015. 
9. 
Kaplan LD, Jung S-H, Stock W, et al. Bortezomib maintenance versus consolidation following 
aggressive immunochemotherapy and autologous stem cell  transplant for untreated mantle cell 
lymphoma: CALGB (Alliance) 50403. Blood 2015, 126: 337. 
10. 
Chang JE, Li H, Smith MR, et al: Phase II study of VcR-CVAD with maintenance rituximab for 
untreated mantle cell lymphoma: an Eastern Cooperative Oncology Group Study (E1405). Blood, 
2014. 
11. 
William BM, Allen MS, Loberiza FR, Jr., et al: Phase I/II Study of Bortezomib-BEAM and 
Autologous Hematopoietic Stem Cell Transplantation for Relapsed Indolent Non-Hodgkin 
Lymphoma, Transformed, or Mantle Cell Lymphoma. Biol Blood Marrow Transplant, 2014. 
12. 
Axelrod M, Ou Z, Brett LK, et al: Combinatorial drug screening identifies synergistic co-targeting 
of Bruton's tyrosine kinase and the proteasome in mantle cell lymphoma. Leukemia 28:407-10, 
2014. 
13. 
Kupperman E, Lee EC, Cao Y, et al: Evaluation of the proteasome inhibitor MLN9708 in 
preclinical models of human cancer. Cancer Res 70:1970-80, 2010. 
14. 
Lee EC, Fitzgerald M, Bannerman B, et al: Antitumor activity of the investigational proteasome 
inhibitor MLN9708 in mouse models of B-cell and plasma cell malignancies. Clin Cancer Res 
17:7313-23, 2011. 
15. 
Martin P, Chang J, Cheson BD, et al: Weekly MLN9708, an Investigational Proteasome Inhibitor, 
in Patients with Relapsed/Refractory Lymphoma: Phase 1 Dose-Escalation Study. 
Hematological Oncology 31 (Suppl. 1):151-200, 2013. 
16. 
Kumar S, Bensinger WI, Zimmerman TM, et al: Weekly MLN9708, an investigational oral 
proteasome inhibitor (PI), in relapsed/refractory multiple myeloma (MM): Results from a phase I 
study after full enrollment. J Clin Oncol 31:8514, 2013. 


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17. 
Lonial S, Baz RC, Wang M, 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). Journal of Clinical Oncology 30, 2012. 
18. 
Kumar SK, Berdeja JG, Niesvizky R, et al: A Phase 1/2 Study of Weekly MLN9708, an 
Investigational 
Oral 
Proteasome 
Inhibitor, 
in 
Combination 
with 
Lenalidomide 
and 
Dexamethasone in Patients with Previously Untreated Multiple Myeloma (MM). Blood 120, 2012. 
19. 
Gupta, N., et al., Clinical Pharmacokinetics of Intravenous and Oral MLN9708, An Investigational 
Proteasome Inhibitor: An Analysis of Data From Four Phase 1 Monotherapy Studies. in 52nd ASH 
Annual Meeting and Exposition, 2010. 116(21): p. abstr 1813. 
20. 
Chow, L.Q., et al. MLN9708, an investigational proteasome inhibitor, in patients with solid 
tumors; Updated phase 1 results in Head and Neck Symposium. 2012. Phoenix, AZ. 
21. 
Assouline, S., et al. Once-weekly MLN9708, an investigational proteasome inhibitor, in patients 
with relapsed/refractory lymphoma: results of a phase 1 dose-escalation study in 17th EHA 
Annual Congress. 2012. Amsterdam, the Netherlands. 
22. 
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. 
23. 
Kumar S, et al. Weekly Dosing of the Investigational Oral Proteasome Inhibitor MLN9708 in 
Patients with Relapsed and/or Refractory Multiple Myeloma: Results From a Phase 1 Dose- 
Escalation Study In 53rd ASH Annual Meeting and Exposition; 2011 10-13 Dec; San Diego, CA; 
p. abstr 816. 
24. 
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. 
25. 
Kumar, S. et al. A Phase 1/2 Study of Weekly MLN9708, an Investigational Oral Proteasome 
Inhibitor, in Combination with Lenalidomide and Dexamethasone in Patients with Previously 
Untreated Multiple Myeloma (MM) in 54th ASH Annual Meeting and Exposition. 2012. Atlanta, 
Georgia. 
26. 
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. 
27. 
San Miguel, J., et al. Oral MLN9708, an an investigational proteasome inhibitor, in combination 
with melphalan and prednisone in patients with previously untreated multiple myeloma: a phase 
1 study in 17th EHA Annual Congress. 2012. Amsterdam, the Netherlands. 
28. 
Assouline, S.E., et al. Phase 1 dose-escalation study of IV ixazomib, an investigational 
proteasome inhibitor, in patients with relapsed/refractory lymphoma. Blood Cancer Journal 
(2014) 4, e251; doi:10.1038/bcj.2014.71; published online 17 October 2014. 
29. 
Maddocks K, Christian B, Jaglowski S, et al: A phase 1/1b study of rituximab, bendamustine, 
and ibrutinib in patients with untreated and relapsed/refractory non-Hodgkin lymphoma. Blood 
125:242-8, 2015. 
30. 
Wang M, Hagemeister F, Westin JR, et al: Ibrutinib and Rituximab Are an Efficacious and Safe 
Combination in Relapsed Mantle Cell Lymphoma: Preliminary Results from a Phase II Clinical 
Trial. Blood 124, 2014. 
31. 
Woyach JA, Furman RR, Liu TM, et al: Resistance mechanisms for the Bruton's tyrosine kinase 
inhibitor ibrutinib. N Engl J Med 370:2286-94, 2014. 


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32. 
Dasmahapatra G, Patel H, Dent P, et al: The Bruton tyrosine kinase (BTK) inhibitor PCI-32765 
synergistically increases proteasome inhibitor activity in diffuse large-B cell lymphoma (DLBCL) 
and mantle cell lymphoma (MCL) cells sensitive or resistant to bortezomib. Br J Haematol 
161:43-56, 2013. 
33. 
Cheson BD, Pfistner B, Juweid ME, et al: Revised response criteria for malignant lymphoma. J 
Clin Oncol 25:579-86, 2007. 
34. 
Kumar S, Bensinger W, Reeder C, Zimmerman T, Berenson J, Liu G, et al. Weekly dosing of the 
investigational oral proteasome inhibitor MLN9708 in patients (pts) with relapsed/refractory 
multiple myeloma (MM): A phase I study. Journal of Clinical Oncology 2012 ASCO Annual 
Meeting Proceedings 2012: Abstract 8034. 
35. 
Barrington SF, Mikhaeel NG, et al: Role of Imaging in the Staging and Response Assessment of 
Lymphoma: Consensus of the International Conference on Malignant Lymphomas Imaging 
Working Group. J Clin Oncol 32:3028-3058, 2014. 
36. 
Millennium Pharmaceuticals, Inc. Ixazomib (MLN9708) Investigator's Brochure, Edition 9; Issue 
Date: 17 August 2015. 
37. 
IMBRUVICA
TM (ibrutinib), Prescribing Information; Initial US Approval 2013; revised June 2016. 


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Appendix I 
ECOG Performance Status 
 
PS 0 
Fully active, able to carry on all pre-disease performance 
without restriction 
PS 1 
Restricted in physically strenuous activity but ambulatory 
and able to carry out work of a light or sedentary nature e.g. 
light house work, office work. 
PS 2 
Ambulatory and capable of all self-care but unable to carry 
out any work activities. Up and about more than 50% of 
waking hours. 
PS 3 
Capable of only limited self-care, confined to bed or chair 
more than 50% of waking hours. 
PS 4 
Completely disabled. Cannot carry on any self-care. Totally 
confined to bed or chair. 
Source: Eastern Cooperative Oncology Group, Robert Comis M.D., Group Chair 


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Appendix II: NYHA Classification 
 
Class 
Symptoms 
Class I 
Patients with cardiac disease but without resulting limitation of 
physical activity. Ordinary physical activity does not cause 
undue fatigue, palpitation, dyspnea (shortness of breath), or 
anginal pain. 
Class II 
Patients with cardiac disease resulting in slight limitation of 
physical activity. Comfortable at rest. Ordinary physical activity 
results in fatigue, palpitation, dyspnea or anginal pain. 
Class III 
Patients with cardiac disease resulting in marked limitation of 
physical activity. Comfortable at rest. Less than ordinary 
physical activity causes fatigue, palpitation, dyspnea or anginal 
pain. 
Class IV 
Patients with cardiac disease resulting in inability to carry out 
any physical activity without discomfort. Symptoms of cardiac 
insufficiency or the anginal syndrome may be present even at 
rest. If any physical activity is undertaken, discomfort is 
increased. 
Oxford Textbook of Internal Medicine. Vol. 2, pp 2228. Oxford University Press. 1997 
 


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Appendix III: Ixazomib Medication Diary 
 
Site #:___________ 
Subject #:___________ 
Subject Initials:____________ 
Cycle:___________ 
Dose:_______________ 
Number of Capsules: ___ mg: ________ 
 
Patient Instructions: 
1. Complete each form as instructed by your physician or study nurse. Please complete in ink. 
2. Please complete this diary every day you take ixazomib. Write the date of each dose of ixazomib you 
take. 
3. Ixazomib should be swallowed whole with a glass of water. Capsule should not be opened, broken or 
chewed. Ixazomib should be taken on an empty stomach (no food or drink) at least 1 hour before or 
at least 2 hours after food. Each capsule should be swallowed separately with a sip of water. A total 
of approximately 8 ounces of water should be taken with the capsule. 
4. If a dose is not taken at the scheduled time, it can be taken as soon as you remember if the next 
scheduled dose is 72 hours or more away (beginning with Cycle 2). 
5. Extra capsules should not be taken to make up for the missed dose. If you vomit after taking a dose, 
do not repeat the dose but resume dosing at the time of the next scheduled dose. Please mark dates 
of any missed capsule on your record. 
6. Store your medication refrigerated (36°F to 46°F) for the duration of each cycle. 
7. If you have any side effects or comments, please note in the comment section or on the back of the 
page. If you have questions or concerns, please call ______________________________________ 
at: (_____) _____ - _________. 
Please bring your ixazomib blister packs (unused medication and empty blister packs) and this 
form to every appointment with your study doctor. 
 
DAY 
DATE 
DOSE 
COMMENTS 
1 
____/____/____ 
______mg 
 
8 
____/____/____ 
______mg 
 
15 
____/____/____ 
______mg 
 


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Appendix IV: Ibrutinib Medication Diary 
 
Site #:___________ 
Subject #:___________ 
Subject Initials:____________ 
Cycle:___________ 
Dose:_______________ 
Number of Capsules: 140 mg: ________ 
 
Patient Instructions: 
1. Complete each form as instructed by your physician or study nurse. Please complete in ink. 
2. Please complete this diary every day. Write the date of each dose of ibrutinib you take. 
3. Ibrutinib should be swallowed whole with a glass of water. Capsules should not be opened, broken or 
chewed. You should take the capsules at approximately the same time each day. 
4. If a dose is not taken at the scheduled time, it can be taken as soon as possible on the same day with 
a return to the normal schedule the following day. 
5. Extra capsules should not be taken to make up for the missed dose. If you vomit after taking a dose, 
do not repeat the dose but resume dosing at the time of the next scheduled dose. Please mark dates 
of any missed capsule on your record. 
6. You should not drink grapefruit juice, eat grapefruit, or eat Seville oranges (often used in marmalades) 
while you are taking ibrutinib. These products may increase the amount of ibrutinib in your blood. 
7. Store ibrutinib at room temperature 68°-77°F. 
8. If you have any side effects or comments, please note in the comment section or on the back of the 
page. If you have questions or concerns, please call ______________________________________ 
at: (_____) _____ - _________. 
Please bring your ibrutinib bottle(s) (unused medication and empty bottles) and this form to every 
appointment with your study doctor. 
 
DAY 
DATE 
DOSE 
COMMENTS 
1 
____/____/____ 
______mg 
 
2 
____/____/____ 
______mg 
 
3 
____/____/____ 
______mg 
 
4 
____/____/____ 
______mg 
 
5 
____/____/____ 
______mg 
 
6 
____/____/____ 
______mg 
 
7 
____/____/____ 
______mg 
 
8 
____/____/____ 
______mg 
 
9 
____/____/____ 
______mg 
 
10 
____/____/____ 
______mg 
 
11 
____/____/____ 
______mg 
 


PrECOG Protocol Number: PrE0404 
Confidential 
Date: 8/21/2020 
 
77 
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PrECOG Protocol Number: PrE0404 
Confidential 
Date: 8/21/2020 
 
78 
Appendix V: Investigator’s Statement 
1. 
I have carefully read this protocol entitled “A Phase I/II Study of Ixazomib and 
Ibrutinib in Patients with Relapsed/Refractory Mantle Cell Lymphoma”, Version 
3.0 dated 8/21/2020 (Protocol Number PrE0404) and agree that it contains all the 
necessary information required to conduct the study. I agree to conduct the study as 
outlined in the protocol. 
2. 
I agree to conduct this study according to the moral, ethical and scientific principles 
governing clinical research as set out in the Declaration of Helsinki, the principles of 
Good Clinical Practice (GCP) as described in 21 Code of Federal Regulations (CFR) 
and any applicable local requirements. 
3. 
I understand that this trial and any subsequent changes to the trial will not be initiated 
without approval of the appropriate Institutional Review Board, and that all 
administrative requirements of the governing body of the institution will be complied 
with fully. 
4. 
Informed written consent will be obtained from all participating patients in accordance 
with institutional and Food and Drug Administration (FDA) requirements as specified in 
Title 21, CFR, Part 50. 
5. 
I understand that my signature on the electronic Case Report Form (eCRF) indicates 
that I have carefully reviewed each page and accept full responsibility for the contents 
thereof. 
6. 
I understand that the information presented in this study protocol is confidential, and I 
hereby assure that no information based on the conduct of the study will be released 
without prior consent from PrECOG, LLC unless this requirement is superseded by the 
FDA. 
Principal Investigator (PI): 
PI Name: 
 
 
 
 
 
 
 
 
 
 
Site Name: 
 
 
 
 
 
 
 
 
 
 
Signature of PI: 
 
 
 
 
 
 
 
 
 
Date of Signature: 
 
 
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