Clinical trial NCT02898259
Conditions: B Cell Lymphoma Lymphoma
Keywords: Lenalidomide Ixazomib Rituximab
Sponsor: Brian Hill
Start date: 2017-02-20; Completion date: 2022-06-06
Enrollment: 19 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
A Phase IB/II Trial of Lenalidomide (Revlimid®), Ixazomib and Rituximab (RIXAR) as Front-line Therapy for High Risk Indolent B cell Lymphoma

Detailed description:
Primary:

To determine the maximum tolerated dose and toxicity of the combination of oral ixazomib and lenalidomide plus rituximab in patients with previously untreated low-grade B cell lymphoma having high tumor burden by GELF criteria or FLIPI 3-5

Secondary:

* To determine overall response rate in an expanded cohort at the MTD for follicular lymphoma and for non-follicular low-grade B cell lymphoma
* Duration of response, time to progression, progression free survival, time to treatment failure and overall survival
* Create tissue microarray from paraffin embedded tissue for future studies.
* Assessment of baseline lymphocyte subsets as prognostic markers.

Overview of Study Design:

This study combines three classes of agents that have non-overlapping mechanisms of action and toxicity profiles, with each pair having demonstrated clinical evidence of benefit without unexpected toxicity. We use the lenalidomide-rituximab backbone, feasible and active in lymphoma, and add a novel oral proteasome inhibitor to potentially enhance efficacy, minimize toxicity and limit patient visits for treatment.

Patients with previously untreated low-grade B cell lymphoma having high tumor burden by GELF criteria or FLIPI 3-5 will be treated with the combination of oral ixazomib + lenalidomide + rituximab.

The primary objective is to determine the maximum tolerated dose and toxicity of this regimen. The study will use a standard 3 + 3 design for determination of MTD during cycle 1. There will be three dose levels for escalation, followed by two expansion cohorts of 12 patients each at the MTD, one cohort with follicular lymphoma and one cohort with non-follicular low-grade lymphoma (SLL, marginal zone, lymphoplasmacytic).

Arms: arm 1: Ixazomib will be orally administered with a starting dose of 2.0mg. Lenalidomide will be administered orally with a starting dose of 20mg. Rituximab will be administered intravenously at the standard dose of 375mg/m2. The study will use a standard 3 + 3 design for determination of MTD during cycle 1. There will be three dose levels for escalation, followed by two expansion cohorts of 12 patients each at the MTD, one cohort with follicular lymphoma and one cohort with non-follicular low-grade lymphoma (SLL, marginal zone, lymphoplasmacytic). Patients will be treated for 12 cycles of 4 week duration.
Interventions: intervention 1: Ixazomib intervention 2: Lenalidomide intervention 3: Rituximab
Intervention descriptions: intervention 1: The prescribed administration of ixazomib doses in this study is 2.0, 3.0 or 4.0 mg ixazomib on days 1, 8 and 15 of each 28 day cycle. intervention 2: Lenalidomide starting dose will be based on baseline calculated creatinine clearance as follows:

* Starting lenalidomide Dose (20mg)
* Calculated Creatinine Clearance: \>=60ml/min receive 20 mg daily on Days 1 - 21 of each 28-day cycle
* Calculated Creatinine Clearance: \>= 30 and \< 60 ml/min receive 10 mg daily on Days 1 - 21 of each 28-day cycle intervention 3: Rituximab is administered intravenously at 375mg/m2 on days 1, 8, and 15 of cycle 1, day 1 of cycles 2-6 and day 1 of cycles 8, 10, and 12.

Protocol documents:
ICF_001.pdf: 
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Prot_SAP_002.pdf: 
 
CASE1414 RIXAR 
Protocol Version 8, 4/11/2022 
 
1 
 
 
 
 
 
 
 
 
 
 
CASE COMPREHENSIVE CANCER CENTER 
__________________________________________________________________ 
 
STUDY NUMBER:   
 
CASE1414 
 
ClinicalTrials.gov NCT #:         NCT02898259 
 
PROTOCOL DATE:  
 
April 11, 2022 
 
STUDY TITLE:   
 
A Phase IB/II Trial of Lenalidomide (Revlimid®), Ixazomib 
and Rituximab (RIXAR) as Front-line Therapy for High 
Risk Indolent B cell Lymphoma 
 
 
 
 
PRINCIPAL INVESTIGATOR: Brian Hill, MD, PhD 
 
 
 
 
Case Comprehensive Cancer Center 
 
 
 
 
Cleveland Clinic Foundation 
Taussig Cancer Center 
 
9500 Euclid Avenue  
 
 
 
Cleveland, OH  44195 
  
 
 
 
 
 
 
CO-PI: 
 
 
 
Brenda Cooper, MD 
 
 
 
 
Case Comprehensive Cancer Center 
 
 
 
 
Department of Medicine – Hematology and Oncology 
 
 
 
 
University Hospitals Case Medical Center 
 
 
 
 
11100 Euclid Avenue,  
 
 
 
 
Cleveland, OH  44106 
 
 
 
CO- INVESTIGATORS: 
Cleveland Clinic 
 
 
 
 
Robert Dean, MD 
 
 
 
 
Deepa Jagadeesh, MD 
 
 
 
 
Brad Pohlman, MD 
 
 
 
 
Christopher D’Andrea, PA-C 


 
CASE1414 RIXAR 
Protocol Version 8, 4/11/2022 
 
2 
 
 
 
 
Matt Kalaycio, MD 
 
 
 
 
Omer Koc, MD 
 
 
 
 
Allison Winter, MD 
 
 
 
 
Chieh-Lin Fu, MD 
 
 
 
 
Chakra Chaulagain, MD 
 
 
 
 
 
 
 
 
     University Hospitals 
 
Kristen Bakalarz, CNP 
Molly Gallogly, MD 
Ehsan Malek, MD 
Leland Metheny, MD 
Benjamin Tomlinson, MD 
 
 
 
 
STATISTICIAN:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
STUDY COORDINATOR: 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
SPONSOR:  
 
 
Case Comprehensive Cancer Center 
 
 
SUPPORT: 
 
 
Millennium, Takeda Oncology 
 
 
 
 
Celgene 
 
 
 
 
SUPPLIED AGENTS:  
Lenalidomide 
 
 
 
 
Ixazomib 
 
IND Number:            
 
   
 
  
 
OTHER AGENT: 
 
Rituximab 
 
 
 


 
CASE1414 RIXAR 
Protocol Version 8, 4/11/2022 
 
3 
Summary of Changes 
 
    Protocol Date 
        Section 
Change 
8.3.2016 
 
Initial IRB approval 
2.2.2017 
 
Removing Mitchell Smith and adding Brian Hill as PI/Sponsor 
3.24.2017 
4 / Appendix V 
Updating FLIPI requirement to ≥5 nodal sites  
3.24.2014 
6 
Antiviral prophylaxis therapy is now required 
3.24.2017 
11 
Adding +/- 3 day window for day 1 visits 
3.24.2017 
13.1 
Adding Overture database  
10.11.2017 
Schedule of 
Events 
Correcting footnotes to be consistent with calendar and 
adding footnote 17 
10.11.2017 
1.6.3 
Removing section, MRD testing is not available 
10.11.2017 
4.1.7 
Clarifying heme parameters for patients with heavy disease 
burden 
10.23.2018 
3.1 
Clarifying Phase 2 dose level. 
10.23.2018 
Page 1-2 
Updating Co-Investigators and study personnel, adding 
Florida 
10.23.2018 
Schedule of 
Events 
Footnote 14 
Adding a window of +/- 7 days for follow-up visits 
10.23.2018 
Schedule of 
Events 
Adding a window of +/- 2 days for C 1-3 days 8 and 15 
10.23.2018 
Schedule of 
Events 
Adding HIV testing for screening 
10.23.2018 
Table 7-3 
Removal of Action of ANC dose modification 
10.23.2018 
6.2 
Removing Dose Escalation section 
10.23.2018 
Appendix VI 
Clarifying Blood Specimen Handling Instructions 
04.23.2019 
Page 1-2 
Updating Co-Investigators, adding regional sites 
04.23.2019 
Tables 7-2 
and 7-3 
Dose Adjustment Criteria Update 
04.23.2019 
 
Phase 2 Cohort Changes 
09.05.2019 
Page 2 
Updating Co-Investigators 
09.05.2019 
Tables 7-2 
and 7-3 
Clarifying Dose Adjustment Criteria 
12.02.2019 
Page 2 
Removing Regional Co-Investigators 
12.02.2019 
Section 7.1.2 
Clarifying Dose Adjustment  Criteria 
01.18.2022 
Page 1-2 
Updating Co-Investigators and research coordinator on cover 
page.  


 
CASE1414 RIXAR 
Protocol Version 8, 4/11/2022 
 
4 
    Protocol Date 
        Section 
Change 
01.18.2022 
Section 
10.1.2 
Removing Dr. Eric Hsi and adding Dr. Sarah Ondrejka as 
laboratory contact. Updating medical secretary and contact  
information. 
04.11.2022 
Page 5 
Updated duration of study   
04.11.2022 
Section 6.6 
Updated duration of follow up  
04.11.2022 
Schedule of 
Events 
Footnote 14 
Updated follow up duration for 2 years and CT Chest. 
Abdomen and Pelvis, Neck frequency.  
04.11.2022 
Schema  
Updated duration of follow up 
04.11.2022 
Study 
Parameters 
and Schedule 
of Events 
Footnote 14 
Updated follow up duration for 2 years and CT Chest. 
Abdomen and Pelvis, Neck frequency. 
 
 
 
PROTOCOL SUMMARY 
A Phase II Trial of Lenalidomide (Revlimid®), Ixazomib and Rituximab (RIXAR) as 
Front-line Therapy for High Risk Indolent B cell Lymphoma (CASE1414) 
Phase:  II 
Number of Patients:  33-42 
Study Objectives:  
Primary(Phase I): 
To determine the maximum tolerated dose and toxicity of the combination of oral 
ixazomib and lenalidomide plus rituximab in patients with previously untreated low-
grade B cell lymphoma having high tumor burden by GELF criteria or FLIPI 3-5 
 
Secondary (Phase II): 
 
To determine overall response rate in an expanded cohort at the MTD for 
follicular lymphoma (FL)  
 
Duration of response, time to progression, progression free survival, time to 
treatment failure and overall survival 
 
Create tissue microarray from paraffin embedded tissue for future studies. 
 
Assessment of baseline lymphocyte subsets as prognostic markers. 
 
Assessment of blood flow cytometric evaluation of minimal residual disease 
post-treatment correlation with PFS 
 
 
Overview of Study Design:   


 
CASE1414 RIXAR 
Protocol Version 8, 4/11/2022 
 
5 
 
 
 
 
 
 
 
 
 
 
 
 
This study combines three classes of agents that have non-overlapping mechanisms 
of action and toxicity profiles, with each pair having demonstrated clinical evidence of 
benefit without unexpected toxicity. We use the lenalidomide-rituximab backbone, 
feasible and active in lymphoma, and add a novel oral proteasome inhibitor to 
potentially enhance efficacy, minimize toxicity and limit patient visits for treatment. 
 
Patients with previously untreated low-grade B cell lymphoma having high tumor 
burden by GELF criteria or FLIPI 3-5 (for FL only) will be treated with the combination 
of oral ixazomib + lenalidomide + rituximab.  
 
The primary objective was to determine the maximum tolerated dose and toxicity of 
this regimen. The study used a standard 3 + 3 design to determine the MTD during 
cycle 1.There were three dose levels for escalation,12 patients total. The MTD was 
determined to be DL3. There will be one expansion cohort of 18 patients with 
follicular lymphoma 
 
 
Study Population:   
 
Adult patients with previously untreated low-grade B cell lymphoma with high 
tumor burden by GELF criteria and/or FLIPI 3-5 (for FL only). 
 
ECOG PS 0-2. 
 
Adequate organ function. 
 
No grade 3 (or grade 2 with pain) neuropathy. 
 
Able to swallow pills. 
 
Not requiring ongoing treatment with drugs that strongly induce CYP3A. 
 
Agree to contraceptive measures if fertile.  
 
Duration of Study:  
Patients will receive treatment for 1 year and are assessed for response 1-3 months 
later (up to 15 months total).  
 
Following treatment for 1 year, patients will be assessed per clinical standards, generally 
every 3 months (+/- 7 days) for 2 years. 
 
Study accrual will be over 2 years, with 15 month additional as above, for total of 39 
months. 
 


 
CASE1414 RIXAR 
Protocol Version 8, 4/11/2022 
 
6 
Schedule of Events 
Parameter 
Pre-study1 
 
Day 1 of Every 
Cycle2 (+/-3) 
 
Cycle 1  
Day 8(+/-
2) 
 
Cycle 1 
 Day 
15(+/-2) 
 
Cycle 1 
Day 22 
Restaging12 and Follow-up14 
Assignment of FLIPI scores2 
X 
 
 
 
 
 
Notation of GELF criteria2 
X 
 
 
 
 
 
History and Physical examination 
X 
X 
 
 
 
X 
Performance Status 
X 
X 
 
 
 
X 
Tumor Measurements by Physical 
Exam (if applicable) 
X 
X 
 
 
 
X 
CBC and Differential 
X3 
X 
X4 
X4 
X4 
X 
Serum Chemistries (electrolytes, 
AST, ALT, total bilirubin, direct 
bilirubin5, creatinine, glucose, 
alkaline phos, and calcium) 
X7 
X 
X 
X 
 
X 
LDH 
X 
X 
X 
X 
 
X 
Beta-2-microglobulin 
X 
 
 
 
 
 
HIV testing 
X 
 
 
 
 
 
Uric acid 
X 
X  
Cycles 3-6 only if > 
ULN prior cycle 
X 
X 
 
 
Monoclonal protein determination13 
X 
X13 
 
 
 
X13 
Bone marrow aspirate biopsy 
If not known to be involved 
X 
(up to 90 
days) 
 
 
 
 
After cycle 12  
if in CR6 
Pregnancy test (for women of child-
bearing potential)7 
X7 
 
 
 
 
 
Hepatitis B surface antigen and core 
antibody testing8 
X8 
 
 
 
 
 
T4, TSH 
X 
Day 1 Cycle 7 only  
 
 
 
X15 
Immunodeficiency Panel16 
X 
Day 1 cycle 7 only 
 
 
 
After cycle 12 
Creatinine clearance 
X 
calculated 
 
 
 
 
CT Chest, Abdomen, and Pelvis; Neck 
X9 
 
 
 
 
After cycles 3 and 610 


 
CASE1414 RIXAR 
Protocol Version 8, 4/11/2022 
 
7 
 
 
Schedule of Events 
On rituximab treatment days 8 and 15 of cycle 1, patients will be assessed by a nurse for toxicity, and CBC, serum 
chemistries, LDH and uric acid will be performed. Pre-study parameters can be up to 30 days prior to start of treatment, 
except bone marrow aspirate and biopsy can be up to 90 days, if not known to be positive for lymphoma 
 
1. Cycles are every 28 days. Patients may be evaluated in the office more frequently at the physician’s discretion. 
 
2. Yes/No should be entered for each criterion of GELF and FLIPI, as well as absolute calculation of FLIPI-1 and FLIPI-2. (See 
Appendix V). 
 
3. At baseline: please record the absolute lymphocyte count.  
 
4. Cycles 2 and 3 for dose escalation cohorts only : CBC and differential is required on Days 8, 15 and 22. Other labs ( 
chem, LDH, UA ) should be done days 8, 15 of cycle 1 only, not in cycles 2-3  
 
5. Direct bilirubin is required only if total bilirubin is elevated. 
 
6. Repeat bone marrow biopsy core and aspirate only if positive at baseline and otherwise meets criteria for CR.  
 
7. Within 2 weeks of start of induction treatment. For definition of woman of childbearing potential (WOCBP) see lenalidomide 
(Revlimid®) REMS program. Before starting lenalidomide (Revlimid®): WOCBP must have two negative pregnancy tests 
(sensitivity of at least 50 mIU/mL) prior to starting study drug. The first pregnancy test must be performed within 10-14 days 
prior to the start of study drug and the second pregnancy test must be performed within 24 hours prior to the start of study 
drug. The subject may not receive study drug until the Investigator has verified that the results of these pregnancy tests are 
negative. Female subjects will be warned that sharing study drug is prohibited and will be counseled about pregnancy 
precautions and potential risks of fetal exposure. During study participation and for 28 days following discontinuation 
from the study: WOCBP with regular cycles must agree to have pregnancy tests weekly for the first 28 days of study 
participation and then every 28 days while on study, at study discontinuation, and at day 28 following discontinuation from 
the study. If menstrual cycles are irregular, the pregnancy testing must occur weekly for the first 28 days and then every 14 
days while on study, at study discontinuation, and at days 14 and 28 following discontinuation from the study. In addition to 
the required pregnancy testing, the Investigator must confirm with WOCBP that she is continuing to use two reliable 
(if involved) 
PET/CT Scan 
X9 
 
 
 
 
After cycle 1211 
Baseline Symptoms/AE Evaluation17 
X 
X 
X 
X 
 
X 


 
CASE1414 RIXAR 
Protocol Version 8, 4/11/2022 
 
8 
methods of birth control at each visit. Counseling about pregnancy precautions and the potential risks of fetal exposure must 
be conducted at a minimum of every 28 days. During counseling, subjects must be reminded to not share study drug and to 
not donate blood. Pregnancy testing and counseling must be performed if a subject misses her period or if her pregnancy 
test or her menstrual bleeding is abnormal. Study drug treatment must be discontinued during this evaluation. If pregnancy 
or a positive pregnancy test does occur in a study subject or the partner of a male study subject during study participation, 
study drug must be immediately discontinued.  
 
8. Patients must be tested for hepatitis B surface antigen within 6 weeks of randomization. Liver function tests and quantitative 
PCR assay for HBV levels in serum to be performed monthly until 6 months following last rituximab dose for HBcAb positive 
patients.  Further, consideration should be given to treat such patients with anti-viral prophylaxis (e.g., lamivudine 100mg po 
QD) prior to, during, and for 6 months after completion of the last dose of rituximab. Patients who are positive for HBsAg 
(surface antigen) are not allowed to enroll on study. 
 
9. If PET/CT scan has been done, do not need separate diagnostic quality CT unless the only measurable disease is in the 
mesentery and not measurable without oral contrast, in which case CT abdomen/pelvis with oral/IV contrast should be done 
prior to treatment. 
 
10. CT scans (chest/abdomen/pelvis; neck if involved) should be done to evaluate response every 3 months (12 weeks). If a 
PET/CT is done, then CT does not need to be done, unless the only initially measurable disease was in the mesentery and 
not measurable without oral contrast, in which case CT abdomen/pelvis with oral/IV contrast should be done. 
 
11. Once patient enters PET negative complete remission, then only CT’s (chest/abdomen/pelvis, include neck if previously 
involved) need to be done in follow-up 
 
12. Restaging will be 8 - 12 weeks after day 1 cycle 12 (or after day 1 of last cycle of treatment if stopped early). Repeat bone 
marrow only if it was involved prior to treatment and patient otherwise meets criteria for CR.  
 
13. Monoclonal protein (M-protein) blood determination includes: serum immunofixation, quantitative IgG, IgA, IgM,. If M-protein 
is detected, the abnormal value will be checked every other cycle beginning with cycle 2, and during follow-up at months 6, 
12, 24, 36, 48 and 60 (each  30 days) or until the patient comes off the study 
 
14. FOLLOW-UP: per clinical standards, generally every 3 months (+/- 7 days) for 2 years, then every 6 months (+/- 7 days) 
years 2, or as clinically indicated, with: History and Physical examination, Performance Status, Tumor Measurements by 
Physical Exam (if applicable), CBC and Differential, Serum Chemistries and LDH. CT [Chest, Abdomen, and Pelvis, Neck if 
previously involved] at months 6, 12, and 24 (each  30 days). Follow-up visit and CT schedule should count from end of 
treatment restaging scan. Once the patient has disease progression or otherwise meets criteria for treatment failure, patient 
can be followed for survival by telephone or other contact without in-person visit or protocol-mandated CT scans. 


 
CASE1414 RIXAR 
Protocol Version 8, 4/11/2022 
 
9 
 
15. Thyroid functions at baseline, pre- cycle 7, at re-staging and once 6 months later 
 
16. Immunodeficiency Panel: One anti-coagulated (prefer purple-top) tube sent to Tomsich Flow laboratory. See Appendix VI 
for details. Draw at baseline, before cycle 7 and again at restaging after cycle 12.  
 
17. Baseline Symptoms and AE assessments should be done on days 8 and 15 for Cycle 1 only. For Cycles 2 and 3, 
assessments will be performed on Day 1


 
CASE1414 RIXAR 
Protocol Version 8, 4/11/2022 
 
10 
SCHEMA 
Population (N = 33-42) 
Previously untreated indolent B-cell lymphoma  
High risk =  
 
(1) high tumor burden (by GELF criteria; see Appendix 1)  AND/OR  
(2) FLIPI 3-5 for FL patients (see Appendix 1) 
ECOG PS 0-2 
Adequate organ function 
Induction Treatment (28 days (4 weeks) per cycle, for 12 cycles): 
 
Ixazomib oral at 4.0 mg on days 1, 8, 15 + 
Lenalidomide oral 20 mg/day days 1-21 + 
Rituximab IV 375 mg/m2 
days 1, 8, 15 of cycle 1, 
day 1 only of  cycles 2-6, 
day 1 only of cycles 8, 10 and 12 
Disease Assessment 
Evaluation every 3 cycles (12 weeks) 
while on treatment.  
Scans after cycles 3, 6, and 12. 
 
Continue treatment unless: 
Disease progression 
Unacceptable toxicity 
Patient withdraws consent 
 
Follow up 
Assess for response and study related toxicities 2-3 months after last dose 
of study drug. 
Follow per standard clinical measures for disease progression and survival 
for 24 months after the last dose of study drug. 


 
CASE1414 RIXAR 
Protocol Version 8, 4/11/2022 
 
11 
ABBREVIATIONS  
 
ADCC  
 
Antibody-Dependent Cell-Mediated Cytotoxicity 
AE 
 
 
Adverse Event 
Akt 
 
 
Protein Kinase B 
AL 
 
 
Amyloid Light-Chain 
ALT 
 
 
Alanine Aminotransferase 
AML  
 
Acute Myeloid Leukemia 
ANC  
 
Absolute Neutrophil Count 
AP-1  
 
Activator Protein 1 
AST  
 
Aspartate Aminotransferase 
AUC  
 
Area Under Curve 
Bcl-2  
 
B-Cell Lymphoma 2 
bFGF  
 
Basic Fibroblast Growth Factor 
BSA  
 
Body Surface Area 
BCRP  
 
Breast Cancer Resistance Protein 
CAEPR 
 
Comprehensive Adverse Events and Potential Risks List 
CBC  
 
Complete Blood Count 
CCCC  
 
Case Comprehensive Cancer Center 
CCF  
 
Cleveland Clinic Foundation  
CD4  
 
Cluster of Differentiation 4 
CHO  
 
Chinese Hamster Ovary 
CHOP  
 
Cyclophosphamide, Hydroxydoxorubicin, Oncovin, Prednisone 
CL 
 
 
Clearance 
CLL 
 
 
Chronic Lymphocytic Leukemia 
cm 
 
 
Centimeter 
CMV  
 
Cytomegalovirus 
CR 
 
 
Complete Response  
CrCl  
 
Creatinine Clearance 
CRu  
 
Complete Response, Unconfirmed 
CRF  
 
Case Report Form 
CT 
 
 
Computed Tomography 
CTC  
 
Common Toxicity Criteria 
CTCAE 
 
Common Terminology Criteria for Adverse Events 
CTEP  
 
Cancer Therapy Evaluation Program  
CVA  
 
Cerebrovascular Accident 
CVP  
 
Cyclophosphamide, Vincristine, Prednisone 
CYP1A2 
 
Cytochrome P450 1A2 
CYP3A 
 
Cytochrome P450 3A 
DDI 
 
 
Drug-Drug Interaction 
Dex 
 
 
Dexamethasone 
DFS  
 
Disease-Free Survival 
dL 
 
 
Deciliter 
DLT 
 
 
Dose-Limiting Toxicity 
DNA  
 
Deoxyribonucleic Acid 
DOR  
 
Duration of Response 


 
CASE1414 RIXAR 
Protocol Version 8, 4/11/2022 
 
12 
DSTC  
 
Data Safety and Toxicity Committee 
DVT  
 
Deep Vein Thrombosis 
ECOG 
 
Eastern Cooperative Oncology Group 
Fab 
 
 
Fragment Antigen-Binding 
Fc 
 
 
Fragment Crystallizable 
FDA  
 
Food and Drug Administration 
FDG  
 
Fluorodeoxyglucose 
FFPE  
 
Formalin-Fixed, Paraffin Embedded 
FL 
 
 
Follicular Lymphoma 
FLIPI  
 
Follicular Lymphoma International Prognostic Index 
GCP  
 
Good Clinical Practice 
G-CSF 
 
Granulocyte Colony Stimulating Factor 
GELF  
 
Groupe d’Etude des Lymphomes Folliculaires 
GI 
 
 
Gastrointestinal 
GM 
 
 
Gram 
GM-CSF 
 
Granulocyte Macrophage-Colony Stimulating Factor 
HBcAb 
 
Hepatitis B Core Antibody 
HBsAg 
 
Hepatitis B Surface Antigen 
HBV  
 
Hepatitis B Virus 
HCV  
 
Hepatitis C Virus 
HIPAA 
 
Health Insurance Portability and Accountability Act 
HIV 
 
 
Human Immunodeficiency Virus 
HTB  
 
High Tumor Burden 
IB 
 
 
Investigator’s Brochure 
ICF 
 
 
Informed Consent Form 
ICH 
 
 
International Conference on Harmonisation 
IDB 
 
 
Investigational Drug Branch 
IND 
 
 
Investigational New Drug 
INF 
 
 
Interferon 
IgA 
 
 
Immunoglobulin A 
IgG 
 
 
Immunoglobulin G 
IgM 
 
 
Immunoglobulin M 
IL 
 
 
Interleukin 
iNHL  
 
Indolent Non-Hodgkin Lymphoma 
INR 
 
 
International Normalized Ratio 
IPI 
 
 
International Prognostic Index 
IRB 
 
 
Institutional Review Board 
IV 
 
 
Intravenous 
IWG  
 
International Working Group 
L 
 
 
Liter 
LDH  
 
Lactate Dehydrogenase 
LenDex 
 
Lenalidomide plus Dexamethasone 
M 
 
 
Meter 
MDS  
 
Myelodysplastic Syndrome 
MedDRA 
 
Medical Dictionary for Regulatory Activities 
mg 
 
 
Milligram 


 
CASE1414 RIXAR 
Protocol Version 8, 4/11/2022 
 
13 
Min 
 
 
Minute 
mL 
 
 
Milliliter 
mm 
 
 
Millimeter 
MM 
 
 
Multiple Myeloma  
M-Protein 
 
Monoclonal Protein 
MRI 
 
 
Magnetic Resonance Imaging 
MRD  
 
Minimal Residual Disease  
MRP2  
 
Multidrug Resistance Associated Protein 
MTD  
 
Maximum Tolerated Dose 
NCI 
 
 
National Cancer Institute 
NDMM 
 
Newly Diagnosed Multiple Myeloma 
NEC  
 
Not Elsewhere Classified 
NHL  
 
Non-Hodgkin Lymphoma 
NK 
 
 
Natural Killer 
NOS  
 
Not Otherwise Specified 
NSAIDs 
 
Nonsteroidal Anti-Inflammatory Drugs 
ORR  
 
Overall Response Rate 
OS 
 
 
Overall Survival 
PCR  
 
Polymerase Chain Reaction 
PD 
 
 
Progressive Disease 
PE 
 
 
Pulmonary Embolism 
PET  
 
Positron Emission Tomography 
PFS  
 
Progression-Free Survival 
Pgp 
 
 
P-glycoprotein 
PI 
 
 
Principal Investigator 
PK 
 
 
Pharmacokinetic 
PO 
 
 
Orally 
PRMC 
 
Protocol Review and Monitoring Committee 
QD 
 
 
One a Day 
R 
 
 
Rituximab 
R2 
 
 
Rituximab-Lenalidomide 
R-CHOP 
 
Rituximab, Cyclophosphamide, Doxorubicin Hydrochloride,  
 
 
 
Vincristine, Prednisone  
RevDex 
 
Revlimid and Dexamethasone 
R-HyperCVAD 
Rituximab, Cyclophosphamide, Vincristine, Doxorubicin, 
 
 
 
Dexamethasone, Methotrexate, Cytarabine 
RIXAR 
 
Lenalidomide (Revlimid®), Ixazomib, and Rituximab 
RNA  
 
Ribonucleic Acid 
RP2D  
 
Recommended Phase 2 Dose 
RR 
 
 
Relapsed and/or Refractory 
RRAL  
 
Relapsed/Refractory Primary Systemic Light Chain (AL)  
 
 
 
Amyloidosis 
RRMM 
 
Relapsed/Refractory Multiple Myeloma 
SAE  
 
Serious Adverse Event 
SD 
 
 
Stable Disease 
SLL 
 
 
Small Lymphocytic Lymphoma 


 
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SMA  
 
Safety Management Attachment 
SOC  
 
Standard of Care 
SPD  
 
Sum of Products of the Diameters 
TBD  
 
To Be Determined 
TEAE  
 
Treatment-Emergent Adverse Event 
TLS 
 
 
Tumor Lysis Syndrome 
TMA  
 
Tissue Microarray 
TNF  
 
Tumor Necrosis Factor 
TTF 
 
 
Time to Treatment Failure 
TTP 
 
 
Thrombotic Thrombocytopenic Purpura 
TTP 
 
 
Time to Progression 
TW 
 
 
Twice Weekly 
UH 
 
 
University Hospitals 
ULN  
 
Upper Limit of Normal 
UTI 
 
 
Urinary Tract Infection 
VEGF  
 
Vascular Endothelial Growth Factor 
VR-CAP 
 
Rituximab, Cyclophosphamide, Doxorubicin, Prednisone,  
 
 
 
Bortezomib 
W 
 
 
Weekly 
WCOBP 
 
Woman of Child-Bearing Potential 
WM 
 
 
Waldenstrom’s Macroglobulinemia 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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TABLE OF CONTENTS 
 
SCHEMA 
 
1.0  
INTRODUCTION   
1.1 
Indolent Non-Hodgkin Lymphoma (iNHL) 
1.2  
Ixazomib 
1.3       Lenalidomide (Revlimid ®) 
1.4       Rituximab 
1.5       Rationale   
1.6       Lab Correlative Studies 
 
2.0 
OBJECTIVES 
2.1 
Primary Objective 
 
2.2  
Secondary Objectives 
2.3 
Study Endpoints 
 
3.0 
STUDY DESIGN 
3.1 
Overview 
3.2 
Number of Patients 
3.3 
Duration of Study 
 
4.0 PATIENT SELECTION 
4.1 
Inclusion Criteria 
4.2  
Exclusion Criteria 
4.3 
Inclusion of Women and Minorities 
 
5.0 
REGISTRATION 
 
 
6.0  
TREATMENT PLAN 
6.1 
Agent Administration  
 
6.1.1 Ixazomib 
 
 
6.1.2 Lenalidomide 
 
 
6.1.3 Rituximab  
6.2  
Dose Escalation 
6.3 
Definition of Dose Limiting Toxicity 
6.4 
General Concomitant Medications and Supportive Care Guidelines  
6.5 
Duration of Therapy 
6.6 
Duration of Follow Up 
 
7.0 
DOSE DELAYS / DOSE MODIFICATIONS 
 
 
8.0 
ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS  
 
8.1 
Adverse Events and Potential Risk List  
 
8.1.1 Ixazomib 
 
8.1.2 Lenalidomide 
 
8.1.1 Rituximab 
8.2 
Definitions 
 
8.2.1    Adverse Events 
 
8.2.2    Significance of an Adverse Event 


 
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8.2.3    Serious Adverse Events 
 
8.2.4    Expectedness 
 
8.2.5    Attribution 
8.3 
Reporting Procedures for All Adverse Events 
8.4 
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events 
8.5 
Data Safety Toxicity Committee    
 
 
9.0 
PHARMACEUTICAL INFORMATION  
9.1 
Ixazomib 
 
9.2 
Lenalidomide 
9.3 
Rituximab 
 
 10.0 
CORRELATIVE / SPECIAL STUDIES  
 10.1  
Tissue Microarray 
 10.2 
Flow Cytometry on Peripheral Blood 
 
 11.0 
STUDY PARAMETERS AND CALENDAR 
 11.1  
Study Parameters 
 11.2  
Calendar 
 
 12.0 
MEASUREMENT OF EFFECT  
 
 13.0 
RECORDS TO BE KEPT/REGULATORY CONSIDERATIONS 
 13.1 
Data Reporting 
 13.2 
Regulatory Considerations  
 
 
 14.0 
STATISTICAL CONSIDERATIONS 
 
REFERENCES 
 
APPENDICES        
 
 
APPENDIX I 
 
ECOG Performance Status 
 
 
APPENDIX II 
 
Cockcroft-Gault formula for Creatinine Clearance 
 
APPENDIX III 
 
Potential CYP1A2 and CYP3A4 Interactions    
 
 
 
 
 
 
APPENDIX IV 
 
Patient Pill Diary  
 
 
APPENDIX V  
 
Risk Factors: GELF Tumor Burden Criteria and FLIPI Score 
 
 
 
APPENDIX VI 
 
Blood Specimen Handling 
 
 


 
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1.0 
INTRODUCTION 
 
1.1 
Indolent B Cell Non-Hodgkin Lymphoma (iNHL)  
Indolent B cell non-Hodgkin lymphoma (iNHL) consists of several categories of lymphoid 
malignancies arising from B cells. The most common type of iNHL in the U.S. is follicular 
lymphoma. Other less common types include small lymphocytic lymphoma, marginal zone 
lymphoma (nodal, extranodal and splenic) and lymphoplasmacytic lymphoma. While they differ as 
to molecular drivers and in some clinical behavior, these iNHL are often grouped together as 
treatable, but not curable, B cell lymphoproliferative disorders. As such, they are often approached 
similarly in the clinic with observation if there are no signs or symptoms related to the disease, and 
treatment indicated when signs or symptoms of disease occur. As patient selection can 
significantly affect outcomes, patient populations in most current studies of untreated iNHL have 
been divided into low and high tumor burden (HTB) populations according to GELF criteria, with 
HTB iNHL representing higher risk disease and worse outcomes. Low tumor burden patients who 
require therapy may receive as a single agent the anti-CD20 monoclonal antibody rituximab. The 
most common therapy for untreated HTB indolent NHL remains rituximab (R) combined with 
standard cytotoxic chemotherapy, usually CHOP, CVP or bendamustine. Another way to stratify 
iNHL in terms of survival prognosis is the follicular lymphoma (FL) international prognostic index 
(IPI) FLIPI, although these data antedated use of rituximab. FLIPI-2 was updated in the rituximab 
era. FLIPI scores of 3-5 are associated with shorter TTP after therapy and OS. While the GELF 
criteria and FLIPI were developed for FL, they have been applied to all subtypes of iNHL. Of note, 
is that there are no data that early treatment even in these groups alters outcome.  
 
Few series of patients with HTB iNHL treated with rituximab-chemotherapy have reported long-
term follow-up (i.e., median follow-up >4 years), and in these latter reports the 4-year time to 
progression (TTP) and overall survival (OS) rates were 44-56% and 83-90%, respectively. In 
addition, more tolerable therapeutic regimens for patients with HTB iNHL who are older or have co-
morbidities and other contraindications to chemotherapy are an unmet medical need.  
Encouraging data from phase 1 and 2 trials examining non-cytotoxic therapy for untreated patients 
with iNHL have been reported. Several trials have administered rituximab-lenalidomide (R2), 
leading to the ongoing randomized phase 2 trial (RELEVANCE) of R2 compared with R-
chemotherapy.  
 
Bortezomib is a proteasome inhibitor with encouraging activity in relapsed or refractory iNHL and 
mantle cell lymphoma. It has been combined with R-chemo in lymphoma trials, as well being 
effective and well-tolerated in combination with lenalidomide in myeloma. We carried out a phase 
1B/2 trial of R-bortezomib as initial therapy for HTB iNHL.  
 
Based on the above findings that R2 as well as R + proteasome inhibitor are promising regimens 
for therapy of iNHL, and that lenalidomide + various proteasome inhibitor combinations are highly 
active against another B cell disorder myeloma, combining R2 + a proteasome inhibitor is a rational 
concept to study as initial therapy in HTB iNHL. For this study we have chosen to use the novel 
oral proteasome inhibitor ixazomib to decrease expected neurotoxicity and to reduce patient visits 
and injections. 
  
1.2 
Ixazomib (MLN9708)  
 
1.2.1 Preclinical Experience 
Please refer to the current ixazomib Investigator’s Brochure (IB) 
 
 
 


 
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1.2.2 Clinical Experience 
As ixazomib has been recently approved in the setting of myeloma, but remains investigational for 
lymphoma, data continue to accumulate and the most current IB should be consulted for detailed 
information. Ixazomib has been evaluated as an oral single agent in phase 1 studies that have 
included patients with advanced solid tumors, lymphoma, relapse/refractory MM (RRMM), and 
relapsed or refractory light-chain (AL) amyloidosis and demonstrated early signs of activity. 
Ongoing studies continue to investigate both single-agent ixazomib and ixazomib in combination 
with standard treatments. Based on encouraging preliminary data observed in patients with MM 
requiring systemic treatment, 2 phase 3 trials in newly diagnosed MM (NDMM) (C16014) and 
RRMM (C16010) patient populations are currently evaluating ixazomib in combination with 
lenalidomide (Revlimid ) and Dexamethasone (RevDex) versus placebo/RevDex. Both trials are 
combining ixazomib at a weekly dose of 4.0 mg on Days 1, 8, and 15 in a 28-day cycle to a 
standard dose of lenalidomide with a weekly dexamethasone dose of 40 mg. In addition, clinical 
pharmacology studies have evaluated drug-drug interactions with ketoconazole, clarithromycin, 
and rifampin, as well as the effect of food, renal impairment, and hepatic impairment on the PK of 
ixazomib. Studies evaluating the safety and pharmacokinetics (PK) of ixazomib alone (in Japanese 
patients) and in combination with lenalidomide and dexamethasone in Asian adult patients 
(including Japanese patients) with a diagnosis of RRMM are ongoing. 
 
As of 27 March 2013, preliminary clinical data is available for a total of 653 patients across 13 
studies. The emerging safety profile indicates that ixazomib is generally well tolerated. The 
adverse events (AEs) are consistent with the class-based effects of proteasome inhibition and are 
similar to what has been previously reported with VELCADE though the severity of some, for 
example peripheral neuropathy, is less. While some of these potential toxicities may be severe, 
they can be managed by clinical monitoring and standard medical intervention, or, as needed, 
dose modification or discontinuation. 
 
Fatigue was the most common AE reported among 384 patients treated in the oral (PO) studies 
(47%). Other common AEs reported in the pooled intravenous (IV) and PO safety populations 
include nausea, thrombocytopenia, diarrhea, and vomiting. Rash is also a commonly reported 
treatment-emergent event; however, there is some variety in its characterization and causality 
resulting in different preferred terms to describe it. A high-level term outline of rash events includes 
rashes, eruptions and exanthems NEC; pruritus NEC; erythemas; papulosquamous conditions; 
and exfoliative conditions. The dose escalation phases of most trials reported in the IB have now 
completed enrollment, and gastrointestinal (GI) symptoms were the common dose-limiting toxicities 
(DLTs) when the use of prophylactic anti-emetics was not permitted per protocol. In the expansion 
cohorts or phase 2 cohorts (as per each study), the incidence and severity of GI symptoms was 
mitigated by the use of the lower maximum tolerated dose (MTD)/recommended phase 2 dose 
(RP2D) (as per each study) and standard clinical usage of anti-emetics and/or antidiarrheal 
medications as deemed appropriate. Prophylactic use of anti-emetics has not been required as 
with other agents but (as outlined in Section 6.2.4) has been used according to standard practice 
and are effective. 
 
The most frequent (at least 20%) treatment-emergent adverse events (TEAEs) reported with the 
PO formulation pooled from single-agent studies (n = 201) irrespective of causality to ixazomib, 
include nausea (53%), fatigue (51%), diarrhea (44%), thrombocytopenia (34%), vomiting (38%), 
decreased appetite (32%), fever (21%), and anemia (21%). The most frequent (at least 20%) 
TEAEs reported with the PO formulation pooled from combination trials (irrespective of the 
combination) (n = 173), irrespective of causality to ixazomib, include diarrhea (47%), fatigue (44%), 
nausea (38%), peripheral edema (35%), constipation (33%), insomnia (29%), thrombocytopenia 


 
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(28%), anemia (26%), vomiting (26%), neutropenia (25%), back pain (24%), pyrexia (23%), 
peripheral edema (21%, each), fever (20%), cough (20%), hypokalemia (20%), neutropenia (20%), 
and upper respiratory tract infection (20%). Overall rash of all grades is reported in approximately 
50% of patients and is more common when ixazomib is given in combination with lenalidomide 
where rash is an overlapping toxicity. 
 
Additional detailed information regarding the clinical experience of ixazomib may be found in the 
IB, including information on the IV formulation.   
 
1.2.3 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 postdose. The plasma exposure (AUC) of 
ixazomib increases in a dose-proportional manner over a dose range of 0.2 to 10.6 mg based on 
population PK analysis. The absolute oral bioavailability (F) of ixazomib is estimated to be 58% 
based on population PK analysis.  A high-fat meal reduced ixazomib Cmax by 69% and AUC0-216 by 
28%.  This indicates that a high-fat meal decreases both the rate and extent of absorption of 
ixazomib. Therefore, ixazomib should be dosed at least 2 hours after food or 1 hour before food. 
 
The steady-state volume of distribution of ixazomib is large and is estimated to be 543 L based on 
a population PK model. Based on in vitro plasma protein binding measurements on samples from 
clinical studies (Studies C16015 and C16018), ixazomib is highly bound to plasma proteins (99%). 
Ixazomib concentrations are higher in whole blood than in plasma, indicating extensive partitioning 
of ixazomib into red blood cells, which are known to contain high concentrations of the 20S 
proteasome. 
 
Metabolism appears to be the major route of elimination for ixazomib. In vitro studies indicate that 
ixazomib is metabolized by multiple cytochrome P450 (CYP) and non-CYP proteins. At 
concentrations exceeding those observed clinically (10 µM), ixazomib was metabolized by multiple 
CYP isoforms with estimated relative contributions of 3A4 (42.3%), 1A2 (26.1%), 2B6 (16.0%), 2C8 
(6.0%), 2D6 (4.8%), 2C19 (4.8%), and 2C9 (1%). At 0.1 and 0.5 µM substrate concentrations, 
which are closer to clinical concentrations of ixazomib following oral administration of 4 mg 
ixazomib, non-CYP mediated clearance was observed and seemed to play a major role in 
ixazomib clearance in vitro.  These data indicate that at clinically relevant concentrations of 
ixazomib, non-CYP proteins contribute to the clearance of ixazomib and no specific CYP isozyme 
predominantly contributes to the clearance of ixazomib. Therefore, at clinically relevant 
concentrations of ixazomib, minimal CYP-mediated DDIs with a selective CYP inhibitor would be 
expected. 
 
Ixazomib is neither a time-dependent inhibitor nor a reversible inhibitor of CYPs 1A2, 2B6, 2C8, 
2C9, 2C19, 2D6, or 3A4/5.  Ixazomib did not induce CYPs 1A2, 2B6, and 3A4/5 activity or 
corresponding immunoreactive protein levels. Thus, the potential for ixazomib to produce DDIs via 
CYP isozyme induction or inhibition is low. 
 
Ixazomib is not a substrate of BCRP, MRP2 and OATPs. Ixazomib is not an inhibitor of P-gp, 
BCRP, MRP2, OATP1B1, OATP1B3, OAT1, OAT3, OCT2, MATE1 and MATE2-K. Ixazomib is 
unlikely to cause or be susceptible to clinical DDIs with substrates or inhibitors of clinically relevant 
drug transporters. 
 
The geometric mean terminal half-life (t1/2) of ixazomib is 9.5 days based on population PK 
analysis. For both IV and oral dosing, there is an approximately average 3-fold accumulation 


 
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(based on AUC) following the Day 11 dose for the twice-weekly schedule and a 2-fold 
accumulation (based on AUC) following the Day 15 dose for the once-weekly schedule. 
 
Mean plasma clearance (CL) of ixazomib is 1.86 L/hr based on the results of a population PK 
analysis. Taken together with the blood-to-plasma AUC ratio of approximately 10, it can be inferred 
that ixazomib is a low clearance drug. Using the absolute oral bioavailability (F) estimate of 58% 
(also from a population PK model), this translates to an apparent oral plasma clearance (CL/F) of 
3.21 L/hr. The geometric mean renal clearance for ixazomib is 0.119 L/hr, which is 3.7% of CL/F 
and 6.4% of CL estimated in a population PK analysis. Therefore, renal clearance does not 
meaningfully contribute to ixazomib clearance in humans. Approximately 62% of the administered 
radioactivity in the ADME study (Study C16016) was recovered in the urine and 22% of the total 
radioactivity was recovered in the feces after oral administration. Only 3.2% of the administered 
ixazomib dose was recovered in the urine as unchanged ixazomib up to 168 hours after oral 
dosing, suggesting that most of the total radioactivity in urine was attributable to metabolites.  
 
The PK of ixazomib was similar with and without co-administration of clarithromycin, a strong 
CYP3A inhibitor, and hence no dose adjustment is necessary when ixazomib is administered with 
strong CYP3A inhibitors. Consistently, in a population PK analysis, co-administration of strong 
CYP1A2 inhibitors did not affect ixazomib clearance. Therefore, no dose adjustment is required for 
patients receiving strong inhibitors of CYP1A2.  Based on information from the clinical rifampin DDI 
study, ixazomib Cmax and AUC0-last were reduced in the presence of rifampin by approximately 54% 
and 74%, respectively. Therefore, the co-administration of strong CYP3A inducers with ixazomib is 
not recommended.  
 
Mild or moderate renal impairment (CrCL ≥ 30 mL/min) did not alter the PK of ixazomib based on 
the results from a population PK analysis. As a result, no dose adjustment is required for patients 
with mild or moderate renal impairment.  In a dedicated renal impairment study (C16015), unbound 
AUC0-last was 38% higher in patients with severe renal impairment or ESRD patients requiring 
dialysis as compared to patients with normal renal function.  Accordingly, a reduced starting dose 
of ixazomib is appropriate in patients with severe renal impairment or ESRD requiring dialysis.  
Pre- and post-dialyzer concentrations of ixazomib measured during the hemodialysis session were 
similar, suggesting that ixazomib is not readily dialyzable, consistent with its high plasma protein 
binding (99%). 
 
The PK of ixazomib is similar in patients with normal hepatic function and in patients with mild 
hepatic impairment, as defined by the National Cancer Institute Organ Dysfunction Working Group 
(total bilirubin <1.5 times the upper limit of normal [ULN]), based on the results from a population 
PK analysis. Consequently, no dose adjustment is required for patients with mild hepatic 
impairment. In a dedicated PK study in patients with moderate (total bilirubin >1.5 to 3 times the 
ULN) or severe (total bilirubin >3 times the ULN) hepatic impairment (Study C16018), unbound 
dose-normalized AUC0-last was 27% higher in patients with moderate or severe hepatic impairment 
as compared to patients with normal hepatic function. Therefore, a reduced starting dose of 
ixazomib is appropriate in patients with moderate or severe hepatic impairment.  
 
There was no statistically significant effect of age (23-91 years), sex, body surface area 
(1.2-2.7 m2), or race on the clearance of ixazomib based on the results from a population PK 
analysis. 
 
 
 


 
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1.2.4 Clinical Trial Experience Using the Oral Formulation of Ixazomib 
As of 27 March 2013, a total of 507 patients with differing malignancies (multiple myeloma, AL 
amyloidosis, non-hematologic cancers, and lymphoma) have been treated in studies evaluating the 
oral ixazomib formulation.  These patients have been treated with different doses of ixazomib 
either as a single-agent treatment (in 201 patients) or in combination with currently clinically 
available treatments (in 306 patients).  Information regarding the ongoing studies, patient 
populations, and doses investigated is included in Table 1-1. 
 


 
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Table 1-1    
Clinical Studies of Oral Ixazomib 
Trial/ 
Population 
Description 
Doses Investigated 
C16003 
RRMM 
N = 60 
PO, TW, single agent 
0.24-2.23 mg/m2 TW 
MTD:  2.0 mg/m2 
DLT:  rash, thrombocytopenia 
Closed to enrollment 
C16004 
RRMM 
N = 60 
PO, W, single agent 
0.24-3.95 mg/m2 W 
MTD:  2.97 mg/m2 
DLT:  rash, nausea, vomiting, diarrhea 
Closed to enrollment 
C16005 
NDMM 
N = 65 
PO, W, combination with LenDex 
28-day cycle 
1.68-3.95 mg/m2 W 
MTD:  2.97 mg/m2 
DLT:  nausea, vomiting, diarrhea, syncope 
RP2Da:  4.0 mg fixed (switched to fixed dosing in 
phase 2, equivalent  to 2.23mg/m2) 
Closed to enrollment 
C16006 
NDMM 
N = 20 
PO, TW (Arm A- 42 day cycle) and 
W (Arm B- 28 day cycle), 
combination with Melphalan and 
Prednisone 
Arm Aa:  3-3.7-mg fixed dose TW 
DLT:  rash, thrombocytopenia, subileus 
Arm Ba:  3-5.5-mg fixed dose, W 
DLT:  Esophageal ulcer nausea, vomiting, 
hematemesis, thrombocytopenia, ileus, 
neurogenic bladder 
MTD = 3.0 mg 
C16007 
RRAL 
N = 27 
PO, W, single agent 
4-5.5-mg fixed dosea W 
DLT:  thrombocytopenia, diarrhea, dyspnea, acute 
rise in creatinine, cardiac arrest  
MTD:  4.0  mg W 
 
C16008 
NDMM 
N = 64 
PO, TW, combination with LenDex 
21-day cycle 
3.0-3.7-mg fixed dosea W 
MTD:  3.0 mg 
Closed to enrollment 
C16009 
Solid tumors, 
Lymphomas 
N = 54 
PO, W, single agent 
5.5-mg fixed dosea W 
C16010 
RRMM 
N = 200 
PO, W, with LenDex versus placebo-
LenDex 
4.0 mg W 
C16011 
RRAL 
N = 4 
PO, W, with Dex versus physician’s 
choice of a Dex-based regimen 
4.0 mg W 


 
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Table 1-1    
Clinical Studies of Oral Ixazomib 
Trial/ 
Population 
Description 
Doses Investigated 
C16013 
RRMM 
N = 9 
PO, W, with LenDex 
4.0 mg W 
C16014 
Symptomatic 
MM 
N=701 
PO, combination with LenDex 
ixazomib 4.0 mg or matching placebo on Days 1, 
8, and 15, plus Len 25 mg on Days 1-21 (10 mg if 
low creatinine clearance, with escalation to 15 mg 
if tolerated) and Dex 40 mg (or 20 mg if >75 
years old) on Days 1, 8, 15, and 22 
C16015 
Symptomatic 
MM with 
normal renal 
function or 
severe renal 
impairment 
N=28 
PO, combination with Dex 
Part A: ixazomib  3.0 mg on Day 1 
Part B: ixazomib  4.0 mg on Days 1, 8, and 15, 
plus Dex 40 mg (or 20 mg if >75 years old) on 
Days 1, 8, 15 and 22 of a 28-day cycle 
 
C16017 
RR follicular 
lymphoma 
N=58 
PO, W 
4.0, 5.3, and 7.0 mg, W 
Treatment at RP2D once determined. 
 
C16018 
Advanced 
solid tumors 
or 
hematologic 
malignancies 
with varying 
degrees of 
liver 
dysfunction 
N=45 
Part A: PO, Day 1 of 15-day cycle 
Part B: PO, W 
1.5 mg (severe hepatic impairment), 2.3 mg 
(moderate hepatic impairment), or 4.0 mg (normal 
hepatic function) 
 
TB-
MC010034 
RRMM 
N = 10 
PO, W 
4.0 mg, W 
Single agent: 4.0 mg 
Combination with Rd 
Abbreviations:  RRAL = Relapsed and/or refractory Primary systemic light chain (AL) amyloidosis; BSA = 
body surface area; Dex=dexamethasone; DLT = dose-limiting toxicity; IV = intravenously; LenDex = 
lenalidomide plus dexamethasone; MTD = maximum tolerated dose; NDMM = newly diagnosed multiple 
myeloma; PO = orally; RR= relapsed and/or refractory; RRAL= relapsed and/or refractory systemic light 
chain amyloidosis RRMM = relapsed and/or refractory multiple myeloma; TBD = to be determined; TW 
= twice weekly; W = weekly; RP2D= recommended phase 2 dose. 
Note that blinded data from pivotal Studies C16010 and C16011 are not included.   
a Approximate BSA and fixed dosing equivalence:  3 mg~ equivalent to 1.68 mg/m2 BSA dosing; 4.0 mg ~ 
equivalent to 2.23 mg/m2 BSA dosing; and 5.5 mg~ equivalent to 2.97 mg/m2 BSA dosing. 
 


 
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1.2.5 Overview of the Oral Formulation of Ixazomib 
The emerging safety profile indicates that ixazomib is generally well tolerated.  The adverse events 
(AEs) are consistent with the class-based effects of proteasome inhibition and are similar to what 
has been previously reported with VELCADE though the severity of some, for example peripheral 
neuropathy, is less.  While some of these potential toxicities may be severe, they can be managed 
by clinical monitoring and standard medical intervention, or, as needed, dose modification or 
discontinuation.   
 
In the 4 ongoing studies (C16003, C16004, C16007, and C16009) investigating single-agent oral 
ixazomib in patients with differing malignancies (multiple myeloma, AL amyloidosis, 
nonhematologic cancers, and lymphoma), a total of 201 patients have been treated as of 27 March 
2013. These patients have been treated with different doses of ixazomib as they are all phase 1 
trials. An overview of the most frequent (at least 10%) AEs occurring in the pooled safety 
population from single-agent oral ixazomib Studies (C16003, C16004, C16007, and C16009) are 
shown in Table 1-2. 
 
Table 1-2    
Most Common (At Least 10% of Total) Treatment-Emergent Adverse 
Events in Oral Single-Agent Studies 
Primary System Organ Class 
     Preferred Term 
1.1.1.1.2 Oral Single Agent 
Total 
n = 201 
n (%) 
Subjects with at Least One Adverse Event 
197 (98) 
Gastrointestinal disorders 
160 (80) 
Nausea 
106 (53) 
Diarrhoea 
88 (44) 
Vomiting 
77 (38) 
Constipation 
46 (23) 
Abdominal pain 
33 (16) 
General disorders and administration site 
conditions 
151 (75) 
Fatigue 
103 (51) 
Pyrexia 
51 (25) 
Oedema peripheral 
27 (13) 
Asthenia 
31 (15) 
Nervous system disorders 
92 (46) 
Headache 
29 (14) 
Dizziness 
26 (13) 
Neuropathy peripheral 
21 (10) 
Metabolism and nutrition disorders 
107 (53) 
Decreased appetite 
64 (32) 
Dehydration 
37 (18) 
Blood and lymphatic system disorders 
98 (49) 
Thrombocytopenia 
68 (34) 


 
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Table 1-2    
Most Common (At Least 10% of Total) Treatment-Emergent Adverse 
Events in Oral Single-Agent Studies 
Primary System Organ Class 
     Preferred Term 
1.1.1.1.2 Oral Single Agent 
Total 
n = 201 
n (%) 
Anaemia 
42 (21) 
Neutropenia 
29 (14) 
Lymphopenia 
20 (10) 
Skin and subcutaneous tissue disorders 
90 (45) 
Rash maculara 
23 (11) 
Musculoskeletal and connective tissue 
disorders 
93 (46) 
Back pain 
24 (12) 
Arthralgia 
28 (14) 
Respiratory, thoracic and mediastinal 
disorders 
78 (39) 
Cough 
28 (14) 
Dyspnoea 
30 (15) 
Infections and infestations 
89 (44) 
Upper respiratory tract infection 
31 (15) 
Source:  Ixazomib Investigator’s Brochure Edition 7 
Abbreviations:  MedDRA = Medical Dictionary for Regulatory Activities, version 15.0. 
Subject Incidence:  A subject counts once for each preferred term.  Percentages use the number of treated 
subjects as the denominator. 
a Note that rash maculopapular and rash macular represent the 2 most common terms used to describe rash. 
 
As of 27 March 2013, there are 5 studies actively enrolling patients with multiple myeloma to 
investigate oral ixazomib in combination with standard combination regimens.   
 
The most frequent (at least 10%) AEs occurring in the pooled safety population from Studies 
C16005, C16006, C16008, and C16013 are shown for all grades (Table 1-3).  Note that in 
combination trials, related is defined as related to any study drug in the combination regimen. 


 
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Table 1-3    
Most Common (At Least 10% of Total) Treatment-Emergent Adverse 
Events in Oral Combination Studies 
Primary System Organ Class 
     Preferred Term 
1.1.1.1.3 Total Oral Combo Agent 
(5/6/8/13) 
n = 173 
n (%) 
Subjects with at Least One Adverse Event 
163 (94) 
Gastrointestinal disorders 
139 (80) 
Nausea 
65 (38) 
Diarrhoea 
81 (47) 
Vomiting 
51 (29) 
Constipation 
57 (33) 
General disorders and administration site 
conditions 
132 (76) 
Fatigue 
76 (44) 
Pyrexia 
39 (23) 
Oedema peripheral 
61 (35) 
Asthenia 
20 (12) 
Nervous system disorders 
115 (66) 
Headache 
28 (16) 
Dizziness 
34 (20) 
Neuropathy peripheral 
45 (26) 
Metabolism and nutrition disorders 
91 (53) 
Decreased appetite 
25 (14) 
Hypokalaemia 
34 (20) 
Blood and lymphatic system disorders 
88 (51) 
Thrombocytopenia 
49 (28) 
Anaemia 
45 (26) 
Neutropenia 
43 (25) 
Lymphopenia 
20 (12) 
Skin and subcutaneous tissue disorders 
102 (59) 
Rash maculopapulara 
29 (17) 
Rash maculara 
22 (13) 
Musculoskeletal and connective tissue 
disorders 
99 (57) 
Back pain 
42 (24) 
Pain in extremity 
31 (18) 
Arthralgia 
22 (13) 
Respiratory, thoracic and mediastinal 
disorders 
80 (46) 
Cough 
36 (21) 


 
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Table 1-3    
Most Common (At Least 10% of Total) Treatment-Emergent Adverse 
Events in Oral Combination Studies 
Primary System Organ Class 
     Preferred Term 
1.1.1.1.3 Total Oral Combo Agent 
(5/6/8/13) 
n = 173 
n (%) 
Dyspnoea 
26 (15) 
Infections and infestations 
92 (53) 
Upper respiratory tract infection 
35 (20) 
Psychiatric disorders 
73 (42) 
Insomnia 
50 (29) 
Source:  Ixazomib Investigator’s Brochure Edition 7 
Abbreviations:  MedDRA = Medical Dictionary for Regulatory Activities, version 15.0. 
Subject Incidence:  A subject counts once for each preferred term.  Percentages use the number of treated 
subjects as the denominator.  
Data from ongoing blinded pivotal trials (C16010) are not included. 
a Note that rash maculopapular and rash macular represent the 2 most common terms used to describe rash..   
 
The clinical experience with ixazomib also shows early signs of antitumor activity as evidenced by 
at least a 50% reduction in disease burden in some patients and prolonged disease stabilization in 
others across all ongoing trials. The antitumor activity has been seen with single-agent ixazomib, 
when combined with established therapies, and across the malignancies studied (advanced solid 
tumors [3], non-Hodgkin’s disease, Hodgkin’s disease [4], relapsed and/or refractory multiple 
myeloma (RRMM) [5; 6], relapsed or refractory systemic light chain amyloidosis (RRAL) [7], and 
newly diagnosed multiple myeloma (NDMM) [8; 9; 10]) to date. 
 
Though additional data are needed to characterize the clinical benefit of this drug, the emerging 
data supports the ongoing development of ixazomib. 
 
1.2.6 Relapsed and/or Refractory Multiple Myeloma 
The early development of ixazomib in patients with RRMM involves 2 studies (C16003 and 
C16004) with similar objectives, but each investigated 1 of the 2 dosing schedules commonly used 
with the first-in-class proteasome inhibitor, VELCADE. 
 
Study C16003 is an open-label, dose escalation, phase 1 study of ixazomib dosing on a twice-
weekly schedule on Days 1, 4, 8, and 11 of a 21-day cycle in adult patients with RRMM.(11, 12)  
Study C16004 is an open-label, dose escalation, phase 1 study of ixazomib dosing on a weekly 
schedule on Days 1, 8, and 15 of a 28-day cycle in adults patients with RRMM.(13, 14, 15)  Both 
studies have now completed enrollment.  The DLTs in Study C16003 were rash macular and 
thrombocytopenia and the DLTs in C16004 were nausea, diarrhea, vomiting, and erythema 
multiforme. 
 
In the dose escalation component of both studies, patients had multiple myeloma that had relapsed 
following at least 2 lines of therapy that must have included bortezomib, thalidomide (or 
lenalidomide), and corticosteroids.  In both studies, when the MTD was established, cohorts of 
patients representing the heterogeneous patient population currently seen in clinical practice were 
to be enrolled into 1 of 4 expansion cohorts, including a relapsed and refractory cohort, a 


 
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carfilzomib cohort, a proteasome inhibitor-naïve cohort, and a VELCADE-relapsed cohort. 
 
Final study results are currently being analyzed, but preliminary data suggest that ixazomib has 
anti-tumor activity in heavily pretreated MM patients, with durable responses/disease control, and 
is generally well tolerated. Please refer to the ixazomib IB and SMA for further information.  
 
1.2.7 Newly Diagnosed Multiple Myeloma (NDMM) 
Multiple research paths are being explored in patients with NDMM with a focus on evaluating 
ixazomib in combination with agents commonly used across treatment settings.  The development 
of ixazomib in combination with lenalidomide with dexamethasone (LenDex) in patients with NDMM 
who are transplant eligible or ineligible involves 2 studies (C16005 and C16008) with similar study 
designs except for a few key differences, namely the schedules of ixazomib and dexamethasone.  
Ixazomib is also being evaluated in combination with melphalan and prednisone (MP) for patients 
who are not transplant eligible due to age or coexisting morbidity (in Study C16006).  
 
All 3 studies are phase 1/2, with phase 1 focusing on safety and phase 2 on efficacy (and further 
characterization of safety).  Please refer to the ixazomib IB and SMA for further information.  
 
1.2.8 Clinical Trial Experience Using Intravenous Formulation of Ixazomib 
See the IB for descriptions of the 2 studies that investigated IV ixazomib in advanced solid tumors 
and advanced lymphoma (Studies C16001 and C16002, respectively). 
 
1.2.9 Potential Risks and Benefits 
Please refer to the current ixazomib IB and SMA. 
 
The clinical benefit of ixazomib continues to be studied in a comprehensive and global 
development plan that involves studies sponsored by Millennium.  Ixazomib appears to show early 
signs of anti-tumor activity as evidenced by at least 50% reduction in disease burden in some 
patients, including patients that have been heavily pretreated as well as those with newly 
diagnosed MM, and prolongs stabilization of the underlying disease in other patients across all 
ongoing trials.  The preliminary findings are favorable when considering historical and currently 
available therapies for the patient populations evaluated.  Though additional data are needed to 
characterize the clinical benefit of this drug, the emerging data supports expanded development of 
ixazomib for the treatment of patients with advanced malignancy. 
 
This study will be conducted in compliance with the protocol, good clinical practice (GCP), 
applicable regulatory requirements, and International Conference on Harmonisation (ICH) 
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1.3 
Lenalidomide (Revlimid ®) 
 
 
1.3.1 Background 
Lenalidomide is a proprietary IMiD® compound of Celgene Corporation.  IMiD® compounds have 
both immunomodulatory and anti-angiogenic properties which could confer antitumor and 
antimetastatic effects.  Lenalidomide has been demonstrated to possess anti-angiogenic activity 
through inhibition of bFGF, VEGF and TNF-alpha induced endothelial cell migration, due at least in 
part to inhibition of Akt phosphorylation response to bFGF. (1)  In addition, lenalidomide has a 
variety of immunomodulatory effects.  Lenalidomide stimulates T cell proliferation, and the 
production of IL-2, IL-10 and IFN-gamma, inhibits IL-1 beta and IL-6 and modulates IL-12 
production. (2)  Upregulation of T cell derived IL-2 production is achieved at least in part through 
increased AP-1 activity. (3) 
 
Although the exact antitumor mechanism of action of lenalidomide is unknown, a number of 
mechanisms are postulated to be responsible for lenalidomide’s activity against multiple myeloma.  
Lenalidomide has been shown to increase T cell proliferation, which leads to an increase in IL-2 
and IFN-gamma secretion.  The increased level of these circulating cytokines augment natural 
killer cell number and function, and enhance natural killer cell activity to yield an increase in 
multiple myeloma cell lysis (4).  In addition, lenalidomide has direct activity against multiple 
myeloma and induces apoptosis or G1growth arrest in multiple myeloma cell lines and in multiple 
myeloma cells of patients resistant to melphalan, doxorubicin and dexamethasone.  
 
1.3.2 Indications and Usage 
Lenalidomide (Revlimid® )is indicated for the treatment of patients with transfusion-dependent 
anemia due to Low- or Intermediate-1-risk myelodysplastic syndromes associated with a deletion 
5q cytogenetic abnormality with or without additional cytogenetic abnormalities.  Lenalidomide 
(Revlimid®) is also approved in combination with dexamethasone for the treatment of patients with 
multiple myeloma that have received at least one prior therapy. In 2013 it was approved for 
treatment of patients with mantle cell lymphoma who were previously treated and whose treatment 
had included bortezomib. 
 
1.3.3 Adverse Events 
Most frequently reported adverse events reported during clinical studies with lenalidomide in 
oncologic and non-oncologic indications, regardless of presumed relationship to study medication 
include: anemia, neutropenia, thrombocytopenia and pancytopenia, abdominal pain, nausea, 
vomiting and diarrhea, dehydration, rash, itching, infections, sepsis, pneumonia, UTI, upper 
respiratory infection, atrial fibrillation, congestive heart failure, myocardial infarction, chest pain, 
weakness, hypotension, hypercalcemia, hyperglycemia, back pain, bone pain, generalized pain, 
dizziness, mental status changes, syncope, renal failure, dyspnea, pleural effusion, pulmonary 
embolism, deep vein thrombosis, CVA, convulsions, dizziness, spinal cord compression, syncope, 
disease progression, death not specified and fractures. 
 
Patients with cancer have a higher risk of developing a second new cancer when compared to 
people without cancer. In clinical studies of newly diagnosed multiple myeloma, a higher number of 
second cancers were reported in patients treated with lenalidomide as induction therapy (treatment 
for several cycles to reduce number of cancer cells) and/or bone marrow transplant followed by 
lenalidomide for a long period of time compared to patients treated with induction therapy and/or 
bone marrow transplant then placebo (a capsule containing no lenalidomide). Patients should 
make their doctors aware of their medical history and any concerns they may have regarding their 
own increased risk of other cancers.  


 
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Complete and updated adverse events are available in the Investigational Drug Brochure and the 
IND Safety Letters. 
 
1.4 
Rituximab 
 
1.4.1 Background 
Rituximab is a chimeric mouse/human anti-CD20 monoclonal antibody that is approved by the FDA 
for several indications, including treatment of indolent, B-cell non-Hodgkin lymphoma.  
Anti-tumor activity is achieved through antibody-dependent cell-mediated cytotoxicity and 
complement-dependent cytotoxicity.  Additional evidence demonstrates that rituximab has anti-
proliferative effects and can induce apoptosis in malignant B-lymphocytes by directly disrupting 
intracellular signaling pathways.  
 
The CD20 antigen is an attractive target for immunotherapeutic agents as it does not internalize on 
antibody binding. In phase 1 studies serum antibody levels were detected in all patients 
immediately after the intravenous infusion. At the usually used dose serum antibody levels can be 
detected 1 month after antibody therapy. In patients with high tumor burden with splenomegaly the 
antibody half-life can be as short as 1.6 days.  
 
1.4.2 Clinical experience 
Among patients with relapsed or refractory low-grade NHL, a standard 4-week course of weekly 
rituximab at 375 mg/m2 induces response rates of 50% with a median progression-free survival of 
12 months. (54) When used in the first-line setting, approximately 70-75% of patients respond to 
single-agent rituximab with durable responses of 18 months. Rituximab is well tolerated in single-
agent studies and myelosuppressive effects are mild.  The most frequent toxicities are transient, 
Grade 1 and 2 fever, chills, and myalgias that occur with the first infusion of rituximab and abate 
with subsequent treatments. More grade 3 and 4 pulmonary symptoms, hypotension, and chills 
were observed when rituximab was used to treat bulky disease.  
 
With demonstrated high efficacy and low toxicity in single-agent studies, rituximab has been 
combined with traditional cytotoxic chemotherapy in multiple studies. Several recent trials have 
reported impressive response rates and durable remissions for patients with indolent NHL treated 
with rituximab combinations.  Rituximab with cyclophosphamide, vincristine, and prednisone (R-
CVP) was compared to the same regimen without rituximab (CVP) in a randomized trial of 321 
previously untreated patients with stage III-IV follicular NHL.  The ORR and CR rates were 81% 
and 41% for patients treated with R-CVP versus 57% and 10% for patients who received CVP 
alone.  Patients in the R-CVP arm also had a significant improvement in time to progression (TTP) 
with a median of 30 months of follow-up (median TTP 32 months for R-CVP versus 15 months for 
CVP, p<.0001).  
 
The use of rituximab as maintenance therapy to maintain partial or complete remissions after initial 
therapy has also been evaluated.  This strategy attempts to take advantage of the agent’s ease of 
administration and favorable efficacy and toxicity profile.   
 
In the PRIMA study, 1217 patients received cytotoxic chemotherapy plus rituximab as per standard 
practice. Of patients who achieved a complete or partial response (1019/1217, 84%), 505 patients 
were randomized to receive rituximab maintenance versus 513 randomized to observation. The 
PFS in the group that got rituximab maintenance was 74.9% versus 57.6% in the group that did 
not. Rituximab essentially cut the risk of progression in half. The CR/CRu rate was 71.5% with 


 
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rituximab and 52.2% without. Infectious grades 2-4 were the most common adverse event 
occurring in 39% of those who got maintenance rituximab and 24% of those who did not.  
 
Rituximab with lenalidomide (R2) is effective and may be synergistic. Lenalidomide may increase 
CD20 expression and enhance ADCC to augment rituximab activity. Rituximab appears to 
enhance the ADCC-promoting activity of lenalidomide.  
 
1.5 
Study Rationale 
Indolent B cell lymphomas are considered incurable with current standard therapy, even with multi-
agent chemotherapeutic regimens such as R-CHOP or high dose chemotherapy with autologous 
stem cell support. Since the advent of antibody-based therapy (rituximab, radioimmunotherapy) 
however, survival has improved. As more intense standard chemotherapy does not lead to cure, 
novel agents with alternative mechanisms of action are being investigated. These are generally 
used in the relapsed/refractory setting to demonstrate activity, then moved earlier in the treatment 
plan.  
 
Lenalidomide (Revlimid®) has significant single agent activity in relapsed aggressive non-Hodgkin 
lymphoma, with response rates of 35% including a CR rate of 12%. (14)  In-vitro studies have 
shown synergy when Lenalidomide and rituximab are combined. Lenalidomide is able to enhance 
the natural killer cell and monocyte mediated antibody dependent cellular cytotoxicity of this 
monoclonal antibody. Recent studies combining lenalidomide and rituximab have shown promising 
activity (overall response rate 90%, complete response rate 66%) with no unexpected toxicities. 
(63, 64) A CALBG trial using this lenalidomideand rituximab biological doublet demonstrated 
benefit with addition of rituximab to lenalidomide [Leonard, ASH 2011]. 
 
We completed a phase II trial of combination Velcade® and rituximab for untreated high tumor 
burden indolent non-Hodgkin lymphoma, The treatment regimen consists of Velcade®  1.6mg/m2 
days 1, 8, 15 and 22 and rituximab 375mg/m2 every week x 4 doses for cycle 1 and then day 1 of 
cycles 2 and 3. Each cycle lasted 5 weeks. After cycle 1 the response rate was 29%, all partial 
responses, but after the three planned induction cycles the overall response rate (ORR) doubled to 
59% and the complete response rate (CR) was 24%. This biological doublet combination is active 
and well tolerated. No grade 4 toxicities occurred. Grade 3 toxicities consisted of lymphopenia, 
partial small bowel obstruction and fatigue (all in 1 patient). No cytopenias or neurotoxicity was 
seen. Velcade® and rituximab provide an attractive treatment combination for indolent NHL 
because each agent has demonstrated efficacy as monotherapy and they are generally well 
tolerated with non-overlapping toxicities.  Each agent has a unique mechanism of action that when 
coupled together should minimize malignant cell cross-resistance.  Each agent also appears to 
promote apoptotic activity though negative effects on bcl-2.  Two Velcade® /rituximab treatment 
regimens were evaluated in a randomized phase II study for patients with relapsed, refractory low 
grade NHL.  Treatment Arm A treated patients with Velcade® 1.3 mg/m2 twice weekly on days 1, 
4, 8, and 11 of a 21-day cycle in combination with 4 doses of rituximab 375mg/m2 given on days 1, 
8, and 15 of cycle 1 and day 1 of cycle 2.  Patients on Treatment Arm B receive Velcade® 
1.6mg/m2 weekly on days 1, 8, 15, and 22 of a 35-day cycle with 4 doses of rituximab 375mg/m2 
weekly on days 1, 8, 15, and 22 of cycle 1.   Study end points include ORR, time to progression, 
and safety and tolerability data. At the time of this report 81 patients were enrolled on the study, 
and preliminary safety data are available for 60 patients.  Grade 3 or 4 adverse events have 
occurred in 54% of patients on Arm A (twice weekly Velcade®), and 18% of patients on Arm B 
(weekly Velcade®), with no grade 4 events on Arm B.  The most common grade 3 or 4 adverse 
events included nausea and/or vomiting (15% Arm A, 3% Arm B), diarrhea (4% Arm A, 9% Arm B), 
peripheral neuropathy (8% Arm A, 3% Arm B) and fatigue (4% Arm A, 6% Arm B).  Based on 


 
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preliminary data the response rate is 51% in Arm A and 54% in Arm B.  
 
Combinations of proteasome inhibitors with standard chemotherapy also appears safe effective, 
exemplified by combination of Velcade in mantle cell lymphoma with either R-HyperCVAD part A 
(E1405) or with R-CHOP without vincristine (VR-CAP).   In multiple myeloma, another indolent B 
cell malignancy, combination of proteasome inhibitors and Imids are effective and well-tolerated 
therapy, having become a standard approach both as initial therapy and at relapse. Drawing on 
these investigations in myeloma, combining Velcade® and lenalidomide is feasible and has 
resulted in promising clinical activity. In both trials the maximum tolerated dose of lenalidomide was 
25mg daily day 1 – 14 and Velcade® 1.3mg/m2 twice a week for 2 weeks. 
 
Lenalidomide, Velcade®   and rituximab are all active as single agents in patients with NHL, with 
response rates of about 29- 35%, 13.3%-33% and 34%-72% respectively when used in the relapse 
setting in patients with B-cell lymphoma. (14, 48, 49, 74, 75, 76)  Response rates can be improved 
when lenalidomide is combined with rituximab with an overall response rate of 86% and complete 
response rate of 79%. (63) Similarly we also get improved response rates when Velcade® is 
combined with rituximab, with overall response rates of 59% and complete responses of 25%. 
However, all 3 drugs have not been used together. Here we propose to use an oral proteasome 
inhibitor with improved toxicity profile and ease of administration. 
 
We will develop this novel biological triplet (RIXAR) by adding ixazomib to the R2 platform as initial 
therapy of high risk/HTB indolent lymphoma.  
 
We hypothesize that this novel biological triplet combination will: (1) have enhanced efficacy, 
assessed by an increase in overall and complete response rates, as well as more durable 
responses; (2) be a safe and well tolerated alternative to traditional cytotoxic chemotherapy in this 
patient population.   
 
This combination will target not just the neoplastic B-cell but will also be an attempt at 
reprogramming the microenvironment and infiltrating immune cells in an attempt to increase, 
deepen and lengthen responses. This approach may very well be the paradigm shift needed to 
impact the course of indolent B-cell lymphoma. 
 
To test our hypothesis, we will conduct a single-arm, phase IB/II clinical trial in which patients with 
untreated, low-grade B-cell NHL will receive an induction course of lenalidomide, ixazomib and 
rituximab limited to 1 year of therapy. 
 
1.6 
Correlative Testing 
 
 
1.6.1 Tissue Microarray 
One of the limitations of laboratory tissue sample analysis has been the cumbersome process of 
processing individual tissues. Tissue microarray is a technique where by multiple tissues can be 
processed simultaneously using high through-put technologies. A full set of tissue samples from 
this study can be stored on a single glass side and processed simultaneously for DNA, RNA or 
protein targets. This provides the ideal method of storing tissues samples so that they can be 
processed at a future time when more information on prognostic and predictive factors become 
available.  
 
1.6.2 Baseline T-Lymphocyte Subsets 
Nodal tissue from B-cell lymphomas also harbor T-cells. Jaffe and colleagues speculated that the 


 
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T-cells, which are normal, were interacting with the malignant clone in a functional way. They 
speculated that this may represent part of the host immune response against the neoplasm. Other 
groups continued to work on this and concluded that the infiltrating T-cells could either be helping 
or hindering the neoplasm.  
 
More recently Dave et al were able to show that the molecular signature of tumor infiltrating cells in 
lymph node biopsies of patients with follicular lymphoma provides prognostic information. Of note, 
the molecular signature was of the non-malignant tumor infiltrating cells, including T-cells, 
monocytes and dendritic cells. Also, T-lymphocyte subsets predict prognosis independently of the 
Follicular Lymphoma International Prognostic Index (FLIPI). CD4+ T-cells, interfollicular CD68+ 
cells (macrophages) are associated with a poor outcome and Follicular FOXP3+ cells, CD8+ cells, 
and programmed  death 1 + cells (PD-1) are associated with a good prognosis.  We have shown 
that absolute NK cells at baseline are a prognostic factor in follicular lymphoma. We plan to 
perform flow cytometry on peripheral blood obtained at diagnosis to evaluate baseline NK and T-
lymphocyte subsets and correlate this to response to therapy and outcomes (DFS, PFS and OS).  
 
2.0 
STUDY OBJECTIVES 
 
2.1 
Primary Objective (Phase I) 
To determine the maximum tolerated dose (MTD) and toxicity of the combination of oral ixazomib 
and lenalidomide plus rituximab in patients with previously untreated low-grade B cell lymphoma 
having high tumor burden by GELF criteria or FLIPI 3-5 (for FL only). 
 
2.2 
Secondary Objectives (Phase II) 
 
To determine overall response rate in an expanded cohort at the MTD for follicular 
lymphoma  
 
Duration of response, time to progression, progression free survival, time to treatment 
failure and overall survival. 
 
Create tissue microarray from paraffin embedded tissue for future studies. 
 
Assessment of baseline lymphocyte subsets as prognostic markers. 
 
2.3 
Study Endpoints 
Primary Endpoints (Phase I) 
 
Maximum tolerated dose (MTD) and toxicity of the combination of oral ixazomib and 
lenalidomide plus rituximab in this patient population.The MTD was determined to be 4 mg 
of Ixazomib. 
 
Secondary Endpoints (Phase II) 
In an expanded cohort at the MTD for follicular lymphoma: 
 
Overall response rate (by IWG criteria) (ORR) 
 
Duration of response (DOR) 
 
Time to progression (TTP) 
 
Progression free survival (PFS) 
 
Time to treatment failure (TTF) 
 
Overall survival   (OS) 
 
 
 
 


 
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3.0 
STUDY DESIGN  
 
3.1 
Overview of Study Design 
 
 
Phase I 
 
 
Patients with previously untreated low-grade B cell lymphoma having high tumor burden by 
GELF criteria and/or FLIPI 3-5 will be treated with the combination of oral ixazomib + 
lenalidomide + rituximab.  
 
The primary objective was to determine the maximum tolerated dose and toxicity of this 
regimen. The study proceded using a standard 3 + 3 design for determination of MTD 
during cycle 1. There were three dose levels for escalation. The MTD was determined to be 
DL3. 
 
 
Phase II 
 
 For the phase II portion of the study, one expansion cohort of 18 patients with follicular 
lymphomawill be treated at the at the MTD (DL3) ,  
Patients will be treated for 12 cycles of 4 week duration, unless disease progresses, 
unacceptable toxicity occurs or patient withdraws consent.  
 
3.2 
Number of Patients 
The phase 1 portion enrolled 12 patients. There will be one expansion cohort of 18 patients each.  
 
Patients will be considered enrolled on the study when they sign informed consent.  
 
3.3 
Duration of Study 
Patients will receive treatment for 1 year and assessed for response 1-3 months later (up to 15 
months total). They will then be followed per usual clinical standard of care. 
 
Study accrual will be over 2 years, with 15 month additional as above, for total of 39 months 
 
Serious adverse events that are still ongoing at the end of the study period will necessitate follow-
up to determine the final outcome. Any serious adverse event that occurs after the study period 
and is considered to be possibly related to the study treatment or study participation will be 
recorded and reported immediately. 
 
 
4.0 
PATIENT SELECTION 
 
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.   
 
4.1 
Inclusion Criteria 
 
Patients must meet all of the following inclusion criteria to be eligible for enrollment:  
 
_____ 4.1.1  Patients must have histologically confirmed, low-grade B-lymphocyte NHL by the 
World Health Organization Classification: 
 
Follicular lymphoma grades 1, 2, and 3a 
 
Marginal zone B-cell lymphoma, including extranodal (MALT), nodal and splenic  


 
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 
Excluding: 
 
 
 Small lymphocytic lymphoma  
 
Lymphoplasmacytic lymphoma/Waldenström’s macroglobulinemia (WM)  
_____ 4.1.2  Must have stage 2, 3 or 4 disease, with either high tumor burden by GELF criteria 
and/or FLIPI 3-5 (for FL) (see Appendix V for definition of nodal groups for FLIPI). 
 
_____ 4.1.2.1  To meet GELF criteria, patient must have at least one criterion (answer yes 
or no for each criterion): 
_____ Nodal or extranodal mass > 7 cm (document here the largest/longest single 
nodal or extranodal mass diameter) 
 
Largest size:__________ 
_____ At least 3 nodal masses: each > 3.0 cm in longest dimension 
_____ Systemic symptoms due to lymphoma or B symptoms 
_____ Splenomegaly with spleen > 16 cm by CT scan 
_____ Evidence of compression syndrome (e.g., ureteral, orbital, gastrointestinal) 
or pleural or peritoneal serous effusion due to lymphoma (irrespective of cell 
content) 
_____ Leukemic presentation (> 5.0 x 109/L malignant circulating follicular cells) 
_____  Cytopenias (absolute neutrophil count < 1.0 X 109/L, hemoglobin  
< 10 gm/dL, and/or platelets <100 x 109/L). 
 
AND/OR 
 
_____ 4.1.2.2  To meet FLIPI criteria for FL (see Appendix V for lymph node diagram), 
patient must have a score of 3, 4, or 5 (one point each for below criterion; answer yes or no 
for each criterion): 
_____ Age > 60 years 
_____ Ann Arbor stage III-IV 
_____ Hemoglobin level < 12 mg/dL 
_____ ≥ 5 nodal areas (see Appendix V for nodal diagram) 
_____ Serum LDH level above normal  
 
_____ 4.1.2.3 FLIPI2 (see Appendix V) 
 
FLIPI 2 is not a criterion for this study, but we would like to capture the elements 
and calculate FLIPI 2 for the protocol population  
 
Each patient should be assessed for the presence or absence of the following 5 
adverse prognostic factors (adverse factor in italics):  
1) 
Age (> 60 years vs. 60 years or less) 
2) 
Hemoglobin level (< 120 g/L vs. 120 g/L or higher) 
3) 
β2-microglobulin (above normal vs. normal or below) 
4) 
Largest involved lymph node (> 6 cm vs. 6cm or lower) 
5) 
Bone marrow (involved by histology vs. not involved)   
  
_____ 4.1.3  Must have previously untreated lymphoma.  A short (< 2 week) course of steroids for 
symptom palliation is permitted. Prior involved field radiotherapy for symptom palliation is permitted 
as long as there is measurable disease outside the radiation port. If radiotherapy has been given, 
there should be at least 7 days between last treatment and beginning of protocol therapy. 
 


 
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_____ 4.1.4  Patients must have measurable disease, defined as at least one lesion that can be 
accurately measured in at least one dimension (see section 11.0) 
 
_____ 4.1.5  Age >18 years.  Because no dosing or adverse event data are currently available on 
the use of ixazomib in combination with lenalidomide in patients <18 years of age, children are 
excluded from this study. 
 
_____ 4.1.6  Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2.  
ECOG PS = ______________ 
            Date: ___________________ 
 
_____ 4.1.7  Patients must have adequate hematologic, hepatic, and renal function as defined 
below. Patients who do not meet hematologic parameters (ANC, Platelets, Hemoglobin) for 
inclusion/exclusion due to marrow infiltration by disease are still eligible for the study): 
 
 
_____ 4.1.7.1  Absolute neutrophil count (ANC) > 1,000/mcL 
 
 
Absolute neutrophil count:  _________ 
 
 
Date of Test:  ____________________ 
 
_____ 4.1.7.2  Platelet count > 75,000/mcL 
 
 
Platelet count:  __________   
 
 
Date of Test:  __________ 
 
Platelet transfusions to help patients meet eligibility criteria are not allowed within 3 
days before study enrollment. 
 
_____ 4.1.7.3  Total bilirubin  1.5 x the upper limit of the normal range (ULN) 
 
 
Total bilirubin:  ___________ 
 
 
Date of Test:   ___________ 
 
_____ 4.1.7.4   AST (SGOT) < 3 x institutional upper limit of normal 
 
 
AST (SGOT):  ____________ 
 
 
Date of Test:  ____________ 
 
_____ 4.1.7.5  ALT (SGPT) < 3 x institutional upper limit of normal 
 
 
ALT (SGPT):  ___________ 
 
 
Date of Test:  ___________ 
 
_____ 4.1.7.6  Calculated creatinine clearance > 30 mL/min/1.73 m2  (see Appendix II) 
 
 
Creatinine clearance:  __________ 
 
 
Date of Test:  __________ 
 
See section below, “Dosing Regimen”, regarding lenalidomide dose adjustment for 
calculated creatinine clearance  30ml/min and < 60ml/min. 
 
_____ 4.1.8  Participants must agree to ongoing anticoagulation as prophylaxis against deep vein 
thrombosis (DVT) using aspirin (81 or 325 mg) daily, warfarin or low molecular weight heparin, or a 
patient already taking another oral anticoagulant (e.g. direct thrombin inhibitors for atrial fibrillation) 
may continue that agent. 
 


 
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_____ 4.1.9  All study participants must be willing to register with the mandatory RevAssist 
program and be willing to comply with its requirements.. 
 
_____ 4.1.10  All study participants must be registered into the mandatory lenalidomide (Revlimid) 
REMS® program, and be willing and able to comply with the requirements of the REMS® program. 
 
A woman of childbearing potential (WOCBP) is a sexually mature female who: 1) has not 
undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal 
for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 
consecutive months). 
 
Female patients who are WOCBP must agree to practice: 
 
2 effective methods of contraception, at the same time, from the time of signing the 
informed consent form through 90 days after the last dose of study drug, OR 
 
True abstinence when this is in line with the preferred and usual lifestyle of the subject.  
(Periodic abstinence [e.g., calendar, ovulation, symptothermal, post-ovulation methods] and 
withdrawal are not acceptable methods of contraception.) 
 
A WOCBP must have a negative serum or urine pregnancy test with a sensitivity of at least 
50 mIU/mL within 10-14 days prior to and again within 24 hours of starting therapy with 
lenalidomide Females of reproductive potential must adhere to the scheduled pregnancy 
testing as required in the lenalidomide (Revlimid)  REMS® program. 
 
Male patients, even if surgically sterilized (i.e., status post-vasectomy), must agree to one of the 
following: 
 
Agree to practice effective barrier contraception during the entire study treatment period 
and through 90 days after the last dose of study drug, OR 
 
Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of 
the subject.  (Periodic abstinence [e.g., calendar, ovulation, symptothermal, post-ovulation 
methods] and withdrawal are not acceptable methods of contraception.) 
 
_____ 4.1.11  Subjects must have the ability to understand and the willingness to sign a written 
informed consent document and HIPAA consent document. Voluntary written consent must be 
given before performance of any study related procedure not part of standard medical care, with 
the understanding that consent may be withdrawn by the patient at any time without prejudice to 
future medical care. 
 
4.2 
Exclusion Criteria 
The presence of any of the following will exclude a patient from study enrollment: 
 
_____ 4.2.1 Patients who are receiving any other investigational agents. 
 
_____ 4.2.2  Female patients who are lactating or have a positive serum pregnancy test during the 
screening period.  
 
_____ 4.2.3  Major surgery within 14 days before enrollment. 
 
_____ 4.2.4  Radiotherapy within 14 days before enrollment. If the involved field is small (single 
nodal area), 7 days will be considered a sufficient interval between treatment and beginning of 
protocol therapy. 
 


 
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_____ 4.2.5  Known central nervous system involvement with the disease under study. 
 
_____ 4.2.6  Infection requiring systemic antibiotic therapy or other serious infection within 14 days 
before study enrollment. 
 
_____ 4.2.7  Evidence of current uncontrolled cardiovascular conditions, including cardiac 
arrhythmias, symptomatic congestive heart failure, unstable angina, or myocardial infarction within 
the past 6 months. 
 
_____ 4.2.8  Systemic treatment, within 14 days before the beginning of protocol therapy, with  
CYP3A inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital), or use 
of St. John’s wort.  
 
Lists including medications or substances known or with the potential to interact with specific 
CYP450 enzymes are provided in Appendix III. 
 
_____ 4.2.9  Known allergy to any of the study medications, their analogues, or excipients in the 
various formulations of any agent. Specifically, prior desquamating rash or erythema nodosum 
during prior thalidomide or other similar agents. 
 
_____ 4.2.10  Known GI disease or GI procedure that could interfere with the oral absorption or 
tolerance of ixazomib or lenalidomide including difficulty swallowing. 
 
_____ 4.2.11  Diagnosed or treated for another malignancy within 2 years before study enrollment 
or previously diagnosed with another malignancy and have any evidence of residual disease.  
Patients with non-melanoma skin cancer or carcinoma in situ of any type are not excluded if they 
have undergone complete resection. 
 
_____ 4.2.12  Patient has  Grade 2 peripheral neuropathy on clinical examination during the 
screening period. 
 
_____ 4.2.13  Participation in other clinical trials, including those with other investigational agents 
not included in this trial, within 30 days of the start of this trial and throughout the duration of this 
trial.  
 
_____ 4.2.14  Any prior use of lenalidomide (Revlimid®) or Velcade®. 
 
_____ 4.2.15  Known seropositivity for, or active viral infection with, HIV, HBV (unless due to 
vaccination), or HCV. HIV-positive patients on combination antiretroviral therapy are ineligible 
because of the potential for pharmacokinetic interactions with lenalidomide and ixazomib.  In 
addition, these patients are at increased risk of lethal infections when treated with marrow 
suppressive therapy.  Appropriate studies will be undertaken in patients receiving combination 
antiretroviral therapy when indicated. 
 
_____ 4.2.16  Pregnant or breastfeeding women are excluded from this study because 
lenalidomide has known teratogenic effects. Because there is an unknown, but potential risk for 
adverse events in nursing infants secondary to treatment of the mother with lenalidomide, 
breastfeeding should be discontinued if the mother is treated with lenalidomide.  These potential 
risks may also apply to other agents used in this study.   
 


 
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4.3 
Inclusion of Women and Minorities   
 
Both men and women and members of all races and ethnic groups are eligible for this trial. 
 
 
 
5.0 
REGISTRATION 
 
All subjects who have been consented are to be registered in the OnCore™ Database. For those 
subjects who are consented, but not enrolled, the reason for exclusion must be recorded. 
 
All subjects will be registered through Cleveland Clinic and will be provided a study number by 
calling the research coordinator listed on the cover page. 
 
6.0 
TREATMENT PLAN 
 
6.1 
Agent Administration 
Appropriate dose modifications for lenalidomide, ixazomib and rituximab are described in Section 
7.0   
 
Reported adverse events and potential risks of lenalidomide, ixazomib and rituximab are described 
in Section 8.0.  
 
No investigational or commercial agents or therapies other than those described below may be 
administered with the intent to treat the patient's malignancy. 
 
6.1.1 Ixazomib Administration 
 
The ixazomib drug product is provided in strengths of 4.0-, 3.0-, 2.3-, 2.0-, 0.5-, and 0.2 mg 
capsules as the active boronic acid. The different dose strengths are differentiated by both capsule 
size and color as described below: 
 
 
 
 
Dose Strength 
Capsule Size 
Capsule Color 
 
 
 
4.0 mg 
Size 4 
Ivory 
3.0 mg 
Size 3 
Light gray 
2.0 mg 
Size 2 
Swedish orange 
0.5 mg 
Size 3 
Dark green 
 
 
 
 
For additional details, please see the ixazomib IB. 
 
Ixazomib Administration 
All protocol-specific criteria for administration of study drug must be met and documented before 
drug administration.  Study drug will be administered or dispensed only to eligible patients under 
the supervision of the investigator or identified sub-investigator(s).  Patients should be monitored 
for toxicity, as necessary, and doses of ixazomib should be modified as needed to accommodate 
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adjustments of ixazomib dose (see Section 7.0). 
 
Capsules of ixazomib will also be referred to as study drug.  Study drug will be supplied by 
Millennium as capsules of 0.5, 2.0, 3.0 and 4.0 mg ixazomib.  
 
The prescribed administration of ixazomib doses in this study is 2.0, 3.0 or 4.0 mg ixazomib on 
days 1, 8 and 15 of each 28 day cycle.  
 
Patients should be instructed to swallow ixazomib capsules whole, with water, and not to break, 
chew, or open the capsules.  Ixazomib should be taken on an empty stomach (no food or drink) at 
least 1 hour before or at least 2 hours after food.  Each capsule should be swallowed separately 
with a sip of water.  A total of approximately 8 ounces (240 mL) of water should be taken with the 
capsules.   
 
Missed doses can be taken as soon as the patient remembers if the next scheduled dose is 72 
hours or more away.  A double dose should not be taken to make up for a missed dose.  If the 
patient vomits after taking a dose, the patient should not repeat the dose but should resume dosing 
at the time of the next scheduled dose. 
 
Ixazomib Destruction 
Investigational ixazomib (expired or end of study) should be destroyed on site according to the 
institution’s standard operating procedure.  Be sure to document removal and destruction on drug 
accountability logs. 
 
Pregnancy 
It is not known what effects ixazomib has on human pregnancy or development of the embryo or 
fetus; however, lenalidomide has known severe adverse effects.  Therefore, female patients 
participating in this study must avoid becoming pregnant, and male patients should avoid 
impregnating a female partner.  Nonsterilized female patients of reproductive age group and male 
patients must use effective methods of contraception through defined periods during and after 
study treatment as specified in the inclusion/exclusion criteria (Section 4.1.10). 
 
6.1.2 Lenalidomide Administration 
 
Lenalidomide (Revlimid®) will be provided to research subjects for the duration of their 
participation in this trial at no charge to them or their insurance providers.  Lenalidomide will be 
provided in accordance with the Celgene Corporation’s lenalidomide (Revlimid) REMS® program.  
Per standard lenalidomide (Revlimid) REMS® program requirements, all physicians who prescribe 
lenalidomide for research subjects enrolled into this trial, and all research subjects enrolled into this 
trial, must be registered in, and must comply with, all requirements of the lenalidomide (Revlimid) 
REMS® program.   
 
Only enough lenalidomide for one cycle of therapy will be supplied to the patient each cycle.  
 
Dosing Information 
Lenalidomide starting dose will be based on baseline calculated creatinine clearance as follows: 
 
Lenalidomide Starting Dose Based on Renal Function at Study Entry 


 
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Baseline Calculated Creatinine 
Clearance (by Cockcroft-Gault) 
Starting Lenalidomide Dose (20 mg) 
 60 ml/min 
20 mg daily on Days 1 - 21 of each 28-day cycle  
 30 and < 60 ml/min 
10 mg daily on Days 1 - 21 of each 28-day cycle 
 
Patients started with a reduced lenalidomide dose due to baseline calculated creatinine clearance 
≥ 30ml/min but < 60ml/min, may have their lenalidomide dose gradually increased in a step-wise 
manner at the start of Cycle 2 or at the start of subsequent treatment cycles, if they tolerated the 
prior treatment cycle without requiring dose modifications, interruptions or delays due to toxicity.  
Lenalidomide dose titrations are permitted in 5 mg increments on the same dosing schedule up to 
the maximum allowable target dose.  The lenalidomide dose may only be increased once every 28 
days (or less frequently), and may only be increased if the prior treatment cycle was completed 
without requiring dose modifications, interruptions or delays due to toxicity.   
 
Dosing will be in the morning at approximately the same time each day.  Prescriptions must be 
filled within 7 days for females of child bearing potential and 14 days for all other risk categories. 
 
Swallow lenalidomide capsules whole with water at the same time each day.  Do not break, chew 
or open the capsules.   
 
If a dose of lenalidomide is missed, it should be taken as soon as possible on the same day.  If it is 
missed for the entire day, it should not be made up. 
 
Patients who take more than the prescribed dose of lenalidomide should be instructed to seek 
emergency medical care if needed and contact study staff immediately. 
 
Pregnancy Testing    
Must follow pregnancy testing requirements as outlined in the lenalidomide (Revlimid) REMS® 
program material. 
 
 
Unused Study Drug Supplies 
Celgene will instruct the Investigator on return or destruction of unused study drug.  If any study 
drug is lost or damaged, its disposition should be documented in the source documents.  Study 
drug supplies will be retained at the clinical site pending instructions for disposition by Celgene.  
Patients will be instructed to return empty bottles or unused capsules to the clinic site.   
 
Special Handling Instructions 
Females of childbearing potential should not handle or administer lenalidomide unless they are 
wearing gloves.  
 
6.1.3 Rituximab (Rituxan ®) 
 
Mode of Action 
Rituximab is a chimeric murine/human IgG1 kappa monoclonal antibody (Chinese hamster ovary 
[CHO] transfectoma). It recognizes the CD20 antigen expressed on normal B cells and most 
malignant B-cell lymphomas, binds with high affinity to CD20+ cells, performs human effector 
functions in vitro, and depletes B cells in vivo. The Fab domain of rituximab binds to CD20 on B-


 
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lymphocytes and the Fc domain recruits immune effector functions to mediate B cell lysis in vitro. 
The biological effect is manifested by B-cell depletion. 
 
Storage and Stability 
Intact vials of rituximab are stored at refrigerated temperatures of 2 - 80C Celsius (36 - 460 
Fahrenheit). Protect vials from direct sunlight. Once diluted to a concentration of 1 - 4 mg/mL in 
polyvinylchloride or polyolefin IV bags containing normal saline or 5% dextrose, product is stable 
for up to 24 hours at 2 - 80 C, and at room temperature for an additional 12 hours after refrigeration 
(for a maximum period of 36 hours) if protected from light. 
 
Preparation 
Withdraw the necessary amount of rituximab and dilute to a final concentration of 1 - 4 mg/mL into 
an infusion bag containing either 0.9% Sodium Chloride or 5% Dextrose in Water. Gently invert the 
bag to mix the solution. Caution should be taken during the preparation of the drug, as shaking can 
cause aggregation and precipitation of the antibody. 
 
Administration 
Rituximab is administered intravenously. An in-line filter is not required. Rituximab infusion rates 
and monitoring should be per institutional guidelines.   
 
Available at the bedside prior to rituximab administration will be epinephrine for subcutaneous 
injection, diphenhydramine hydrochloride for IV injection, and resuscitation equipment for the 
emergency management of anaphylactoid reactions. Do not mix or dilute rituximab with other 
drugs. No incompatibilities between rituximab and polyvinylchloride or polyethylene bags have 
been observed. 
 
Availability 
Commercially available: Please see Package Insert for further information. 
 
6.1.4 Preparation, Reconstitution, and Dispensing 
Ixazomib and lenalidomide are anticancer drugs and as with other potentially toxic compounds 
caution should be exercised when handling ixazomib capsules. 
 
For rituximab see Section 6.1.3. 
 
6.1.4.1  Packaging and Labeling 
Ixazomib:  The study drug ixazomib capsules will be provided by Millennium.  The study drug will 
be labeled and handled as open-label material, and packaging labels will fulfill all requirements 
specified by governing regulations.   
 
The capsules are individually packaged using cold-form foil-foil blisters that are in a child-resistant 
carton.  There are 3 capsules in each wallet/carton.  
 
Lenalidomide:  Celgene Corporation will supply lenalidomide (Revlimid®) to study participants at 
no charge through Celgene’s Revlimid Risk Evaluation and Mitigation Strategy™ (REMS) (formerly 
known as RevAssist® Program).  Lenalidomide will be shipped directly to patients. Lenalidomide 
will be supplied as capsules for oral administration.  Bottles will contain a sufficient number of 
capsules for one cycle of dosing.    
 
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contents as study medication.  In addition, the label will bear Celgene’s name, quantity contained 
and the standard caution statement as follows:  “Caution: New drug - Limited by Federal Law to 
Investigational Use.” The study drug label must be clearly visible.  Additional labels must not cover 
the Celgene label. 
 
Lenalidomide Special Handling Instructions:  Females of childbearing potential should not handle 
or administer lenalidomide unless they are wearing gloves. 
 
6.1.4.2  Storage, Handling, and Accountability 
Ixazomib:  Upon receipt at the investigative site, ixazomib should remain in the blister and carton 
provided until use or until drug is dispensed. The container should be stored at the investigative 
site refrigerated (36°F to 46°F, 2°C to 8°C). Ensure that the drug is used before the retest expiry 
date provided by Millennium. Expiry extensions will be communicated accordingly with updated 
documentation to support the extended shelf life. 
 
In countries where local regulations permit, ixazomib capsules dispensed to the patient for take-
home dosing should remain in the blister packaging and refrigerated as noted above until the point 
of use. The investigative site is responsible for providing the medication to the patient in the correct 
daily dose configurations. Comprehensive instructions should be provided to the patient in order to 
ensure compliance with dosing procedures. Patients who are receiving take-home medication 
should be given only 1 cycle of medication at a time. Patients should be instructed to store the 
medication refrigerated (36°F to 46°F, 2°C to 8°C) for the duration of each cycle. Patients should 
be instructed to return their empty blister packs to the investigative site, rather than discarding 
them. Reconciliation will occur accordingly when the patient returns for their next cycle of take-
home medication. Any extreme in temperature should be reported as an excursion and should be 
dealt with on a case-by-case basis. 
 
Because ixazomib is an investigational agent, it should be handled with due care. Patients should 
be instructed not to chew, break, or open capsules. In case of contact with broken capsules, 
raising dust should be avoided during the clean-up operation. The product may be harmful by 
inhalation, ingestion, or skin absorption. Gloves and protective clothing should be worn during 
cleanup and return of broken capsules and powder to minimize skin contact. 
The area should be ventilated and the site washed with soap and water after material pick-up is 
complete. 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. 
 
Lenalidomide:  Lenalidomide should be stored at room temperature away from direct sunlight and 
protected from excessive heat and cold.     
 
Celgene will instruct the Investigator on the return or destruction of unused study drug.  If any 
study drug is lost or damaged, its disposition should be documented in the source documents.  
Study drug supplies will be retained at the clinical site pending instructions for disposition by 
Celgene. Patients will be instructed to return empty bottles or unused capsules to the clinic site.   


 
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6.1.4.3  Study Compliance 
Study drug will be administered or dispensed only to eligible patients under the supervision of the 
investigator or identified sub-investigator(s).  The appropriate study personnel will maintain records 
of study drug receipt and dispensing. 
 
6.2 
Dose Escalation 
 
 
Not applicable to Phase II. 
 
 
Termination of Treatment and/or Study Participation 
Patients will be informed that they have the right to withdraw from the study at any time for any 
reason, without prejudice to their medical care.  The investigator also has the right to withdraw 
patients from the study for any of the following reasons: 
 
Adverse event 
 
Protocol violation 
 
Lost to follow-up 
 
Progressive disease 
 
Study terminated  
 
Other 
 
Patients who are withdrawn from the Phase 1B portion of the study prior to completion of cycle 1, 
except if removed for DLT, will be replaced. Other patients taken off study prior to the first 
evaluation, unless for progressive disease, will be replaced. 
 
At the time of withdrawal, all study procedures outlined for the End of Study visit should be 
completed. The primary reason for patient’s withdrawal from the study should be recorded in the 
source documents and CRF. 
 
6.3 
Definition of Dose-Limiting Toxicity 
 
Dose limiting toxicity will be defined as any of the following AEs that occur any time from the initial 
dose of study treatment, with severity graded according to the NCI Common Terminology Criteria 
for Adverse Events (CTCAE), Version 4.0: 
 
A DLT is defined as any of the following treatment-related AE that occurs during the first cycle 
graded according to the NCI Common Terminology Criteria for Adverse Events (CTCAE), Version 
4.0: 
 
• Grade 4 neutropenia lasting ≥ 7 days; 
• Grade 3 or 4 neutropenia complicated by fever (a single temperature of >38.30 C (1010F) or a 
sustained temperature of ≥380 C (100.40 F) for more than one hour) or infection; 
• Grade 4 thrombocytopenia; 
• Grade 3 thrombocytopenia complicated by hemorrhage; 
• Grade 3 or 4 anemia. 
• Grade ≥ 3 non-hematologic toxicity except for  alopecia, fatigue or anorexia lasting < 7 days, or 
Grade 3 nausea and/or vomiting that persists for < 2 days with appropriate supportive care. 
Treatment delay of more than 2 weeks in the initiation of the subsequent cycle of treatment 
because of a lack of adequate recovery of treatment related hematological or non-hematologic 
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Treatment Assignment 
Patients will be assigned to the next available dose level during the phase 1B portion of the study. 
Subsequent expansion cohorts will be enrolled at the MTD level. 
 
6.4 
General Concomitant Medications and Supportive Care Guidelines 
 
6.4.1  Excluded Concomitant Medications and Procedures 
 
 
Systemic treatment with any of the following metabolizing enzyme inducers should be avoided, 
unless there is no appropriate alternative medication for the patient’s use (Rationale: if there were 
to be a drug-drug interaction with an inducer, ixazomib exposure would be decreased): 
 
Strong CYP3A inducers:  rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, and 
phenobarbital 
 
The following medicinal products and procedures are prohibited during the study. 
 
Any antineoplastic treatment other than study drugs 
 
Radiation therapy  
 
Platelet transfusions to help patients meet eligibility criteria are not allowed within 3 days 
prior to study drug dosing for any dosing day 
 
Excluded foods and dietary supplements include St. John’s wort  
 
6.4.2  Permitted Concomitant Medications and Procedures  
The following medications and procedures are permitted during the study: 
 
Antiemetics, including 5-HT3 serotonin receptor antagonists, may be used at the discretion 
of the investigator. 
 
Loperamide or other antidiarrheal should be used for symptomatic diarrhea at discretion of 
the investigator. The dose and regimen will be according to institutional guidelines. IVF 
should be given to prevent volume depletion. 
 
Growth factors (e.g., granulocyte colony stimulating factor [G-CSF], granulocyte 
macrophage-colony stimulating factor [GM-CSF]) are permitted. Their use should follow 
published guidelines and/or institutional practice; however, alternative usage may be 
reviewed with the Millennium Clinical or Medical Representative. Their use should follow 
published guidelines and/or institutional practice. Erythropoietin will not be allowed in this 
study. 
 
Patients should be transfused with red cells and platelets as clinically indicated and 
according to institutional guidelines. 
 
All patients should receive antiviral therapy with acyclovir or valcyclovir (400 mg BID) while 
on treatment and for six months after the last dose of study drug.. 
 
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. 
 
6.4.3  Precautions and Restrictions  
 
Fluid deficit should be corrected before initiation of treatment and during treatment. 
 
Nonsteroidal anti-inflammatory drugs (NSAIDs) should be avoided with impaired renal 


 
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function given reported NSAID-induced renal failure in patients with decreased renal 
function. 
 
Pregnancy: It is not known what effects ixazomib has on human pregnancy or development 
of the embryo or fetus; however, lenalidomide has known severe adverse effects.  
Therefore, female patients participating in this study must avoid becoming pregnant, and 
male patients should avoid impregnating a female partner.  Nonsterilized female patients of 
reproductive age group and male patients must use effective methods of contraception 
through defined periods during and after study treatment as specified in the 
inclusion/exclusion criteria (Section 4.1.10). 
 
6.4.4  Management of Clinical Events Associated with Ixazomib 
Adverse drug reactions such as thrombocytopenia, diarrhea, fatigue, nausea, vomiting, and rash 
have been associated with ixazomib treatment.  Management guidelines regarding these events 
are outlined below.  Further details of management of ixazomib AEs are described in Section 6 of 
the ixazomib IB.   
 
Prophylaxis against Risk of Reactivation of Herpes Infection 
Patients may be at an increased risk of infection including reactivation of herpes zoster and herpes 
simplex viruses.  Antiviral therapy such as acyclovir or valacyclovir are to be used prophylactically 
while on treatment and for six months after the last dose of study drug..   
 
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. Fluid deficit should be corrected before initiation of 
study drug and during treatment. 
 
Diarrhea 
Prophylactic anti-diarrheals will not be used in this protocol. However, diarrhea should be managed 
according to clinical practice, including the administration of anti-diarrheals once infectious causes 
are excluded. Fluid intake should be maintained to avoid dehydration. Fluid deficit should be 
corrected before initiation of treatment and during treatment. 
 
Erythematous Rash With or Without Pruritus 
As with bortezomib, rash with or without pruritus has been reported with ixazomib, primarily at the 
higher doses tested and when given with agents where rash is an overlapping toxicity.  Rash due 
to lenalidomide and rituximab have also been reported. 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 with ixazomib is most commonly reported within the first 3 cycles of therapy.  The rash with 
either agent alone is often transient, self-limiting, and is typically Grade 1 to 2 in severity. As there 
are no data about rash with this combination, caution should be exercised; however, bortezomib + 
lenalidomide in combination for myeloma have not led to significant increase in rash.  
 
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 lenalidomide should be modified per protocol and re-initiated at a 


 
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reduced level, per protocol.   
 
In line with clinical practice, dermatology consult and biopsy of Grade 3 or higher rash or any SAE 
involving rash is recommended.  Prophylactic measures should also be considered if a patient has 
previously developed a rash (e.g., using a thick, alcohol-free emollient cream on dry areas of the 
body or oral or topical antihistamines).  The rare risks of Stevens-Johnson Syndrome, a severe and 
potentially life-threatening rash with skin peeling and mouth sores, toxic epidermal necrolysis 
(TEN), drug reaction with eosinophilia and systemic symptoms (DRESS Syndrome) and 
pemphigus vulgaris have been reported in ixazomib-containing oncology studies (or blinded 
studies containing ixazomib/placebo) when given in a multi-therapy regimen in combination with 
agents associated with skin reactions. These reactions should be managed symptomatically 
according to standard medical practice.  Punch biopsies for histopathological analysis are 
encouraged at the discretion of the investigator. 
 
Thrombocytopenia 
Blood counts should be monitored regularly as outlined in the protocol with additional testing 
obtained according to standard clinical practice. Thrombocytopenia may be severe but has been 
manageable with platelet transfusions according to standard clinical practice. Ixazomib 
administration should be modified as noted as per dose modification recommendations in the 
protocol when thrombocytopenia occurs (see Tables 7-1 A and 7-2). Therapy can be reinitiated at 
a reduced level upon recovery of platelet counts. A rare risk is thrombotic thrombocytopenic 
purpura (TTP), a rare blood disorder where blood clots form in small blood vessels throughout the 
body characterized by thrombocytopenia, petechiae, fever, or possibly more serious signs and 
symptoms. TTP should be managed symptomatically according to standard medical practice. 
 
Neutropenia 
Blood counts should be monitored regularly as outlined in the protocol with additional testing 
obtained according to standard clinical practice.  Neutropenia may be severe but has been 
manageable.  All efforts should be made to administer Growth Factor to avoid dose delays or 
reductions. Ixazomib and lenalidomide administration should be modified as per dose modification 
recommendations in the protocol when neutropenia occurs (see Tables 7-1 A, 7-1 B, and 7-2).  
Therapy can be reinitiated at a reduced level upon recovery of ANCs. 
 
Fluid Deficit 
Dehydration should be avoided since ixazomib may cause vomiting, diarrhea, and dehydration.  
Acute renal failure has been reported in patients treated with ixazomib, commonly in the setting of 
the previously noted gastrointestinal toxicities and dehydration. 
 
Fluid deficit should be corrected before initiation of study drug and as needed during treatment to 
avoid dehydration. 
 
Hypotension 
Symptomatic hypotension and orthostatic hypotension with or without syncope have been reported 
with ixazomib, as well as with rituximab.  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. 


 
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Posterior Reversible Encephalopathy Syndrome 
One case of posterior reversible encephalopathy syndrome, which ultimately resolved, has been 
reported with ixazomib; other cases have been reported with rituximab.  This condition is 
characterized by headache, seizures and visual loss, as well as abrupt increase in blood pressure.  
Diagnosis may be confirmed by magnetic resonance imaging (MRI).  If the syndrome is diagnosed 
or suspected, symptom-directed treatment should be maintained until the condition is reversed by 
control of hypertension or other instigating factors. Treatment would be discontinued. 
 
Transverse Myelitis 
Transverse myelitis has also been reported with ixazomib. It is not known if ixazomib causes 
transverse myelitis; however, because it happened to a patient receiving ixazomib, the possibility 
that ixazomib may have contributed to transverse myelitis cannot be excluded. 
 
6.5 
Duration of Therapy 
Therapy will be continued for 12 cycles or until unacceptable toxicity.  
 
6.6 
Duration of Follow Up 
Patients will be followed for toxicity for 30 days after treatment has been discontinued or until 
death, whichever occurs first  
 
Following treatment for 1 year, patients will be assessed per clinical standards, generally every 3 
months (+/- 7 days) for 2 years.  
 
The clinical course of each adverse event will be followed until resolution, stabilization, or until it 
has been determined that the study treatment or participation is not the cause, up to 3 months.   
 
Serious adverse events (SAE) that are still ongoing at the end of the study period will necessitate 
follow-up to determine the final outcome. Any serious adverse event that occurs after the study 
period and is considered to be possibly related to the study treatment or study participation will be 
recorded and reported immediately. 
 
 
7.0 
DOSING DELAYS / DOSE MODIFICATIONS 
 
7.1 
Dose-Modification Guidelines  
All toxicity grading is NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. 
 
Note: Patients at risk of developing tumor lysis syndrome (TLS) should be followed closely and 
appropriate laboratory monitoring performed.  Appropriate medical therapy should be provided for 
patients who develop tumor lysis syndrome.   
 
7.1.1 Rituximab 
If rituximab infusion reactions occur that are not manageable by standard institutional procedures, 
rituximab dose should be divided over 2 days, with 10-25% of the dose on day 1 and the rest on 
day 2. Also, prednisone at up to 60 mg (or equivalent other glucocorticoid) may be given at about 
13, 7 and 1 hour before rituximab is started on day 1. If rituximab cannot be safely administered 
despite these maneuvers due to toxicity, rituximab will be discontinued, but the patient will remain 
on study treatment with the other two agents.  
 


 
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7.1.2  Criteria for Beginning or Delaying a Subsequent Treatment Cycle & Dose 
Modifications for Treatment Associated Toxicity 
Treatment will use a cycle length of 28 days. For a new cycle of treatment to begin: 
 
ANC must be ≥ 1,000/mm3. 
 
Platelet count must be ≥ 75,000/mm3. 
 
All other non-hematologic toxicity (except alopecia) must have resolved to ≤ Grade 2 or to 
the patient’s baseline condition 
 
If ANC is less than 500, dosing should be delayed a week until resolution. Pegfilgrastim or 
filgrastim daily is encouraged 
 
If ANC is between 500 and 1000, pegfilgrastim 6 mg (preferred) or filgrastim 300-400 mg 
should be administered to maintain dose intensity. 
 
 
If the patient fails to meet these criteria for initiation of the next cycle of treatment, dosing should be 
delayed for 1 week. At that time, the patient should be re-evaluated to determine whether the 
criteria have been met. If the patient continues to fail to meet these criteria, delay therapy and 
continue to re-evaluate. The maximum delay before treatment should be discontinued will be 4 
weeks or at the discretion of the Principal Investigator. 
 
For dosing recommendations upon recovery, refer to Table 7-3 and Table 7-4. 
 
Table 7-1 A 
  IXAZOMIB Dose Reduction Steps:  
 
Once ixazomib is reduced for any toxicity, the dose may not be re-escalated.  
Dose Level 
Dose (mg) 
Schedule 
Dose Level 3 
4.0 mg 
Days 1, 8, 15 
Dose Level 2 
3.0 mg 
Days 1, 8, 15 
Dose Level 1 
2.0 mg 
Days 1, 8, 15 
Dose Level -1 
1.0 mg 
Days 1, 8, 15 
Dose Level -2 
1.0 mg 
Day 1 only 


 
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Table 7-1 B    LENALIDOMIDE Dose 
Reduction Steps  
Starting Dose 
 If CrCl 30-60 start dose level -2 
20 mg daily on Days 1-21 every 28 days 
Dose Level – 1 
15 mg daily on Days 1-21 every 28 days 
Dose Level – 2 
10 mg daily on Days 1-21 every 28 days 
Dose Level – 3 
5 mg daily on Days 1-21 every 28 days 
Dose Level – 4 
5 mg on alternate days on Days 1-21 every 28 days 
Lenalidomide 5 mg daily on alternate days on days 1-21 every 28 days is the minimum lenalidomide 
dose.  Discontinue lenalidomide in patients who cannot tolerate this dose. 
Table 7-2  Dose Modifications for Intra-cycle Hematologic Toxicity 
NCI CTC Toxicity Grade 
Dose Modification Instructions for Cycle 1 Only 
Grade 3 neutropenia 
associated with fever 
(temperature ≥ 38.5º C) 
or Grade 4 neutropenia 
 
Hold (interrupt) lenalidomide and ixazomib dosing. 
For cycle 1, day 8 and/or 15 rituximab should be held. 
 
Follow CBC weekly. 
 
Consider G-CSF to improve neutropenia. 
 
When neutropenia has resolved to ≤ grade 2 prior to day 21 
of the current cycle, restart both lenolidomide and ixazomib 
either at the same dose level or 1 dose level lower at the 
discretion of the investigator. Continue at this dose level until 
day 21.  
Thrombocytopenia 
≥Grade 3 (platelet 
count < 50,000/mm³) 
 
Hold (interrupt) lenalidomide and ixazomib dosing. 
 
Follow CBC weekly. 
 
If thrombocytopenia resolves to ≤ grade 2 prior to Day 21 of 
the current cycle, restart lenalidomide and ixazomib at 
current dose level and continue through the scheduled Day 
21 of the current cycle.  Otherwise, omit for remainder of 
cycle and reduce the dose of lenalidomide and ixazomib by 1 
dose level at the start of the next cycle.  Omitted doses are 
not made up. 
 
Hold prophylactic anti-coagulation, if applicable. 
 
Restart prophylactic anti-coagulation when platelet count 
recovers to  grade 2. 


 
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Dosage Adjustments for Hematologic Toxicity 
 
Table 7-3    Dose Modifications in Subsequent Treatment Cycles 2+ for 
Hematologic Toxicity 
Criteria 
Action 
ANC < 0.5 x 109/L, platelet count < 75  109/L, 
or other non-hematologic toxicities > Grade 
1 (except for the AEs noted in table 7-4) or 
not to the patient’s baseline condition 
 
Hold ixazomib and lenalidomide until 
neutropenia and/or thrombocytopenia is ≤ 
grade 2. 
 
Consider G-CSF to improve neutropenia.  
 
Resume ixazomib and lenalidomide at 
same dose level or 1 dose level lower at the 
discretion of the investigator. 
 
The maximum delay before treatment 
should be discontinued will be 4 weeks or at 
the discretion of the PI. 
ANC between 0.5 x 109/L and 1.0 x 109/L, 
platelet count < 75  109/L, or other non-
hematologic toxicities > Grade 1 or not to 
the patient’s baseline condition 
 
Recommend administration of G-CSF. 
 
Resume lenalidomide and ixazomib at 
same dose level or 1 dose level lower at the 
discretion of the investigator. 
 


 
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Treatment modifications due to treatment-related non-hematologic AEs (Table 7-4). 
Table 7-4: Dose Modifications for Non-Hematologic Toxicity 
NCI CTC Toxicity Grade 
Dose Modification Instructions  
Non-blistering rash: 
 
Grade 1-2 
 
Grade 3 
 
Grade 4 
 
 
Grade 1-2, symptomatic intervention; no change in dosing. 
 
If Grade 3, hold (interrupt) lenalidomide and ixazomib.  Follow weekly. 
 
If the toxicity resolves to ≤ grade 1 prior to Day 21 of the current 
cycle, restart lenalidomide at next lower dose level and continue 
through the scheduled Day 21 of the current cycle.  Otherwise, omit 
for remainder of cycle and reduce the dose of lenalidomide by 1 dose 
level at the start of the next cycle.  Omitted doses are not made up. 
 
If Grade 4, discontinue rituximab, lenalidomide and ixazomib.   
Remove patient from study. 
Desquamating 
(blistering) rash: 
 
Any Grade  
 
Discontinue rituximab, lenalidomide and ixazomib.  Remove patient 
from study. 
Peripheral Neuropathy: 
 
Grade 1  
 
Grade 1 with pain or 
Grade 2 
 
Grade 2 with pain or 
Grade 3 
 
Grade 4  
 
If grade 1, without pain, no change in dosing 
 
If Grade 1 with pain or Grade 2, hold lenalidomide and ixazomib until 
resolves to  grade 1 without pain, restart with one dose level 
reduction in ixazomib 
 
If Grade 2 with pain or Grade 3, hold (interrupt) lenalidomide and 
ixazomib dose.  Follow at least weekly.  
 
If the toxicity resolves to ≤ grade 1 prior to Day 21 of the current 
cycle, restart lenalidomide and ixazomib at next lower dose level and 
continue through the scheduled Day 21 of the current cycle.  
Otherwise, omit for remainder of cycle and reduce the dose of 
lenalidomide and ixazomib by 1 dose level at the start of the next 
cycle.  Omitted doses are not made up. 
 
If Grade 4, discontinue lenalidomide and ixazomib.  Remove patient 
from study. 
Venous thrombosis/ 
embolism: 
 
≥ Grade 3 
 
Hold (interrupt) lenalidomide and start therapeutic anticoagulation, if 
appropriate. 
 
Restart lenalidomide at investigator’s discretion (maintain dose level). 
 
Hyperthyroidism or 
hypothyroidism 
 
Omit lenalidomide for remainder of cycle, evaluate etiology, and 
initiate appropriate therapy.  
 
See Instructions for Initiation of a New Cycle and reduce the dose of 
lenalidomide by 1 dose level. 
Other non-hematologic 
toxicity : 
 
≥ Grade 3 
 
Hold (interrupt) lenalidomide and ixazomib dosing.  Follow at least 
weekly. 
 
If the toxicity resolves to ≤ grade 2 prior to Day 21 of the current 
cycle, restart lenalidomide and ixazomib and continue through the 
scheduled Day 21 of the current cycle.  Otherwise, omit for remainder 
of cycle.  Omitted doses are not made up.  For toxicity attributed to 
lenalidomide or ixazomib, reduce the both lenalidomide and ixazomib 
dose by 1 dose level when restarting treatment. 


 
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8.0 
ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS 
 
The following is a list of AEs (Section 8.1) and the reporting requirements associated with 
observed AEs (Sections 8.2 and 8.3).  
 
The clinical course of each event will be followed until resolution, stabilization, or until it has been 
determined that the study treatment or participation is not the cause.  
 
Serious adverse events that are still ongoing at the end of the study period will necessitate follow-
up to determine the final outcome. Any serious adverse event that occurs after the study period 
and is considered to be possibly related to the study treatment or study participation will be 
recorded and reported immediately. 
 
8.1 
Adverse Events and Potential Risks  
 
 
8.1.1  Ixazomib 
See Tables 1-1 and 1-2 for a comprehensive list of reported adverse events and potential risks.  
 
 
8.1.2  Lenalidomide 
Most frequently reported adverse events reported during clinical studies with lenalidomide in 
oncologic and non-oncologic indications, regardless of presumed relationship to study medication 
include: anemia, neutropenia, thrombocytopenia and pancytopenia, abdominal pain, nausea, 
vomiting and diarrhea, dehydration, rash, itching, infections, sepsis, pneumonia, UTI, upper 
respiratory infection, atrial fibrillation, congestive heart failure, myocardial infarction, chest pain, 
weakness, hypotension, hypercalcemia, hyperglycemia, back pain, bone pain, generalized pain, 
dizziness, mental status changes, syncope, renal failure, dyspnea, pleural effusion, pulmonary 
embolism, deep vein thrombosis, CVA, convulsions, dizziness, spinal cord compression, syncope, 
disease progression, death not specified and fractures. 
 
Patients with lymphoma have a higher risk of developing a second new cancer when compared to 
people without lymphoma. In clinical studies of newly diagnosed multiple myeloma, a higher 
number of second cancers were reported in patients treated with lenalidomide as induction therapy 
(treatment for several cycles to reduce number of cancer cells) and/or bone marrow transplant 
followed by prolonged lenalidomide administration compared to patients treated with induction 
therapy and/or bone marrow transplant then placebo. Whether this will occur in patients with 
lymphoma is not known. 
 
8.1.2.1  Comprehensive Adverse Events and Potential Risks list (CAEPR) for 
Lenalidomide (CC-5013, NSC 703813) 
The Comprehensive Adverse Events and Potential Risks List (CAEPR) provides a thorough and 
detailed list of reported and/or potential adverse events associated with the agent below. They are 
developed and continuously monitored by the CTEP Investigational Drug Branch (IDB). The 
information listed in the CAEPR below, as well as the investigator’s brochure, package insert or 
protocol can be used to determine expectedness of an event when evaluating if the event is 
reportable via CTEP-AERS. Frequency is provided based on 4081 patients. Below is the CAEPR 
for lenalidomide (CC-5013). 
 
 
 
       Version 2.5, July 16, 20141 


 
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Adverse Events with Possible 
Relationship to Lenalidomide (CC-5013) 
(CTCAE 4.0 Term) 
[n=4081] 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
Anemia 
 
 
ENDOCRINE DISORDERS 
 
Hypothyroidism 
 
GASTROINTESTINAL DISORDERS 
Constipation 
 
 
Diarrhea 
 
 
 
Nausea 
 
 
 
Pancreatitis 
 
Vomiting 
 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
 
Chills 
 
 
Edema limbs 
 
Fatigue 
 
 
 
Fever 
 
IMMUNE SYSTEM DISORDERS 
 
 
Anaphylaxis 
 
 
Immune system disorders – 
Other (graft vs. host disease)2 
INFECTIONS AND INFESTATIONS 
 
Infection3 
 
INVESTIGATIONS 
 
 
Lipase increased 
 
Lymphocyte count decreased 
 
Neutrophil count decreased 
 
 
Platelet count decreased 
 
 
 
Weight loss 
 
 
White blood cell decreased 
 
METABOLISM AND NUTRITION DISORDERS 
 
Anorexia 
 
 
 
Tumor lysis syndrome 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
 
Arthralgia 
 
 
Back pain 
 
 
Musculoskeletal and 
connective tissue disorders – 
Other (muscle cramp/muscle 
spasm) 
 
 
Myalgia 
 
 
 
 
 


 
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Adverse Events with Possible 
Relationship to Lenalidomide (CC-5013) 
(CTCAE 4.0 Term) 
[n=4081] 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
NEOPLASMS BENIGN, MALIGNANT, AND UNSPECIFIED (INCLUDING CYSTS AND 
POLYPS) 
 
 
Leukemia secondary to 
oncology chemotherapy4 
 
 
Myelodysplastic syndrome4 
 
 
Neoplasms benign, malignant 
and unspecified (incl. cysts 
and polyps) – Other (tumor 
flare)5 
 
 
Treatment related secondary 
malignancy4 
NERVOUS SYSTEM DISORDERS 
 
Dizziness 
 
 
Headache 
 
 
 
Leukoencephalopathy 
PSYCHIATRIC DISORDERS 
 
Insomnia 
 
RENAL AND URINARY DISORDERS 
 
 
Acute kidney injury 
RESPIRATORY, THORACIC, AND MEDIASTINAL DISORDERS 
 
Cough 
 
 
Dyspnea 
 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
 
 
Erythema multiforme 
 
Hyperhidrosis 
 
 
Pruritus 
 
 
Rash maculo-papular 
 
 
Skin and other subcutaneous 
tissue disorders – Other 
(pyroderma gangrenosum) 
 
 
 
Stevens-Johnson syndrome 
 
 
Toxic epidermal necrolysis 
VASCULAR DISORDERS 
 
Thromboembolic event6 
 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed 
to all Principal Investigators at the time of revision.  The current version can be obtained by 
contacting PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, the protocol, and 
the agent should be included in the email. 
 
2Graft vs. host disease has been observed in subjects who have received lenalidomide in the 
setting of allo-transplantation. 
 
3Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC. 
 


 
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4There has been an increased frequency of secondary malignancies (including AML/MDS) in 
multiple myeloma patients being treated with melphalan, prednisone, and lenalidomide post bone 
marrow transplant. 
 
5Serious tumor flare reactions have been observed in patients with Chronic Lymphocytic Leukemia 
(CLL) and lymphoma. 
 
6Significantly increased risk of deep vein thrombosis (DVT) and pulmonary embolism (PE) has 
been observed in patients with multiple myeloma receiving lenalidomide with dexamethasone. 
 
7Gastrointestinal hemorrhage includes: Anal hemorrhage, Cecal hemorrhage, Colonic hemorrhage, 
Duodenal hemorrhage, Esophageal hemorrhage, Esophageal varices hemorrhage, Gastric 
hemorrhage, Hemorrhoidal hemorrhage, Ileal hemorrhage, Intra-abdominal hemorrhage, Jejunal 
hemorrhage, Lower gastrointestinal hemorrhage, Oral hemorrhage, Pancreatic hemorrhage, Rectal 
hemorrhage, Retroperitoneal hemorrhage, and Upper gastrointestinal hemorrhage under the 
GASTROINTESTINAL DISORDERS SOC. 
 
8Gastrointestinal obstruction includes: Colonic obstruction, Duodenal obstruction, Esophageal 
obstruction, Ileal obstruction, Jejunal obstruction, Obstruction gastric, Rectal obstruction, and Small 
intestinal obstruction under the GASTROINTESTINAL DISORDERS SOC. 
 
9Osteonecrosis of the jaw has been seen with increased frequency when lenalidomide is used in 
combination with bevacizumab, docetaxel (Taxotere®), prednisone, and zolendronic acid 
(Zometa®). 
 
NOTE:  
While not observed in human subjects, lenalidomide, a thalidomide analogue, 
caused limb abnormalities in a development monkey study similar to birth defects 
caused by thalidomide in humans.  If lenalidomide is used during pregnancy, it may 
cause birth defects or embryo-fetal death.  Pregnancy must be excluded before start 
of treatment.  Prevent pregnancy during treatment by the use of two reliable 
methods of contraception. 
 
Also reported on lenalidomide (CC-5013) trials but with the relationship to lenalidomide (CC-
5013) still undetermined due to low frequency (i.e., <3%): 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS – Blood and lymphatic system disorders – 
Other (eosinophilia); Blood and lymphatic system disorders – Other (monocytosis); Blood and 
lymphatic system disorders – Other (pancytopenia); Disseminated intravascular coagulation; 
Febrile neutropenia; Hemolysis; Spleen disorder 
 
CARDIAC DISORDERS – Acute coronary syndrome; Atrial fibrillation; Atrial flutter; Atrioventricular 
block first degree; Cardiac arrest; Cardiac disorders – Other (cardiovascular edema); Cardiac 
disorders – Other (ECG abnormalities); Chest pain – cardiac; Heart failure; Left ventricular systolic 
dysfunction; Myocardial infarction; Palpitations; Pericarditis; Sinus bradycardia; Sinus tachycardia; 
Supraventricular tachycardia; Ventricular tachycardia 
 
EAR AND LABYRINTH DISORDERS – Tinnitus  
 
ENDOCRINE DISORDERS – Cushingoid; Hyperthyroidism 
 


 
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EYE DISORDERS – Blurred vision; Conjunctivitis; Dry eye; Flashing lights; Retinopathy 
 
GASTROINTESTINAL DISORDERS – Abdominal distension; Abdominal pain; Anal mucositis; 
Ascites; Colonic perforation; Dry mouth; Dyspepsia; Dysphagia; Flatulence; Gastritis; 
Gastroesophageal reflux disease; Gastrointestinal disorders – Other (Crohn’s Disease 
aggravated); Gastrointestinal disorders – Other (diverticulitis); Gastrointestinal disorders – Other 
(pale feces); Gastrointestinal hemorrhage7; Gastrointestinal obstruction8; Ileus; Mucositis oral; 
Rectal mucositis; Small intestinal mucositis  
 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS – General disorders and 
administration site conditions – Other (edema NOS); Malaise; Multi-organ failure; Non-cardiac 
chest pain; Pain 
 
HEPATOBILIARY DISORDERS – Cholecystitis; Hepatic failure 
 
IMMUNE SYSTEM DISORDERS – Allergic reaction; Immune system disorders – Other 
(angioedema) 
 
INFECTIONS AND INFESTIATIONS – Infections and infestations – Other (Opportunistic infection 
associated with >= grade 2 lymphopenia) 
 
INJURY, POISONING, AND PROCEDUREAL COMPLICATIONS – Bruising; Fall; Fracture; Hip 
fracture; Vascular access complication 
 
INVESTIGATIONS – Activated partial thromboplastin time prolonged; Alanine aminotransferase 
increased; Alkaline phosphatase increased; Aspartate aminotransferase increased; Blood bilirubin 
increased; Cholesterol high; Creatinine increased; Electrocardiogram QT corrected interval 
prolonged; INR increased; Investigations – Other (hemochromatosis)  
 
METABOLISM AND NUTRITION DISORDERS – Acidosis; Dehydration; Hypercalcemia; 
Hyperglycemia; Hyperkalemia; Hyperuricemia; Hypocalcemia; Hypoglycemia; Hypokalemia; 
Hypomagnesemia; Hyponatremia; Hypophosphatemia 
 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS – Arthritis; Bone pain; Chest 
wall pain; Generalized muscle weakness; Joint effusion; Muscle weakness lower limb; 
Musculoskeletal and connective tissue disorders – Other (rhabdomyolysis); Neck pain; 
Osteonecrosis of jaw9; Pain in extremity 
 
NEOPLASMS BENIGN, MALIGNANT, AND UNSPECIFIED (INCL. CYSTS AND POLYPS) – 
Tumor pain 
 
NERVOUS SYSTEM DISORDERS – Ataxia; Cognitive disturbance; Depressed level of 
consciousness; Dysgeusia; Dysphasia; Edema cerebra; Encephalopathy; Intracranial hemorrhage; 
Ischemia cerebrovascular; Memory impairment; Myelitis; Nervous system disorders – Other 
(hyporeflexia); Nervous system disorders – Other (spinal cord compression); Peripheral motor 
neuropathy; Peripheral sensory neuropathy; Seizure; Somnolence; Syncope; Transient ischemic 
attacks; Tremor  
 
PSYCHIATRIC DISORDERS – Agitation; Anxiety; Confusion; Depression; Psychosis 
 


 
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RENAL AND URINARY DISORDERS – Renal and urinary disorders – Other (chromaturia); 
Urinary frequency; Urinary incontinence; Urinary tract pain. 
 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS – Reproductive system and breast 
disorders – Other (hypogonadism); Vaginal hemorrhage 
 
RESPIRATORY, THORACIC, AND MEDIASTINAL DISORDERS – Adult respiratory distress 
syndrome; Allergic rhinitis; Atelectasis; Bronchopulmonary hemorrhage; Epistaxis; Hypoxia; 
Laryngeal mucositis; Pharyngeal mucositis; Pleural effusion; Pneumonitis; Pulmonary 
hypertension; Respiratory failure; Tracheal mucositis; Voice alteration 
 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS – Alopecia; Dry skin; Nail loss; 
Photosensitivity; Rash acneiform; Skin and subcutaneous tissue disorders – Other (Sweet’s 
Syndrome); Urticaria 
 
VASCULAR DISORDERS – Hot flashes; Hypertension; Hypotension; Phlebitis; Vascular disorders 
– Other (hemorrhage NOS) 
 
NOTE:  
Lenalidomide (CC-5013) in combination with other agents could cause an 
exacerbation of any adverse event currently known to be caused by the other agent, 
or the combination may result in events never previously associated with either 
agent. 
 
Please refer to the package insert for the comprehensive list of adverse events. 
 
8.1.3  Rituximab 
 
8.1.3.1  Comprehensive Adverse Events and Potential Risks list (CAEPR) for 
Rituximab (NSC 687451) 
 
The Comprehensive Adverse Events and Potential Risks List (CAEPR) provides a thorough and 
detailed list of reported and/or potential adverse events associated with the agent below. They are 
developed and continuously monitored by the CTEP Investigational Drug Branch (IDB). The 
information listed in the CAEPR below, as well as the investigator’s brochure, package insert or 
protocol can be used to determine expectedness of an event when evaluating if the event is 
reportable via CTEP-AERS. Frequency is provided based on 986 patients. Below is the CAEPR for 
Rituximab (NSC 687451). 
 
Version 2.1, March 19, 20101 
Adverse Events with Possible 
Relationship to Rituximab  
(CTCAE 4.0 Term) 
[n=986] 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
 
Anemia 
 
 
Blood and lymphatic system 
disorders – Other 
(Hyperviscosity: 
Waldenstrom’s) 
 


 
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Febrile neutropenia 
 
 
Adverse Events with Possible 
Relationship to Rituximab  
(CTCAE 4.0 Term) 
[n=986] 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
CARDIAC DISORDERS 
 
Myocardial infarction 
 
 
Sinus tachycardia 
 
 
Supraventricular tachycardia 
 
GASTROINTESTINAL DISORDERS 
 
Abdominal pain 
 
 
Diarrhea 
 
 
Nausea 
 
 
Vomiting 
 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
Chills 
 
 
 
Edema limbs 
 
 
Fatigue 
 
Fever 
 
 
Infusion related reaction 
 
 
 
Pain 
 
IMMUNE SYSTEM DISORDERS 
 
Allergic reaction 
 
 
 
Anaphylaxis 
 
Serum sickness 
 
INFECTIONS AND INFESTATIONS 
 
Infection2 
 
 
Infections and infestations – 
Other (Activation of Hepatitis 
B, C, CMV, parvovirus B19, 
JC virus, varicella zoster, 
herpes simples, West Nile 
virus) 
 
 
Infections and infestations – 
Other (Infection in HIV 
Positive Patients) 
 
INVESTIGATIONS 
Lymphocyte count decreased 
 
 
 
Neutrophil count decreased 
 
 
Platelet count decreased 
 
 
White blood cell decreased 
 
METABOLISM AND NUTRITION DISORDERS 
 
Hyperglycemia 
 
 
Hypocalcemia 
 
 
Hypokalemia 
 
 
 
Tumor lysis syndrome 
 


 
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Adverse Events with Possible 
Relationship to Rituximab  
(CTCAE 4.0 Term) 
[n=986] 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
 
Arthralgia 
 
 
Back pain 
 
 
Myalgia 
 
NEOPLASMS BENIGN, MALIGNANT, AND UNSPECIFIED (INCLUDING CYSTS AND 
POLYPS) 
 
Tumor pain 
 
NERVOUS SYSTEM DISORDERS 
 
Dizziness 
 
 
Headache 
 
 
Lethargy 
 
 
 
Nervous system disorders – 
Other (progressive multifocal 
leukoencephalopathy) 
 
Seizure 
 
RENAL AND URINARY DISORDERS 
 
Acute kidney injury 
 
RESPIRATORY, THORACIC, AND MEDIASTINAL DISORDERS 
 
 
Adult respiratory distress 
syndrome 
 
Allergic rhinitis 
 
 
Bronchospasm 
 
 
Cough 
 
 
Dyspnea 
 
 
Hypoxia 
 
 
Pneumonitis 
 
 
Sore throat 
 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
 
 
Erythema multiforme 
 
Hyperhidrosis 
 
 
Pruritus 
 
 
Rash maculo-papular 
 
 
Skin and other subcutaneous 
tissue disorders – Other 
(angioedema) 
 
 
 
Stevens-Johnson syndrome 
 
 
Toxic epidermal necrolysis 
 
Uticaria 
 
VASCULAR DISORDERS 
 
Flushing 
 
 
Hypertension 
 
 
Hypotension 
 
 


 
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1This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed 
to all Principal Investigators at the time of revision.  The current version can be obtained by 
contacting PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, the protocol, and 
the agent should be included in the email. 
 
2Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC. 
 
3Gastrointestinal obstruction includes Colonic obstruction, Duodenal obstruction, Esophageal 
obstruction, Ileal obstruction, Jejunal obstruction, Obstruction gastric, Rectal obstruction, and Small 
intestinal obstruction under the GASTROINTESTINAL DISORDERS SOC. 
 
4Gastrointestinal perforation includes Colonic perforation, Duodenal perforation, Esophageal 
perforation, Gastric perforation, Ileal perforation, Rectal perforation, and Small intestinal perforation 
under the GASTROINTESTINAL DISORDERS SOC. 
 
Also reported on rituximab trials but with the relationship to rituximab still undetermined: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS – Bone marrow hypocellular; Hemolysis 
 
CARDIAC DISORDERS – Atrial fibrillation; Atrial flutter; Cardiac disorders – Other (cyanosis); Left 
ventricular systolic dysfunction; Sinus bradycardia; Ventricular fibrillation 
 
EYE DISORDERS – Conjunctivitis; Eye disorders – Other (ocular edema); Uveitis; Watering eyes 
 
GASTROINTESTINAL DISORDERS – Constipation; Dyspepsia; Dysphagia; Gastrointestinal 
obstruction3; Gastrointestinal perforation4; Mucositis oral 
 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS – Flu like symptoms; Non-
cardiac chest pain 
 
INFECTIONS AND INFESTATIONS – Infections and infestations – Other (Opportunistic infection 
associated with >= Grade 2 Lymphopenia) 
 
INJURY, POISONING, AND PROCEDURAL COMPLICATIONS – Fracture  
 
INVESTIGATIONS – Alkaline phosphatase increased; Aspartate aminotransferase increased; 
Blood bilirubin increased; Cardiac troponin I increased; Cardiac troponin T increased; Creatinine 
increased; Investigations – Other (hyperphosphatemia); Investigations – Other (LDH increased); 
Weight loss 
 
METABOLISM AND NUTRITION DISORDERS – Anorexia; Hypercalcemia; Hyperkalemia; 
Hypermagnesemia; Hypernatremia; Hyperuricemia; Hypoglycemia; Hypomagnesemia; 
Hyponatremia 
 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS – Arthritis  
 
NERVOUS SYSTEM DISORDERS – Nervous system disorders – Other (Cranial Neuropathy 
NOS); Peripheral motor neuropathy; Peripheral sensory neuropathy; Pyramidal tract syndrome; 
Reversible posterior leukoencephalopathy syndrome; Syncope 
 


 
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PSYCHIATRIC DISORDERS – Agitation; Anxiety; Depression; Insomnia 
 
RESPIRATORY, THORACIC, AND MEDIASTINAL DISORDERS – Epistaxis; Pharyngolaryngeal 
pain; Pleural effusion; Pulmonary edema; Respiratory, thoracic, and mediastinal disorders – Other 
(bronchiolitis obliterans) 
 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS – Alopecia; Skin and subcutaneous tissue 
disorders – Other (paraneoplastic pemphigus) 
 
VASCULAR DISORDERS – Phlebitis; Thromboembolic event; Vasculitis 
 
NOTE:     Rituximab in combination with other agents could cause an exacerbation of any adverse  
    event currently known to be caused by the other agent, or the combination may result in  
    events never previously associated with either agent. 
 
 
Please refer to the package insert for the comprehensive list of adverse events. 
 
8.2 
Definitions  
 
8.2.1  Adverse Event Definition   
Adverse event (AE) means any untoward medical occurrence in a patient or subject administered a 
pharmaceutical product; the untoward medical occurrence does not necessarily have a causal 
relationship with this treatment.  An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the use 
of a medicinal (investigational) product whether or not it is related to the medicinal product.  This 
includes any newly occurring event, or a previous condition that has increased in severity or 
frequency since the administration of study drug. 
 
An abnormal laboratory value will not be assessed as an AE unless that value leads to 
discontinuation or delay in treatment, dose modification, therapeutic intervention, or is considered 
by the investigator to be a clinically significant change from baseline. 
 
  
 8.2.2  Significance of an Adverse Event 
External adverse events are adverse events experienced by subjects enrolled in multicenter 
clinical trials at sites other than the site(s) over which the Institutional Review Board has 
jurisdiction.  Internal adverse events are adverse events experienced by subjects enrolled at the 
site(s) under the IRB’s jurisdiction for either multicentre or single-center research projects.  The 
significance of AEs is used to describe the patient/event outcome or action criteria associated with 
events that pose a threat to a patient’s life or functioning (i.e., moderate, severe, or life 
threatening).  Based on the National Cancer Institute Guidelines for Cancer Therapy Evaluation 
Program, severity can be defined by the following grades of events: 
 
 
Grades 1 are mild adverse events (e.g., minor event requiring no specific medical 
intervention, asymptomatic laboratory findings only, marginal clinical relevance). 
 
 
Grades 2 are moderate adverse events (e.g., minimal intervention, local intervention, non-
invasive intervention, transfusion, elective interventional radiological procedure, therapeutic 
endoscopy or operation). 
 
 
Grades 3 are severe and undesirable adverse events (e.g, significant symptoms requiring 


 
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hospitalization or invasive intervention, transfusion, elective interventional radiological 
procedure, therapeutic endoscopy or operation). 
 
 
Grades 4 are life threatening or disabling adverse events (e.g., complicated by acute, life-
threatening metabolic or cardiovascular complications such as circulatory failure, 
haemorrhage, sepsis, life-threatening physiologic consequences, need for intensive care or 
emergent invasive procedure; emergent interventional radiological procedure, therapeutic 
endoscopy or operation). 
 
 
Grades 5 are fatal adverse events resulting in death. 
 
8.2.3  Serious Adverse Event Definition 
Serious AE (SAE) means any untoward medical occurrence that at any dose: 
 
Results in death. 
 
Is life-threatening (refers to an AE in which the patient was at risk of death at the time of 
the event.  It does not refer to an event which hypothetically might have caused death if it 
were more severe). 
 
Requires inpatient hospitalization or prolongation of an existing hospitalization (see 
clarification in the paragraph below on planned hospitalizations). 
 
Results in persistent or significant disability or incapacity. (Disability is defined as a 
substantial disruption of a person’s ability to conduct normal life functions). 
 
Is a congenital anomaly/birth defect. 
 
Is a medically important event.  This refers to an AE that may not result in death, be 
immediately life threatening, or require hospitalization, but may be considered serious 
when, based on appropriate medical judgment, may jeopardize the patient, require medical 
or surgical intervention to prevent one of the outcomes listed above, or involves suspected 
transmission via a medicinal product of an infectious agent.   Examples of such medical 
events include allergic bronchospasm requiring intensive treatment in an emergency room 
or at home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or 
the development of drug dependency or drug abuse; any organism, virus, or infectious 
particle (e.g., prion protein transmitting Transmissible Spongiform Encephalopathy), 
pathogenic or nonpathogenic, is considered an infectious agent.   
 
Clarification should be made between a serious AE (SAE) and an AE that is considered severe in 
intensity (Grade 3 or 4), because the terms serious and severe are NOT synonymous.  The 
general term severe is often used to describe the intensity (severity) of a specific event; the event 
itself, however, may be of relatively minor medical significance (such as a Grade 3 headache).  
This is NOT the same as serious, which is based on patient/event outcome or action criteria 
described above, and is usually associated with events that pose a threat to a patient’s life or 
ability to function.  A severe AE (Grade 3 or 4) does not necessarily need to be considered serious.  
For example, a white blood cell count of 1000/mm3 to less than 2000 is considered Grade 3 
(severe) but may not be considered serious.  Seriousness (not intensity) serves as a guide for 
defining regulatory reporting obligations. 
 
 
8.2.4  Expectedness   
Adverse Events can be Expected or Unexpected. 
 
 
An expected adverse event is an event previously known or anticipated to result from 


 
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participation in the research study or any underlying disease, disorder, or condition of the 
subject. The event is usually listed in the Investigator Brochure, consent form or research 
protocol.  
 
An unexpected adverse event is an adverse event not previously known or anticipated to 
result from the research study or any underlying disease, disorder, or condition of the 
subject. 
 
8.2.5  Attribution 
Attribution is the relationship between an adverse event or serious adverse event and the study 
drug.  Attribution will be assigned as follows: 
 
 
Definite – The AE is clearly related to the study drug. 
 
Probable – The AE is likely related to the study drug. 
 
Possible – The AE may be related to the study drug. 
 
Unlikely – The AE is doubtfully related to the study drug. 
 
Unrelated – The AE is clearly NOT related to the study drug. 
 
8.3  Procedures for Reporting All Adverse Events 
AEs may be spontaneously reported by the patient and/or in response to an open question from 
study personnel or revealed by observation, physical examination, or other diagnostic procedures.  
Any clinically relevant deterioration in laboratory assessments or other clinical finding is considered 
an AE.  When possible, signs and symptoms indicating a common underlying pathology should be 
noted as one comprehensive event.  For serious AEs, the investigator must determine both the 
intensity of the event and the relationship of the event to study drug administration. For serious 
pretreatment events, the investigator must determine both the intensity of the event and the 
relationship of the event to study procedures.  
 
AEs which are serious must be reported to Millennium Pharmacovigilance (or designee) and to 
Celgene Drug Safety from the first dose of study drug through 30 days after administration of the 
last dost of study drug. Any SAE that occurs at any time after completion of study treatment or after 
the designated follow-up period that the sponsor-investigator and/or sub-investigator considers to 
be related to any study drug must be reported to Millennium Pharmacovigilance (or designee) and 
to Celgene Drug Safety.  In addition, new primary malignancies that occur during the follow-up 
periods must be reported, regardless of causality to study regimen, for a minimum of three years 
after the last dose of the investigational product, starting from the first dose of study drug. All new 
cases of primary malignancy must be reported to Millennium Pharmacovigilance (or designee) and 
to Celgene Drug Safety.  
 
Adverse Event Reporting 
Toxicity will be scored using CTCAE Version 4.0 for toxicity and adverse event reporting.  A copy 
of the CTCAE Version 4.0 can be downloaded from the CTEP homepage (http://ctep.info.nih.gov).  
All appropriate treatment areas should have access to a copy of the CTCAE Version 4.0.  All 
adverse clinical experiences, whether observed by the investigator or reported by the patient, must 
be recorded, with details about the duration and intensity of each episode, the action taken with 
respect to the test drug, and the patient’s outcome.  The investigator must evaluate each adverse 
experience for its relationship to the test drug and for its seriousness. 
 
The investigator must appraise all abnormal laboratory results for their clinical significance.  If any 
abnormal laboratory result is considered clinically significant, the investigator must provide details 
about the action taken with respect to the test drug and about the patient’s outcome. 


 
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Since this is an investigator-initiated study, the principal investigator, Dr. Brian Hill, also referred to 
as the sponsor-investigator, is responsible for reporting serious adverse events (SAEs) to any 
regulatory agency and to the sponsor- investigator’s EC or IRB.    
 
Regardless of expectedness or causality, all SAEs (including serious pretreatment events) must 
also be reported in English to Millennium Pharmacovigilance (or designee): 
 
 
Fatal and Life Threatening SAEs within 24 hours of the sponsor-investigator’s observation 
or awareness of the event 
 
 
All other serious (non-fatal/non-life threatening) events within 4 calendar days of the 
sponsor-investigator’s observation or awareness of the event 
 
See below for contact information for the reporting of SAEs to Millennium Pharmacovigilance and 
to Celgene Drug Safety.   
 
The sponsor-investigator must fax or email the SAE Form per the timelines above.  A sample of an 
SAE Form will be provided.   
 
The SAE report must include at minimum: 
 
Event term(s) 
 
Serious criteria 
 
Intensity of the event(s): Sponsor-investigator’s or sub-investigator’s 
determination.  Intensity for each SAE, including any lab abnormalities, will be determined 
by using the NCI CTCAE version specified in the protocol, as a guideline, whenever 
possible.  The criteria are available online at http://ctep.cancer.gov/reporting/ctc.html. 
 
Causality of the event(s): Sponsor-investigator’s or sub-investigator’s determination of the 
relationship of the event(s) to study drug administration.  
 
Attribution:  Attribution is the relationship between an adverse event or serious adverse 
event and the study drug.  For this study, relationship to all study drugs for each SAE will be 
determined by the investigator or sub-investigator by responding yes or no to the question: 
Is there a reasonable possibility that the AE is associated with the study drug(s)? 
 
Follow-up information on the SAE may be requested by the sponsors of the study.   
 
Intensity for each SAE, including any lab abnormalities, will be determined by using the NCI 
CTCAE version used at your institution, as a guideline, whenever possible.  The criteria are 
available online at http://ctep.cancer.gov/reporting/ctc.html. 
 
Sponsor-investigator must also provide Millennium Pharmacovigilance and Celgene Drug Safety 
with a copy of all communications with applicable regulatory authorities related to the study 
product(s), as soon as possible but no later than 4 calendar days of such communication. 
 
 
 
 


 
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SAE and Pregnancy Reporting Contact Information 
 
MILLENNIUM 
 
Fax Number: 1-800-963-6290 
Email: TakedaOncoCases@cognizant.com 
 
CELGENE 
 
Celgene Corporation      
Global Drug Safety and Risk Management    
Fax: 
(908) 673-9115 
E-mail: drugsafety@celgene.com 
 
 
 
Suggested Reporting Form:   
 
SAE Report Form (provided by Millennium) 
 
US FDA MedWatch 3500A:  
http://www.fda.gov/Safety/MedWatch/HowToReport/DownloadForms/default.htm 
 
Any other form deemed appropriate by the sponsor-investigator 
 
Institutional Review Board Reporting Requirements: 
Investigative sites will report adverse events to their respective IRB according to the local IRB’s 
policies and procedures in reporting adverse events.  
 
8.4  Procedures for Reporting Drug Exposure During Pregnancy and Birth Events 
If a woman becomes pregnant or suspects that she is pregnant while participating in this study or 
within 90 days after the last dose, she must inform the investigator immediately and permanently 
discontinue study drug.  The sponsor-investigator must immediately fax a completed Pregnancy 
Form to the Millennium Department of Pharmacovigilance or designee (see Section 8.3) and to 
Celgene Drug Safety.  The pregnancy must be followed for the final pregnancy outcome. 
 
If a female partner of a male patient becomes pregnant during the male patient’s participation in 
this study, the sponsor-investigator must also immediately fax a completed Pregnancy Form to the 
Millennium Department of Pharmacovigilance or designee (see Section 8.3) and to Celgene Drug 
Safety.  Every effort should be made to follow the pregnancy for the final pregnancy outcome. 
 
Suggested Pregnancy Reporting Form: 
 
Pregnancy Report Form (provided by Millennium or Celgene)   
 
8.5 
Data Safety Toxicity Committee 
It is the Case Comprehensive Cancer Center’s Principal Investigator’s responsibility to ensure that 
ALL serious adverse events are reported to the Case Comprehensive Cancer Center’s Data Safety 
Toxicity Committee. This submission is simultaneous with their submission to the Sponsor or other 
Regulatory body.  
 


 
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The sponsor-investigator is responsible for submitting an annual report to the DSTC as per 
CCCC Data and Safety Monitoring Plan. 
 
8.6 
Data and Safety Monitoring Plan (DSMP) 
This protocol will adhere to the policies of the Case Comprehensive Cancer Center Data and 
Safety Monitoring Plan in accordance with NCI guidelines  
 
 
9.0 
PHARMACEUTICAL INFORMATION    
 
A list of the adverse events and potential risks associated with the investigational or commercial 
agents administered in this study can be found in Section 8.0.    
 
 
Agents are listed in alphabetical order.   
 
9.1 
Ixazomib 
 
 
Chemical Name:      2,2’-{2-[(1R)-1-1({[(2,5-dichlorobenzoyl)amino]acetyl}amino)-3-methylbutyl]-
5-oxo-1,3,2-dioxoborolane-4,4-diyl}diacetic acid 
 
Other Names:         MLN9708 
 
Classification:          proteasome inhibitor (as the boronic acid) 
 
Molecular Formula:  C20H23BCl2N2O9 
 
 
Mode of Action:      proteasome inhibitor 
 
Metabolism:    
hydrolysis, hydroxylation, dehydrogenation and N-dealkylation 
 
Product Description: 
capsule   
 
 
Solution Preparation: 
NA  
 
Storage Requirements: 
The container should be stored at the investigative site refrigerated 
(36°F to 46°F, 2°C to 8°C).  Patients should be instructed to store the medication refrigerated (36°F 
to 46°F, 2°C to 8°C) for the duration of each cycle. 
 
 
Route of Administration: 
oral   
 
Drug Procurement:  Ixazomib will be supplied for this study by Millennium, a Takeda corporation.  
 
Drug Accountability: The investigator or designated study personnel are responsible for 
maintaining accurate dispensing records of the study drug.  All study drugs must be accounted for, 
including study drug accidentally or deliberately destroyed.  Under no circumstances will the 
investigator allow the investigational drug to be used other than as directed by the protocol.  If 
appropriate, drug storage, drug dispensing, and drug accountability may be delegated to the 
pharmacy section of the investigative site.   
 
Drug Destruction: At the completion of the study, there will be a final reconciliation of drug 


 
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shipped, drug consumed, and drug remaining. This reconciliation will be logged on the drug 
reconciliation form, signed and dated. Any discrepancies noted will be investigated, resolved, and 
documented prior to return or destruction of unused study drug. Drug destroyed on site will be 
documented in the study files. 
 
9.2 
Lenalidomide 
  
Chemical Name:      3-(4-amino-1-oxo 1,3-dihydro -2H-isoindol-2-yl) piperidine-2,6-dione 
 
Other Names:         NA 
 
Classification:          Immunomodulatory agent 
 
Molecular Formula:  C13H13N3O3 
 
 
Mode of Action:      Immunomodulatory agent 
 
Metabolism:    
rapidly absorbed following oral administration; approximately two-thirds is 
eliminated unchanged through urinary excretion 
 
Product Description: 
 
Capsules   
 
 
Solution Preparation: 
NA  
 
Storage Requirements: 
Room temperature  
 
Stability:  
Not defined  
 
Route of Administration: 
Oral   
 
Drug Procurement:  Lenalidomide will be supplied for this study by Celgene. 
 
Drug Accountability: The investigator or designated study personnel are responsible for 
maintaining accurate dispensing records of the study drug.  All study drugs must be accounted for, 
including study drug accidentally or deliberately destroyed.  Under no circumstances will the 
investigator allow the investigational drug to be used other than as directed by the protocol.  If 
appropriate, drug storage, drug dispensing, and drug accountability may be delegated to the 
pharmacy section of the investigative site.   
 
Drug Destruction: At the completion of the study, there will be a final reconciliation of drug 
shipped, drug consumed, and drug remaining. This reconciliation will be logged on the drug 
reconciliation form, signed and dated. Any discrepancies noted will be investigated, resolved, and 
documented prior to return or destruction of unused study drug. Drug destroyed on site will be 
documented in the study files. 
 
9.3 
Rituximab 
  
Other Names:         Rituxan ®; MabThera ®, IDEC-C2B8 
 
Classification:          Monoclonal antibody 


 
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Mode of Action:      Binding to CD20 
 
Product Description: 
chimeric murine/human gamma 1 kappa monoclonal antibody 
(Chinese hamster ovary [CHO] transfectoma) 
 
 
Solution Preparation: 
diluted to a concentration of 1 to 4 mg/mL in polyvinylchloride or 
polyolefin IV bags containing normal saline or 5% dextrose 
 
Stability:  
Intact vials of rituximab are stored refrigerated at 2 – 8oC (36 - 46oF). Protect vials 
from direct sunlight. Once diluted as above, stable for up to 24 hr. at 2 – 8oC, and at room 
temperature for an additional 12 hrs. after refrigeration (for a maximum period of 36 hrs.) if 
protected from light. 
 
Route of Administration: 
Intravenous slow infusion   
 
Drug Procurement:  Rituximab must be obtained from commercial sources.   
 
Commercially available: Preservative-free injection 10mg/mL, in 10 and 50 mL single-unit vials. 
Please see Package Insert for further information. 
 
The cost of this agent will be the subject’s responsibility, often covered by medical insurance.  
 
 
10.0 
CORRELATIVE / SPECIAL STUDIES 
 
10.1 
Tissue Microarray 
 
10.1.1  Background and Rationale 
Predictive biomarkers for response and resistance to biologically targeted agents should improve 
our ability to personalize therapy by selecting agents most likely to be effective based on the 
biomarker. No such validated biomarkers exist for indolent non-Hodgkin’s Lymphoma, iNHL, 
treated with the agents in this study.  A set of tissue samples from patients enrolled in this study 
will be stored on glass slides (tissue microarray or TMA) for future processing for appropriate 
studies focused on biomarker development simultaneously for DNA, RNA, or protein targets. TMA 
provides an ideal method of storing fixed tissue samples so that they can be processed at a future 
time when more information on prognostic and predictive factors becomes available.   
 
10.1.2  Collection of Specimens 
Formalin-fixed, paraffin embedded (FFPE) diagnostic tissue biopsies from all patients for whom 
these are available will have a core removed from the FFPE tissue block and placed into the TMA, 
by standard procedures in the Tomsich Pathology Laboratory.  The site should prepare the patient 
block, provide the de-identified number for the study and ship as soon as readily available.  
Shipment of these samples at ambient temperature is satisfactory.   
 
The pathology procedure is to perform an H&E stain to order to identify the tumor tissue in the 
block and have it marked by the pathologist. Tumor cores of 1 mm size will be taken from the 
marked area(s) by the research tech. For the TMA and duplicate TMA, 4 cores would be required 
because each TMA would also include a duplicate core. Additional 2-4 cores, depending on the 
tissue size, would also be collected and saved in a labeled Eppendorf tube for future molecular 


 
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studies. The TMA will be gradually built and the core locations mapped in a TMA schematic as the 
tissue specimens arrive in the laboratory. 
 
Any remaining block can be returned to the site. Please contact Dr. Ondrejka or the research 
laboratory (Lisa Durkin) with any questions regarding the collection of the specimen: 
 
         
 
 
 
 
 
 
 
 
    
The site is instructed to ship to the address and label as shown below. Include the name of the 
study, CASE 1414 on the shipping label. About 24 hours prior to shipment, provide the shipping 
information to Lisa Durkin, durkinl@ccf.org, and Dr. Ondrejka’s medical secretary, Linda Rosa, 
lrosa@ccf.org. 
 
Cleveland Clinic 
2119  East 93rd. Street 
Desk L15 
Cleveland, OH 44106 
 
Attn: Durkin/Rosa/Ondrejka 
 
 
10.1.3  Handling of Specimens  
TMA will be stored in the Tomsich Pathology Laboratory in a secure ambient temperature 
monitored location. All patient tissue must be de-identified prior to placing in the TMA. 
 
10.1.4  Correlative Methods  
Precise plans for analysis of TMA by immunohistochemistry and/or macromolecule isolation will 
depend on future knowledge. This correlative is simply to store samples in usable form at this time. 
  
10.2 
Flow Cytometry on Peripheral Blood 
 
10.2.1  Background and Rationale 
Flow cytometry is commonly used to identify and quantitate normal and abnormal circulating 
lymphocytes. It is sensitive and specific for detecting small numbers of circulating lymphoma cells, 
as well as providing insight into the host immune response of normal lymphocyte subsets.  
 
Baseline evaluation of blood lymphocytes subsets may be a marker of nodal immune response, 
and the molecular signature of tumor infiltrating cells in lymph node biopsies of patients with 
follicular lymphoma does provide prognostic information while nodal T-lymphocyte subset 
evaluation predicts prognosis independently of the Follicular Lymphoma International Prognostic 
Index (FLIPI). Specifically, CD4+ T-cells and interfollicular CD68+ cells (macrophages) are 
associated with a poor outcome, while FOXP3+ cells, CD8+ cells, and programmed  death 1 (PD-
  Dr. Sarah Ondrejka, M.D. 
  Ph.    216-445-1662 
  Fax   216-445-7253 
  Email: ondrejs@ccf.org  
 Lisa Durkin 
 Ph. 216-445-9452 
 Email: durkinl@ccf.org  
 


 
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1) + cells are associated with a good prognosis.  We have shown that absolute NK cells at baseline 
are a prognostic factor in follicular lymphoma.  In this study, we will use the immunodeficiency 
panel as standardly performed in the Tomsich laboratory to assess lymphocyte subsets at baseline 
and end of treatment. This measures CD3, CD4 and CD8 T cells, NK cells and CD19+ B cells. 
 
Serial quantitation of remaining circulating lymphoma cells may be an indicator of systemic 
response and outcome. Minimal residual disease (MRD) refers to submicroscopic disease burden 
remaining in a patient after therapy for a neoplasm. Attaining a state of undetectable MRD has 
been shown to correlate with longer progression free survival and decreased relapse risk in some 
diseases. Whether this is merely a marker for those with more responsive disease or whether more 
therapy aimed at eradicating MRD is beneficial is not always clear. 
 
Some patients will achieve a state of no MRD after therapy; however, as time from end of therapy 
lengthens MRD may become detectable. Theoretically it is possible to react and treat a patient 
much earlier before the disease burden increases and the patient becomes more difficult to treat.  
 
There are several methods of monitoring MRD. Molecular techniques using polymerase chain 
reaction can be applied if there is a stable molecular abnormality in the disease, like t(14;18) in 
follicular lymphoma. In the absence of a recurring translocation, the patient specific clonal V-D-J 
immunoglobulin gene rearrangement can be assessed, though this is labor and cost intensive. 
Also it is not clear that the detection of the molecular abnormality with PCR correlates clinically with 
outcomes. Newer NexGen sequencing methods can also be used to quantitate residual clonal cells 
(Adaptiv LymphoSight® assay). Another method of evaluating for MRD is multicolor flow cytometry 
to detect clonal B cells using cell surface antigens unique to the malignant clone. The ability to 
evaluate for multiple antigens on the cell allows for accurate identification of a malignant cell in a 
population of mainly normal cells. Standard flow assays can be adapted for this and validated, but 
are not routinely done in pathology labs, including at CCF. Standard lymphocyte analysis by flow 
measures the percentage of B cells, from which an absolute number of B cells can be calculated.   
 
In this study we will evaluate residual B  cells pre- and post-treatment as potential biomarkers. We 
will extract and store DNA from these samples for possible future NexGen sequencing assessment 
of MRD.  
 
10.2.2  Collection of Specimens 
Blood samples will be drawn into anti-coagulated tubes (see Appendix VI) as per standard 
procedures. All such samples will be at the time of clinically indicated blood sampling so no extra 
venipunctures are needed.  
 
 
10.2.3  Handling of Specimens  
Blood samples will be sent to the flow cytometry lab of the Tomsich Pathology Laboratory (see 
Appendix VI) for processing and fluorescent staining and flow cytometric analysis by standard 
procedures. 
 
10.2.4  Correlative Methods  
Patients whose blood has no detectable  B cells (MRD negative status) will be compared with 
those in whom  B cells remain detectable in terms of PFS and OS to determine if this can be an 
early marker of outcome for patients with iNHL treated with the treatment regimen in this protocol.  
 
Baseline T cell subset levels will be correlated with outcome as before. 


 
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11.0 
STUDY PARAMETERS AND CALENDAR  
 
11.1 
Study Parameters and Schedule of Events 
Parameter 
Pre-
study1 
 
Day 1 of Every 
Cycle (+/- 3 days) 
 
Cycle 
1-3  
Day 8 
 
Cycle 
1-3 
 Day 15 
 
Cycle 
1-3 
Day 22 
Restaging12 and Follow-up14 
Assignment of FLIPI scores2 
X 
 
 
 
 
 
Notation of GELF criteria2 
X 
 
 
 
 
 
History and Physical examination 
X 
X 
 
 
 
X 
Performance Status 
X 
X 
 
 
 
X 
Tumor Measurements by Physical 
Exam (if applicable) 
X 
X 
 
 
 
X 
CBC and Differential 
X3 
X 
X4 
X4 
X4 
X 
Serum Chemistries 
(electrolytes, AST, ALT, total 
bilirubin, direct bilirubin5, 
creatinine, glucose, alkaline 
phos, and calcium) 
X7 
X 
X 
X 
 
X 
LDH 
X 
X 
X 
X 
 
X 
Beta-2-microglobulin 
X 
 
 
 
 
 
HIV testing 
X 
 
 
 
 
 
Uric acid 
X 
X  
Cycles 3-6 only if > 
ULN prior cycle 
X 
X 
 
 
Monoclonal protein determination13 
X 
X13 
 
 
 
X13 
Bone marrow aspirate biopsy 
If not known to be involved 
X 
(up to 90 
days) 
 
 
 
 
After cycle 12  
if in CR6 
Pregnancy test (for women of child-
bearing potential)7 
X7 
 
 
 
 
 
Hepatitis B surface antigen and 
core antibody testing8 
X8 
 
 
 
 
 


 
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On rituximab treatment days 8 and 15 of cycle 1, patients will be assessed by a nurse for toxicity, and CBC, serum 
chemistries, LDH and uric acid will be performed. Pre-study parameters can be up to 30 days prior to start of treatment, 
except bone marrow aspirate and biopsy can be up to 90 days, if not known to be positive for lymphoma 
 
1. 
Cycles are every 28 days. Patients may be evaluated in the office more frequently at the physician’s discretion. 
2. 
Yes/No should be entered for each criterion of GELF and FLIPI, as well as absolute calculation of FLIPI-1 and FLIPI-2. (See 
Appendix V). 
3. 
At baseline: please record the absolute lymphocyte count.  
4. 
Cycles 2 and 3 for dose escalation cohorts only : CBC and differential is required on Days 8, 15 and 22. Other labs ( chem, 
LDH, UA ) should be done days 8, 15 of cycle 1 only, not in cycles 2-3  
5. 
Direct bilirubin is required only if total bilirubin is elevated. 
6. 
Repeat bone marrow biopsy core and aspirate only if positive at baseline and otherwise meets criteria for CR.  
7. 
Within 2 weeks of start of induction treatment. For definition of woman of childbearing potential (WOCBP) see lenalidomide 
(Revlimid®)REMS program. Before starting lenalidomide: WOCBP must have two negative pregnancy tests (sensitivity of at 
least 50 mIU/mL) prior to starting study drug. The first pregnancy test must be performed within 10-14 days prior to the start 
of study drug and the second pregnancy test must be performed within 24 hours prior to the start of study drug. The subject 
may not receive study drug until the Investigator has verified that the results of these pregnancy tests are negative. Female 
subjects will be warned that sharing study drug is prohibited and will be counseled about pregnancy precautions and 
potential risks of fetal exposure. During study participation and for 28 days following discontinuation from the study: WOCBP 
with regular cycles must agree to have pregnancy tests weekly for the first 28 days of study participation and then every 28 
days while on study, at study discontinuation, and at day 28 following discontinuation from the study. If menstrual cycles are 
irregular, the pregnancy testing must occur weekly for the first 28 days and then every 14 days while on study, at study 
T4, TSH 
X 
Day 1 Cycle 7 only  
 
 
 
X15 
Immunodeficiency Panel16 
X 
Day 1 cycle 7 only 
 
 
 
After cycle 12 
Creatinine clearance 
X 
calculated 
 
 
 
 
CT Chest, Abdomen, and Pelvis; 
Neck (if involved) 
X9 
 
 
 
 
After cycles 3 and 610 
PET/CT Scan 
X9 
 
 
 
 
After cycle 1211 
Baseline Symptoms/AE 
Evaluation17 
X 
X 
X 
X 
 
X 


 
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discontinuation, and at days 14 and 28 following discontinuation from the study. In addition to the required pregnancy 
testing, the Investigator must confirm with WOCBP that she is continuing to use two reliable methods of birth control at each 
visit. Counseling about pregnancy precautions and the potential risks of fetal exposure must be conducted at a minimum of 
every 28 days. During counseling, subjects must be reminded to not share study drug and to not donate blood. Pregnancy 
testing and counseling must be performed if a subject misses her period or if her pregnancy test or her menstrual bleeding is 
abnormal. Study drug treatment must be discontinued during this evaluation. If pregnancy or a positive pregnancy test does 
occur in a study subject or the partner of a male study subject during study participation, study drug must be immediately 
discontinued.  
8. 
Patients must be tested for hepatitis B surface antigen within 6 weeks of randomization. Liver function tests and quantitative 
PCR assay for HBV levels in serum to be performed monthly until 6 months following last rituximab dose for HBcAb positive 
patients.  Further, consideration should be given to treat such patients with anti-viral prophylaxis (e.g., lamivudine 100mg po 
QD) prior to, during, and for 6 months after completion of the last dose of rituximab. Patients who are positive for HBsAg 
(surface antigen) are not allowed to enroll on study. 
9. 
If PET/CT scan has been done, do not need separate diagnostic quality CT unless the only measurable disease is in the 
mesentery and not measurable without oral contrast, in which case CT abdomen/pelvis with oral/IV contrast should be done 
prior to treatment. 
10. 
CT scans (chest/abdomen/pelvis; neck if involved) should be done to evaluate response between days 22 – 29 after cycle 3 
and after cycle 6. If a PET/CT is done, then CT does not need to be done, unless the only initially measurable disease was 
in the mesentery and not measurable without oral contrast, in which case CT abdomen/pelvis with oral/IV contrast should be 
done. 
11. 
Once patient enters PET negative complete remission, then only CT’s (chest/abdomen/pelvis, include neck if previously 
involved) need to be done in follow-up 
12. 
Restaging will be 8 - 12 weeks after day 1 cycle 12 (or after day 1 of last cycle of treatment if stopped early). Repeat bone 
marrow only if it was involved prior to treatment and patient otherwise meets criteria for CR.  
13. 
Monoclonal protein (M-protein) blood determination includes: serum immunofixation, quantitative IgG, IgA, IgM,. If M-protein 
is detected, the abnormal value will be checked every other cycle beginning with cycle 2, and during follow-up at months 6, 
12, 24, 36, 48 and 60 (each  30 days) or until the patient comes off the study 
14. 
FOLLOW-UP: per clinical standards, generally every 3 months for 2 yearsor as clinically indicated, with: History and 
Physical examination, Performance Status, Tumor Measurements by Physical Exam (if applicable), CBC and Differential, 
Serum Chemistries and LDH. CT [Chest, Abdomen, and Pelvis, Neck if previously involved] at months 6, 12,  and 24(each  
30 days). Follow-up visit and CT schedule should count from end of treatment restaging scan. Once the patient has disease 


 
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progression or otherwise meets criteria for treatment failure, patient can be followed for survival by telephone or other 
contact without in-person visit or protocol-mandated CT scans. 
15. 
Thyroid functions at baseline, pre- cycle 7, at re-staging and once 6 months later 
16. 
Immunodeficiency Panel: One anti-coagulated (prefer purple-top) tube sent to Tomsich Flow laboratory. See Appendix VI for 
details. Draw at baseline, before cycle 7 and again at  
17. 
Baseline Symptoms and AE assessments should be done on days 8 and 15 for Cycle 1 only. For Cycles 2 and 3, 
assessments will be performed on Day 1. 


 
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12.0 
MEASUREMENT OF EFFECT   
 
Non-Hodgkin Lymphoma Response Criteria 
NOTE: These criteria are based on the Revised Response Criteria for Malignant Lymphoma, 
(Cheson et al., Journal of Clinical Oncology, 2007, 25:579-586). 
 
The criteria use the following categories of response as described by the working group: Complete 
Response (CR), Partial Response (PR), Stable Disease (SD), Relapse and Progression (PD). In 
the case of stable disease, follow-up assessments must have met the SD criteria at least once 
after study entry at a minimum interval of six weeks.  
 
The following guidelines are to be used for establishing tumor measurements at baseline and for 
subsequent comparison: 
 
The six largest dominant nodes or extranodal masses must be identified at baseline.  
 
If there are 6 or fewer nodes and extranodal masses, all must be listed as dominant. 
 
If there are more than 6 involved nodes or extranodal masses, the 6 largest dominant 
nodes or extranodal masses should be selected according to the following features: a) they 
should be clearly measurable in at least two perpendicular measurements; b) they should 
be from as disparate regions of the body as possible; and c) they should include 
mediastinal and retroperitoneal areas of disease whenever these sites are involved.  
 
Measurements for all dominant nodes and extranodal masses will be reported at baseline. 
Measurements on non-dominant nodes are not required. 
 
The lymph nodes or extranodal masses selected for measurement should be measured in 
two perpendicular diameters, one of which is the longest perpendicular diameter. The 
lymph nodes should be measured in centimeters to the nearest one tenth of a centimeter 
(e.g. 2.0 cm, 2.1 cm, 2.2 cm, etc.) 
 
The two measured diameters of each lymph node site or extranodal mass should be 
multiplied giving a product for each nodal site or extranodal mass. The product of each 
nodal site should be added, yielding the sum of products of the diameters (SPD). The SPD 
will be used in determining the definition of response for those who have less than a 
complete response. 
 
12.1 
Complete Response (CR) 
Complete disappearance of all detectable clinical evidence of disease, and disease-related 
symptoms if present prior to therapy. 
 
12.1.1 In patients with a typically FDG-avid lymphoma with no pre-treatment PET scan, or 
for lymphomas for which the PET scan was positive prior to therapy: a post-
treatment residual mass of any size is permitted as long as it is PET-negative. 
 
12.1.2 For variably FDG-avid lymphomas without a pretreatment PET scan, or if a 
pretreatment PET scan was negative:  all lymph nodes and extranodal masses must 
have regressed on CT to normal size (< 1.5 cm in their greatest transverse diameter 
for nodes > 1.5 cm prior to therapy).  Previously involved nodes that were 1.1-1.5 
cm in their long axis and >1.0 cm in their short axis prior to treatment must have 
decreased to < 1 cm in their short axis after treatment. 
 
12.1.3 The spleen and/or liver, if considered enlarged prior to therapy on the basis of a 
physical examination or CT scan, should not be palpable on physical examination, 
and nodules related to lymphoma should disappear. However, no normal size can 


 
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be specified because of the difficulties in accurately evaluating splenic and hepatic 
size and involvement.  For instance, a spleen considered normal size may contain 
lymphoma, whereas an enlarged spleen may not necessarily reflect the presence of 
lymphoma, but variations in anatomy, blood volume, the use of hematopoietic 
growth factors, or other causes. 
 
12.1.4 If the bone marrow was involved by lymphoma prior to treatment, the infiltrate must 
have cleared on repeat bone marrow biopsy.  The biopsy sample on which this 
determination is made must be adequate (with a goal of > 20 mm unilateral core).  If 
the sample is indeterminate by morphology, it should be negative by 
immunohistochemistry. A sample that is negative by immunohistochemistry but 
demonstrating a small population of clonal lymphocytes by flow cytometry will be 
considered a CR until data become available demonstrating a clear difference in 
patient outcome. 
 
NOTE: Complete Remission/unconfirmed (CRu): Using the above definition for CR and that below 
for PR eliminates the category of CRu. 
 
12.2 
Partial Response (PR) 
The designation of PR requires all of the following: 
 
12.2.1 A ≥ 50% decrease in sum of the product of the diameters (SPD) of up to 6 of the 
largest dominant nodes or extranodal masses. These nodes or masses should be 
selected according to the following: (a) they should be clearly measurable in at least 
2 perpendicular dimensions; if possible, they should be from disparate regions of the 
body; (b) they should include mediastinal and retroperitoneal areas of disease 
whenever these sites are involved. 
 
12.2.2 No increase in the size of other nodes, liver or spleen. 
 
12.2.3 Bone marrow assessment is irrelevant for determination of a PR if the sample was 
positive prior to treatment. However, if positive, the cell type should be specified, 
e.g. large-cell lymphoma or small cleaved cell lymphoma. 
 
12.2.4 No new sites of disease. 
 
12.2.5 For a typically FDG-avid lymphoma with no pretreatment PET scan or one that was 
PET-positive prior to therapy, the post-treatment PET should be positive at any 
previously involved sites. 
 
12.2.6 For variably FDG-avid lymphomas/FDG-avidity unknown, without a pretreatment 
PET scan, or if a pretreatment PET scan was negative, CT scan criteria should be 
used. 
 
12.2.7 Patients who achieve a CR by the above criteria, but who have persistent 
morphologic bone marrow involvement will be considered partial responders. 
 
12.2.8 When the bone marrow was involved before therapy and a clinical CR was 
achieved, but with no bone marrow assessment after treatment, patients should be 
considered partial responders. 


 
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12.3 
Stable Disease (SD) 
 
12.3.1 Failing to attain the criteria needed for a PR or CR, but not fulfilling those for 
progressive disease (see below). 
 
12.3.2 Typically FGD-avid lymphomas: The PET should be positive at prior sites of disease 
with no new areas of involvement on the post-treatment CT or PET. 
 
12.3.3 For variably FDG-avid lymphomas/FDG-avidity unknown: For patients without a 
pretreatment PET scan or if the pre-treatment PET was negative, there must be no 
change in the size of the previous lesions on the post-treatment CT scan. 
 
12.4 
Progression (PD) and Relapse 
For determination of relapsed and progressive disease, lymph nodes should be considered 
abnormal if the long axis is more than 1.5 cm, regardless of the short axis.  If a lymph node has a 
long axis of 1.1 to 1.5 cm, it should only be considered abnormal if the short axis is more than 1 
cm.  Lymph nodes < 1 x < 1 cm will not be considered as abnormal for relapse or progressive 
disease. 
 
Treatment decisions in patients with presumed refractory, relapsed or progressive disease should 
not be made solely on the basis of a single PET scan without histologic confirmation. 
 
12.4.1 Appearance of any new lesion more than 1.5 cm in any axis during or at the end of 
therapy, even if other lesions are decreasing in size. 
 
 
Increased FDG uptake in a previously unaffected site should only be considered 
relapsed or progressive disease after confirmation with other modalities.  In patients 
with no prior history of pulmonary lymphoma, new lung nodules identified by CT are 
mostly benign. Thus, a therapeutic decision should not be made solely on the basis 
of the PET without histologic confirmation. 
 
12.4.2 At least a 50% increase from nadir in the SPD of any previously involved nodes or 
extranodal masses, or in a single involved node or extranodal mass, or the size of 
other lesions (e.g. splenic or hepatic nodules).  To be considered progressive 
disease, a lymph node or extranodal mass with a diameter of the short axis of less 
than 1.0 cm must increase by > 50% and to a size of 1.5 cm x 1.5 cm or more than 
1.5 cm in the long axis. 
 
12.4.3 At least a 50% increase in the longest diameter of any single previously identified 
node or extranodal mass more than 1 cm in its short axis. 
 
12.4.4 Lesions should be PET positive if observed in a typical FDG-avid lymphoma or the 
lesion was PET positive before therapy unless the lesion is too small to be detected 
with current PET systems (< 1.5 cm in its long axis by CT). 
 
12.4.5 Measurable extranodal disease should be assessed in a manner similar to that for 
nodal disease.  For these response criteria, the spleen is considered nodal disease.  
Disease that is only assessable (e.g., pleural effusions, bone lesions) will be 
recorded as present or absent only, unless, while an abnormality is still noted by 


 
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imaging studies or physical examination, it is found to be histologically negative. 
 
12.5 
Duration of Response 
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date that 
recurrent or progressive disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that progressive disease is objectively documented. 
 
12.6 
Progression-Free Survival (PFS) 
PFS is defined as the duration of time from start of treatment to time of progression or death, 
whichever occurs first.  
 
12.7 
Time to Treatment Failure 
Time to treatment failure (event-free survival) is defined as the time from study entry to first event 
of disease progression, discontinuation of treatment for any reason, initiation of new treatment, or 
death. 
 
12.8 
Overall Survival 
Overall survival is defined as the date of study entry to the date of death. 
 
 
13.0 
RECORDS TO BE KEPT / REGULATORY CONSIDERATIONS  
 
ADMINISTRATIVE REQUIREMENTS  
 
Product Complaints   
A product complaint is a verbal, written, or electronic expression that implies dissatisfaction 
regarding the identity, strength, purity, quality, or stability of a drug product.  Individuals who 
identify a potential product complaint situation should immediately contact MedComm Solutions 
(see below) and report the event.  Whenever possible, the associated product should be 
maintained in accordance with the label instructions pending further guidance from a Millennium 
Quality representative. 
 
For Product Complaints, 
Phone: 1-877-N1-POINT (1-844-617-6468) 
E-mail: GlobalOncologyMedInfo@takeda.com 
FAX: 1-800-881-6092 
Hours: Mon-Fri, 9 a.m. – 7 p.m. ET(US) 
 
 
Product complaints in and of themselves are not AEs.  If a product complaint results in an SAE, an 
SAE form should be completed and sent to Millennium Pharmacovigilance (refer to Section 8.3).  
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 8.0 
(Adverse Events: List and Reporting Requirements). 
 
13.1 
Data Reporting  
 


 
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The Overture and OnCore™ Databases will be utilized, as required by the Case 
Comprehensive Cancer Center, to provide data collection for both accrual entry and 
trial data management. Overture and OnCore™ are Clinical Trials Management 
Systems housed on secure servers maintained at Case Western Reserve 
University. Access to data through Overture and OnCore™ is restricted by user 
accounts and assigned roles. Once logged into the Overture or OnCore™ system 
with a user ID and password, Overture and OnCore™ define roles for each user 
which limits access to appropriate data. User information and password can be 
obtained by contacting the OnCore™ Administrator at OnCore-
registration@case.edu. 
 
Overture and OnCore™ are designed with the capability for study setup, activation, 
tracking, reporting, data monitoring and review, and eligibility verification. This study 
will utilize electronic Case Report Form completion in the Overture database. A 
calendar of events and required forms are available in Overture and OnCore™. 
 
13.2 
Regulatory Considerations 
The study will be conducted in compliance with ICH guidelines and with all applicable federal 
(including 21 CFR parts 56 & 50), state or local laws.  
 
13.2.1  Written Informed Consent 
Provision of written informed consent must be obtained prior to any study-related procedures.  The 
Principal Investigator will ensure that the subject is given full and adequate oral and written 
information about the nature, purpose, possible risks and benefits of the study as well as the 
subject’s financial responsibility.  Subjects must also be notified that they are free to discontinue 
from the study at any time.  The subject should be given the opportunity to ask questions and 
allowed time to consider the information provided.  
 
The original, signed written Informed Consent Form must be kept with the Research Chart in 
conformance with the institution’s standard operating procedures. A copy of the signed written 
Informed Consent Form must be given to the subject. 
 
13.2.2  Subject Data Protection 
In accordance with the Health Information Portability and Accountability Act (HIPAA), a subject 
must sign an authorization to release medical information to the sponsor and/or allow the sponsor, 
a regulatory authority, or Institutional Review Board access to subject’s medical information that 
includes all hospital records relevant to the study, including subjects’ medical history. 
 
13.2.3  Accessing Electronic Medical Records for University Hospitals Health 
System: NA   
 
13.2.4  Retention of Records 
The Principal Investigator of The Case Comprehensive Cancer Center supervises the retention of 
all documentation of adverse events, records of study drug receipt and dispensation, and all IRB 
correspondence for as long as needed to comply with national and international regulations. No 
records will be destroyed until the Principal Investigator confirms destruction is permitted.  
 
13.2.5  Audits and Inspections  
Authorized representatives of the sponsor, a regulatory authority, an Independent Ethics 


 
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Committee (IEC) or an Institutional Review Board (IRB) may visit the Center to perform audits or 
inspections, including source data verification.  The purpose of an audit or inspection is to 
systematically and independently examine all study-related activities and documents to determine 
whether these activities were conducted, and data were recorded, analyzed, and accurately 
reported according to the protocol, Good Clinical Practice (GCP), guidelines of the International 
Conference on Harmonization (ICH), and any applicable regulatory requirements. 
   
 
14.0 
STATISTICAL CONSIDERATIONS 
 
14.1 
Populations for Analysis 
Patients in Phase 1B considered evaluable for toxicity to determine MTD will include those 
that complete the first 4 week cycle or those removed for DLT in cycle 1. 
 
Patients evaluable for response will be those who complete 3 cycles of therapy and at least 
one post-baseline response assessment or those who are taken off study for progressive 
disease. 
 
14.2 
Methods 
Phase 1 B consisted of up to three dose levels (See Section 6).  12 patients total were 
enrolled and the MTD was determined to be at DL3. 
 
Phase 2 will follow as one expansion cohort treated at the MTD which was determined to 
be DL3.  It will comprise of 18 patients evaluable for response, with follicular lymphoma  A 
maximum of 24patients will be available for this portion of the analysis, 18 from expansion 
cohorts, and 6 who were treated at the RP2D. 
 
 
14.3 
Efficacy Analysis 
Response criteria are outlined in Section 12. 
 
14.4 
Early Stopping Toxicity 
If 2 of the first 6 patients treated at the RP2D experience an SAE, or if 
subsequently the fraction of patients experiencing SAE exceeds 1/3, accrual to 
the trial will be halted and trial continuation reassessed with the Case 
Comprehensive Cancer Center’s Data Safety Toxicity Committee in concert with the 
Millennium Pharmacovigilance and Celgene Drug Safety Departments. 
 
 
 
 
 
 
 


 
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REFERENCES 
1. 
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. 
2. 
Gupta, N., M. Saleh, and K. Venkatakrishnan. Flat-Dosing Versus BSA-Based Dosing 
for MLN9708, An Investigational Proteasome Inhibitor: Population Pharmacokinetic 
(PK) Analysis of Pooled Data From 4 Phase-1 Studies in 53rd ASH Annual Meeting and 
Exposition. 2011. San Diego, CA; p. abstr 1433 
3. 
Chow, L.Q., et al. MLN9708, an investigational proteasome inhibitor, in patients with 
solid tumors; Updated phase 1 results in Head and Neck Symposium. 2012. Phoenix, 
AZ 
4. 
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. 
5. 
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. 
6. 
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.. 
7. 
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. 
8. 
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. 
9. 
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. 
10. 
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. 
11. 
Richardson P, Baz R, Wang L, Jakubowiak A, Berg D, Liu G, et al. Investigational Agent 
MLN9708, An Oral Proteasome Inhibitor, in Patients (Pts) with Relapsed and/or 
Refractory Multiple Myeloma (MM): Results From the Expansion Cohorts of a Phase 1 
Dose-Escalation Study In: 53rd ASH Annual Meeting and Exposition; 2011 10-13 Dec; 
San Diego, CA; p. abstr 301. 
12. 
Lonial S, Baz R, Wang M, Talpaz M, Liu G, Berg D, et al. Phase I study of twice weekly 
dosing of the investigational oral proteasome inhibitor MLN9708 in patients (pts) with 
relapsed and/or refractory multiple myeloma (MM). J Clin Oncol (ASCO Meeting 
Abstracts) 2012;30(15 suppl):abstr 8017. 
13. 
Kumar S, Bensinger W, Reeder C, Zimmerman T, Berenson J, Berg D, et al. Weekly 
Dosing of the Investigational Oral Proteasome Inhibitor MLN9708 in Patients with 


 
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Relapsed and/or Refractory Multiple Myeloma: Results From a Phase 1 Dose- 
Escalation Study In: 53rd ASH Annual Meeting and Exposition; 2011 10-13 Dec; San 
Diego, CA; p. abstr 816. 
14. 
Kumar S, 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. 
15. 
Kumar S, Niesvizky R, Berdeja J, Bensinger W, Zimmerman T, Berenson J, et al. 
Safety and Pharmacokinetics of Weekly MLN9708, an Investigational Oral Proteasome 
Inhibitor, Alone and in Combination. Clinical Lymphoma Myeloma and Leukemia 
2013;13(Supplement 1):S154; abstr P-230 
16. 
Common Terminology Criteria for Adverse Events (CTCAE). 2010. 
 
 


 
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APPENDICES: 
 
Appendix I 
Eastern Cooperative Oncology Group (ECOG) Scale for Performance Status 
 
Grade 
Description 
0 
Normal activity.  Fully active, able to carry on all predisease performance 
without restriction 
1 
Symptoms but ambulatory.  Restricted in physically strenuous activity, but 
ambulatory and able to carry out work of a light or sedentary nature (e.g., 
light housework, office work) 
2 
In bed < 50% of the time.  Ambulatory and capable of all self-care, but 
unable to carry out any work activities.  Up and about more than 50% of 
waking hours. 
3 
In bed > 50% of the time.  Capable of only limited self-care, confined to bed 
or chair more than 50% of waking hours. 
4 
100% bedridden.  Completely disabled.  Cannot carry on any self-care.  
Totally confined to bed or chair 
5 
Dead 
Source:  Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET et al. 
Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin 
Oncol 1982; 5 (6):649-55.  
 
 
 
Appendix II 
Cockcroft-Gault Equation 
 
Creatinine Clearance = CrCl 
 
For males: 
 
CrCl = (140–age [years]  weight [kg]) 
72  (serum creatinine [mg/dL])  
 
For females: 
CrCl = 0.85 (140–age [years]  weight [kg]) 
72  (serum creatinine [mg/dL])  
 
Source:  Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. 
Nephron 1976;16(1):31-41. 
 
 
 
 
 
 
 
 
 


 
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85 
 
Appendix III List of Potential Medication Interactions Affected by CYP3A4 Systems of 
Enzymes 
Potential Medication Interactions Affected by CYP3A4 Systems of Enzymes 
 
 
List of Known CYP3A4 Inhibitors 
Indinavir 
Erythromycin 
Diethyldithiocarbamate 
Nelfinavir 
Fluconazole 
Fluvoxamine 
Ritonavir 
Grapefruit Juice 
Gestodene 
Clarithromycin 
Verapamil 
Imatinib 
Itraconazole 
Diltiazem 
Mibefradil 
Ketaconazole 
Cimetidine 
Mifepristone 
Nefazodone 
Amiodarone 
Norfloxacin 
Saquinavir 
Chloramphenicol 
Norfluoxetine 
Suboxone 
Boceprevir 
Starfruit 
Telithromycin 
Ciprofloxacin 
Telaprevir 
Aprepitant 
Delaviridine 
Voriconazole 
 
 
 
List of Known CYP3A4 Inducers 
Efavirenz 
Phenobarbital 
Nevirapine 
Phenytoin 
Barbiturates 
Pioglitazone 
Carbamazepine 
Rifabutin 
Glucocorticoids 
Rifampin 
Modafinil 
St. John’s Wort 
Oxacarbazepine 
Troglitazone 
 
 


 
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86 
Appendix IV Patient Pill Diary  
 
Subject Number: _________________ 
Subject Initials: _______________ 
Cycle #____________ 
 
 
Case1414 Daily Pill Diary  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dear Subject / Legal Guardian, 
Thank you for participating in this clinical research study.  As part of this research study, we are asking that each day you record in this 
diary information about the date and time of each dosing of study medication.  Bring this diary with you to each appointment until the 
diary is collected by the study site staff. 
 
INSTRUCTIONS FOR TAKING LENALIDOMIDE (DAYS 1-21 OF EACH 28-DAY CYCLE) 
 
Take your medication at approximately the same time in the morning every day. 
 
Swallow lenalidomide capsules whole with water at the same time each day.  Do not break, chew or open the capsules.   
 
If a dose of lenalidomide is missed, it should be taken as soon as possible on the same day.  If it is missed for the entire day, it 
should not be made up. 
INSTRUCTIONS FOR TAKING IXAZOMIB (DAYS 1, 8, 15 OF EACH 28-DAY CYCLE) 
 
Swallow ixazomib capsules whole, with water.  Do not 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 you remember if the next scheduled dose is 72 hours or more away.  A double dose should 
not be taken to make up for a missed dose.  If you vomit after taking a dose, do not repeat the dose.  Resume dosing at the time of 
the next scheduled dose. 
GENERAL INSTRUCTIONS 
 
If you did not take your daily dose, please write down why in the space provided. 
 
If you experience side effects, please write these down in the space provided as well. 
 
Call your nurse if you have any questions about taking either medication. 
 
Name of Site Contact: ____________________________ 
 
Phone Number: _____________________ 
 
 
Return this diary at the end of every cycle to site staff. 
 
 


 
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87 
Day 
Date 
Time Pills 
Taken 
Dose 
Taken 
Indicate Which Pill Taken 
(Place “X” in Corresponding 
Box) 
Comments/Side Effects 
Month 
Day 
Year 
AM 
PM 
mg 
Lenalidomide 
Ixazomib 
Reason for missed doses or any side 
effects you have when taking the 
medications. 
1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2 
 
 
 
 
 
 
 
 
 
3 
 
 
 
 
 
 
 
 
 
4 
 
 
 
 
 
 
 
 
 
5 
 
 
 
 
 
 
 
 
 
6 
 
 
 
 
 
 
 
 
 
7 
 
 
 
 
 
 
 
 
 
8 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9 
 
 
 
 
 
 
 
 
 
10 
 
 
 
 
 
 
 
 
 
11 
 
 
 
 
 
 
 
 
 
12 
 
 
 
 
 
 
 
 
 
13 
 
 
 
 
 
 
 
 
 
14 
 
 
 
 
 
 
 
 
 
15 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
16 
 
 
 
 
 
 
 
 
 
17 
 
 
 
 
 
 
 
 
 
18 
 
 
 
 
 
 
 
 
 
19 
 
 
 
 
 
 
 
 
 
20 
 
 
 
 
 
 
 
 
 
21 
 
 
 
 
 
 
 
 
 
22 
No study medication taken on this day. 
 
23 
No study medication taken on this day. 
 
24 
No study medication taken on this day. 
 
25 
No study medication taken on this day. 
 
26 
No study medication taken on this day. 
 
27 
No study medication taken on this day. 
 
28 
No study medication taken on this day. 
 


 
88 
 
Appendix V Risk Factors: GELF tumor burden criteria and FLIPI score 
GELF 
 
To meet GELF criteria, patient must have at least one criterion: 
 
 
Nodal or extranodal mass > 7 cm 
 
At least 3 nodal masses: each > 3.0 cm in longest dimension 
 
Systemic symptoms due to lymphoma or B symptoms 
 
Splenomegaly with spleen > 16 cm by CT scan 
 
Evidence of compression syndrome (e.g., ureteral, orbital, gastrointestinal) or pleural or 
peritoneal serious effusion due to lymphoma (irrespective of cell content) 
 
Leukemic presentation (> 5.0 x 109/L malignant circulating follicular cells) 
 
Cytopenias (absolute neutrophil count < 1.0 x 109/L, hemoglobin < 10 gm/dL, and/or platelets 
<100 x 109/L). 
 
FLIPI  
 
Each patient should be assessed for the presence or absence of the following 5 adverse 
prognostic factors (adverse factor in italics):  
 
1) Age (> 60 years vs. 60 years or less) 
2) Ann Arbor stage (III-IV vs. I-II) 
3) Hemoglobin level (< 120 g/L vs. 120 g/L or higher) 
4) Number of nodal areas  ≥ 5 or less; see figure below) 
5) Serum LDH level (above normal vs. normal or below) 
 
Each patient should then be assigned into one of the following 3 risk groups:  
 
low risk (0-1 adverse factor) 
 
intermediate risk (2 factors) 
 
poor risk (3 adverse factors) 
                       
Nodal map according to FLIPI model. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
89 
 
 
Solal-Celigny P, et al. Blood 2004; 104:1258-1265; and Buske C, et al. Blood. 2006;108:1504-150 
 
FLIPI-2 
 
An updated analysis of the FLIPI was reported (FLIPI-2).  This analysis was completed on 832 
follicular lymphoma patients treated from 2003 through 2005, of who the majority received 
rituximab-based therapy.  Five clinical factors were identified as being correlated with survival.  
Three of the parameters were different than the original FLIPI (FLIPI-1), while two were similar (i.e., 
anemia and older age). 
 
Each patient should be assessed for the presence or absence of the following 5 adverse 
prognostic factors (adverse factor in italics):  
 
1) Age (> 60 years vs. 60 years or less) 
2) Hemoglobin level (< 120 g/L vs. 120 g/L or higher) 
3) β2-microglobulin (above normal vs. normal or below) 
4) Largest involved lymph node (> 6 cm vs. 6cm or lower) 
5) Bone marrow (involved vs. not involved)   
 
Federico M, et al.  J Clin Oncol  2009; 2. 


 
90 
 
Appendix VI:  
Blood Specimen Handling 
 
One tube of EDTA anti-coagulated blood (purple top) will be drawn at baseline, with day 1 cycle 7 
lab draw and at re-staging after cycle 12, at a regularly scheduled venipuncture time. The tube will 
be labeled with the patient information and a study specific requisition will be attached to the 
specimen. The specimen will be delivered to the Tomsich Reference Laboratory.  The blood 
specimen and requisition form must be received and processed within 48 hours by the Tomsich 
flow cytometry lab, available Monday through Friday. 
 
If drawn at Cleveland Clinic, samples will be sent by the same mechanism as for standard blood 
tests.  
 
If drawn at University Hospitals, tubes can be sent with the regularly scheduled Cleveland Clinic 
daily lab pick up at 2085 Adelbert Road Cutting Room 231(Andrew Wing of Bishop) which runs 
Monday through Friday. Samples need to be at the designated pick-up spot by 2:45pm. If missed 
Monday through Thursday, samples will be picked up the next day. If delivered after 2:45pm on 
Friday, samples will not be able to be run.  
 
The Immunodeficiency (CDC) Panel will be run and reported in SunQuest.