Clinical trial NCT01216683
Conditions: Lymphoma
Keywords: contiguous stage II grade 1 follicular lymphoma contiguous stage II grade 2 follicular lymphoma contiguous stage II grade 3 follicular lymphoma noncontiguous stage II grade 1 follicular lymphoma noncontiguous stage II grade 2 follicular lymphoma noncontiguous stage II grade 3 follicular lymphoma stage III grade 1 follicular lymphoma stage III grade 2 follicular lymphoma stage III grade 3 follicular lymphoma stage IV grade 1 follicular lymphoma stage IV grade 2 follicular lymphoma stage IV grade 3 follicular lymphoma
Sponsor: ECOG-ACRIN Cancer Research Group
Start date: 2011-02-09; Completion date: 2019-12-02
Enrollment: 289 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
RATIONALE: Drugs used in chemotherapy, such as bendamustine hydrochloride, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as rituximab, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them. Bortezomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Biological therapies, such as lenalidomide, may stimulate the immune system in different ways and stop cancer cells from growing. It is not yet known whether giving bendamustine hydrochloride and rituximab together alone is more effective than giving bendamustine hydrochloride and rituximab together with bortezomib or lenalidomide in treating follicular lymphoma.

PURPOSE: This randomized phase II trial is studying giving bendamustine hydrochloride and rituximab together with or without bortezomib followed by rituximab with or without lenalidomide to see how well they work in treating patients with high-risk stage II, stage III, or stage IV follicular lymphoma.

Detailed description:
OBJECTIVES:

Primary

* To compare the complete remission rate in patients with high-risk follicular lymphoma receiving induction therapy comprising bendamustine hydrochloride and rituximab with vs without bortezomib.
* To compare the 1-year post-induction disease-free survival rate in patients receiving continuation therapy comprising rituximab with vs without lenalidomide.

Secondary

* To determine the 3-year progression-free survival and the 5-year overall survival of these patients.
* To evaluate patient-reported outcomes at baseline and during treatment to determine differences in symptom palliation, treatment-related symptoms, and overall health-related quality of life.
* To examine the association between baseline Follicular Lymphoma International Prognostic Index (FLIPI) information and outcome of these patients.
* To examine the association between baseline and end-of-treatment patient comorbidities assessed by the Cumulative Illness Rating Scale (CIRS) and outcome.
* To create an image and tissue bank including serial PET/CT scans, diagnostic paraffin-embedded tissue, germline DNA, and serial blood and bone marrow samples sufficient to support proposed and future studies of tumor and host characteristics that may predict for clinical outcome, including treatment arm effects, and enhance existing prognostic indices. (exploratory)
* To evaluate the rate of peripheral neuropathy associated with subcutaneous and intravenous bortezomib.

OUTLINE: Patients are stratified according to FLIPI-1score (0-2 vs 3 vs 4-5) and Groupe d'Etude des Lymphomes Folliculaires (GELF) tumor burden (low vs high). Patients are randomized to 1 of 3 treatment arms.

* Arm A then Arm D

  * Arm A (induction): Patients receive rituximab intravenously (IV) on day 1 and bendamustine hydrochloride IV over 1 hour on days 1 and 2. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity.
  * Arm D (continuation): Beginning 4 weeks after the completion of induction therapy, patients who have stable disease or better at time of post-induction restaging receive rituximab IV on day 1. Treatment repeats every 8 weeks for 2 years in the absence of disease progression or unacceptable toxicity.
* Arm B then Arm E

  * Arm B (induction): Patients receive rituximab IV on day 1; bortezomib IV on days 1, 4, 8, and 11; and bendamustine hydrochloride IV over 1 hour on days 1 and 4. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity.
  * Arm E (continuation): Beginning 4 weeks after the completion of induction therapy, patients who have stable disease or better at time of post-induction restaging receive rituximab as in arm D.
* Arm C then Arm F

  * Arm C (induction): Patients receive rituximab IV on day 1 and bendamustine hydrochloride IV over 1 hour on days 1 and 2. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity.
  * Arm F (continuation): Immediately after completing induction therapy, patients who have stable disease or better at time of post-induction restaging receive oral lenalidomide on days 1-21. Treatment repeats every 4 weeks for 13 courses in the absence of disease progression or unacceptable toxicity. Beginning 4 weeks after the completion of induction therapy, these patients receive rituximab IV on day 1. Treatment repeats every 8 weeks for 2 years in the absence of disease progression or unacceptable toxicity.

Quality of life (including fatigue, neurotoxicity, anxiety, and depression) is assessed by questionnaire at baseline and periodically during study therapy.

Blood, bone marrow, and tissue samples may be collected periodically for correlative studies and for a repository.

After completion of study therapy, patients are followed up periodically for 15 years.

Arms: arm 1: Arm A (induction): Patients receive rituximab intravenously (IV) on day 1 and bendamustine hydrochloride IV over 1 hour on days 1 and 2. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity.

Arm D (continuation): Beginning 4 weeks after the completion of induction therapy, patients who have stable disease or better at time of post-induction restaging receive rituximab IV on day 1. Treatment repeats every 8 weeks for 2 years in the absence of disease progression or unacceptable toxicity. arm 2: Arm B (induction): Patients receive rituximab IV on day 1; bortezomib IV on days 1, 4, 8, and 11; and bendamustine hydrochloride IV over 1 hour on days 1 and 4. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity.

Arm E (continuation): Beginning 4 weeks after the completion of induction therapy, patients who have stable disease or better at time of post-induction restaging receive rituximab as in arm D. arm 3: Arm C (induction): Patients receive rituximab IV on day 1 and bendamustine hydrochloride IV over 1 hour on days 1 and 2. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity.

Arm F (continuation): Immediately after completing induction therapy, patients who have stable disease or better at time of post-induction restaging receive oral lenalidomide on days 1-21. Treatment repeats every 4 weeks for 13 courses in the absence of disease progression or unacceptable toxicity. Beginning 4 weeks after the completion of induction therapy, these patients receive rituximab IV on day 1. Treatment repeats every 8 weeks for 2 years in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: rituximab intervention 2: Bendamustin intervention 3: bortezomib intervention 4: lenalidomide
Intervention descriptions: intervention 1: Given IV intervention 2: Given IV intervention 3: Given IV intervention 4: Given orally

Protocol documents:
Prot_SAP_000.pdf: 
E2408 
 
1 
A 3-Arm Randomized Phase II Trial of Bendamustine-Rituximab (BR) 
Followed by Rituximab vs Bortezomib-BR (BVR) Followed by Rituximab vs 
BR Followed by Lenalidomide/Rituximab in High Risk Follicular Lymphoma 
STUDY CHAIR: 
Andrew M. Evens, D.O., M.S. 
STUDY CO-CHAIRS: 
Thomas Habermann, M.D. 
 
Ranjana Advani, M.D.   
PATHOLOGY CO-CHAIR: 
Randy Gascoyne, M.D. 
CORRELATIVE STUDIES GROUP:  Thomas Witzig, M.D. 
Andrew M. Evens, D.O, M.S. 
Randy Gascoyne, M.D. 
Lisa H. Butterfield, Ph.D. 
RADIOLOGY CO-CHAIR: 
Andy Quon, M.D. 
PATIENT OUTCOMES AND SURVIVORSHIP 
CO-CHAIR: 
Lynne Wagner, Ph.D. 
STUDY STATISTICIAN: 
Fangxin Hong, Ph.D. 
LYMPHOMA COMMITTEE CHAIR: 
Brad Kahl, M.D. 
 
 
Version Date:  June 15, 2016 
NCI Update Date:  January 23, 2015 
STUDY PARTICIPANTS 
ACTIVATION DATE 
US Sites Only 
December 13, 2010 
 
PRE-ACTIVATION DATE  
 
November 1, 2010 
 
Addendum #1 – Incorporated Prior to Activation 
 
Update #1 – Incorporated Prior to Activation 
 
Update #2 – 12/10 
 
Addendum #2 – 5/11 
 
Addendum #3 – 10/11 
 
Addendum #4 – 5/12 
 
Update #3 – 4/12 
 
Update #4 – 8/12 
 
Addendum #5 – 4/13 
 
Addendum #6 – 9/13 
 
Addendum #7 – 2/14 
 
Addendum #8 – 9/14 
 
Addendum #9 – 9/14 
 
Addendum #10 – 10/14 
 
Addendum #11 – 1/15 
 
Update #5 – 1/15 
 
Addendum #12 – 7/16 
Bortezomib (NSC# 681239) Supplied by Millennium 
Lenalidomide (NSC# 703813) Supplied by Celgene 
Bendamustine (NSC# 138783) Supplied by Teva Oncology 
Rev. 2/14 
Rev. 9/14 


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Table of Contents 
Schema ...................................................................................................................... 6 
1. Introduction ........................................................................................................ 7 
1.1 Natural History of Indolent Lymphoma .................................................... 7 
1.2 Treatment for Indolent Lymphoma .......................................................... 7 
1.3 Defining High-Risk Follicular Lymphoma ................................................. 13 
1.4 Bortezomib .............................................................................................. 15 
1.5 Lenalidomide ........................................................................................... 20 
1.6 Quality of Life in Lymphoma ................................................................... 24 
1.7 Rationale and Importance of Current Study ........................................... 26 
1.8 Gender and Ethnicities Statement .......................................................... 26 
1.9 Overall Summary/Hypothesis ................................................................. 26 
2. Objectives ......................................................................................................... 28 
2.1 Primary Objectives .................................................................................. 28 
2.2 Secondary Objectives .............................................................................. 28 
3. Selection of Patients ......................................................................................... 29 
3.1 Randomization to Induction (Step 1) ...................................................... 29 
3.2 Registration to Continuation Therapy (Step 2) ....................................... 34 
4. Registration and Randomization Procedures ................................................... 38 
4.1 Randomization (Step 1) ........................................................................... 41 
4.2 Registration (Step 2)................................................................................ 43 
4.3 Investigator’s Drug Brochure and Safety Alerts ...................................... 44 
4.4 IND Status ................................................................................................ 45 
5. Treatment Plan ................................................................................................. 46 
5.1 Arm A - BENDAMUSTINE-RITUXIMAB (BR) INDUCTION FOLLOWED BY 
RITUXIMAB CONTINUATION (ARM D) ..................................................... 46 
5.2 Adverse Event Reporting Requirements ................................................. 57 
5.3 Comprehensive Adverse Events and Potential Risks List (CAEPR) .......... 61 
5.4 Dose Modifications ................................................................................. 73 
5.5 Supportive Care (non-HIV) ...................................................................... 82 
5.6 Supportive care therapy for HIV positive patients. ................................. 82 
5.7 Duration of Therapy ................................................................................ 83 
5.8 Duration of Follow-up ............................................................................. 84 
6. Measurement of Effect ..................................................................................... 85 
6.1 Complete Response ................................................................................ 85 
6.2 Partial Response (PR) .............................................................................. 86 
6.3 Stable Disease (SD) .................................................................................. 86 
6.4 Progression (PD) and Relapse ................................................................. 87 
6.5 Duration of Response .............................................................................. 88 
6.6 Survival .................................................................................................... 88 
6.7 Progression-Free Survival ........................................................................ 88 


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6.8 Time to Progression ................................................................................ 88 
6.9 Time to Treatment Failure ...................................................................... 88 
6.10 Disease-Free Survival .............................................................................. 88 
6.11 Disease-Specific Survival ......................................................................... 89 
6.12 Quality of Life Measurement .................................................................. 89 
7. Study Parameters .............................................................................................. 92 
7.1 Therapeutic Parameters.......................................................................... 92 
7.2 Biological Sample Submissions ............................................................... 96 
8. Drug Formulation and Procurement ................................................................. 98 
8.1 Bendamustine (NSC 138783) .................................................................. 98 
8.2 Rituximab .............................................................................................. 104 
8.3 Bortezomib (NSC 681239) ..................................................................... 108 
8.4 Lenalidomide (NSC 703813) .................................................................. 113 
9. Statistical Considerations ................................................................................ 120 
9.1 Primary Endpoints ................................................................................. 120 
9.2 Secondary Endpoints............................................................................. 121 
9.3 Gender and Ethnicity ............................................................................ 127 
10. Pathology Review ............................................................................................ 128 
10.1 Submitting Diagnostic Material ............................................................ 128 
10.2 Materials Required For This Protocol ................................................... 128 
10.3 Shipping Procedures ............................................................................. 129 
10.4 ECOG-ACRIN Sample Tracking System .................................................. 129 
10.5 Central Biorepository and Pathology Facility: Sample Processing and 
Routing .................................................................................................. 130 
10.6 Banking .................................................................................................. 130 
11. Correlative Studies .......................................................................................... 131 
11.1 Submission of Scans and Biological Materials ...................................... 131 
11.2 Identification of Relevant Biomarkers for Comparison of Treatment 
Effects .................................................................................................... 136 
11.3 Banking .................................................................................................. 140 
11.4 Sample Inventory Submission Guidelines ............................................. 140 
11.5 Lab Data Transfer Guidelines ................................................................ 140 
12. Records to Be Kept .......................................................................................... 141 
12.1 Records Retention ................................................................................. 141 


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13. Patient Consent and Peer Judgment .............................................................. 141 
14. References ...................................................................................................... 142 
Appendix I  Informed Consent Template for Cancer Treatment Trials (English 
Language) [Deleted in Addendum #5] ............................................................ 154 
Appendix II  Pathology Submission Guidelines ..................................................... 155 
Appendix III  Patient Thank You Letter .................................................................. 160 
Appendix IV  Follicular Lymphoma International Prognostic Index (FLIPI) ........... 161 
Appendix V  Patient Pill Diary for Lenalidomide.................................................... 163 
Appendix VI  FDG-PET IMAGING ........................................................................... 165 
Appendix VII  Bendamustine Reconciliation ......................................................... 172 
Appendix VIII  Risks of Fetal Exposure, Pregnancy Testing Guidelines and 
Acceptable Birth Control Methods ................................................................. 173 
Appendix IX  RevAssist for Study Participants ....................................................... 175 
Appendix X  Modified Cumulative Illness Rating Scale (CIRS) ............................... 177 
Appendix XI  Modified Ann Arbor Staging System ................................................ 188 
Appendix XII  Bortezomib Drug Ordering Form..................................................... 189 
Appendix XIII  Bendamustine Drug Ordering Form ............................................... 192 
Appendix XIV  Lenalidomide Information Sheet ................................................... 193 
Appendix XV  Investigator Statement ................................................................... 195 
Appendix XVI  Instructions for Reporting Pregnancies on a Clinical Trial ............. 196 
 


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Rev. 10/11, 9/13, 9/14 
STUDY CHAIR 
 
 
Andrew M. Evens, D.O., M.Sc. 
Professor of Medicine 
Tufts Medical Center 
Director, Lymphoma Program 
Tufts Cancer Center 
800 Washington Street 
Boston, Massachusetts 02111 
Phone (617) 636 8077 
Fax (617) 636 7060 
Email: AEvens@tuftsmedicalcenter.org 
 
 
STUDY CO-CHAIRS 
 
 
Ranjana Advani, MD  
Stanford Comprehensive Cancer Center 
875 Blake Wilbur Drive 
Stanford, CA 94303 
Phone: 650-724-8372 
Fax: 650-725-9113 
Email:  radvani@stanford.edu 
 
 
 
Thomas M. Habermann, MD  
Mayo Clinic 
200 First St., SW-W10A 
Rochester, MN 55905 
Phone: (507) 284-2511 
Fax: (507) 266-4972 
Email: habermann.thomas@mayo.edu 
 
 
Rev. 10/11, 4/13, 2/14, 
9/14 
STUDY CHAIR LIAISON (SCL) 
 
 
Livia (Terezi) Gjylameti 
The Neely Center for Clinical Cancer Research 
Tufts Medical Center 
800 Washington St., Box 245 
Boston, MA 02111 
Phone: (617) 636-5409 
Fax: (617) 636-8886 
Email: lterezi@tuftsmedicalcenter.org 
 
 
 
PATIENT OUTCOMES AND SURVIVORSHIP CO-CHAIR  
 
 
Lynne I. Wagner, Ph.D. 
Northwestern University 
625 N. Michigan Ave 
Suite 2700 
Chicago, IL 60611 
Phone: (312) 503-3529 
Fax: (312) 503-4800 
Email: lwagner@northwestern.edu 
 
 


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Schema 
R
A
N
D
O
M
I
Z
A
T
I
O
N
Arm A - BR treatment
Rituximab IV 375 mg/m2   Day1  
Bendamustine IV 90 mg/m2   Day1 & 2
x 6 cycles
R
E
G
I
S
T
R
A
T
I
O
N2
Accrual goal = 286 total patients
Cycle length is 28 days (4 weeks)
* Requires High tumor burden per GELF criteria (see Section 3)
**Requires FLIPI Status of 3 or higher (per FLIPI 1 criteria)
1. At time of restaging, if disease progresses, patient discontinues protocol therapy. Restaging for induction and continuation will take place after every three (3) 
Rituximab treatments. See Section 5.1.5 for treatment and restaging schedules.
2. For patients who have stable disease or better at time of post-induction restaging.  
Step 1 - INDUCTION1
Step 2 - CONTINUATION1
Arm B - BVR treatment
Bortezomib IV or SQ 1.3mg/m2   Days 1,4,8,11 
Rituximab IV 375 mg/m2    Day1 
Bendamustine IV  90 mg/m2    Days 1 & 4
x 6 cycles
Arm C - BR treatment
Rituximab IV 375 mg/m2               Day1  
Bendamustine IV 90 mg/m2        Day1 & 2
x 6 cycles
Arm D - Rituximab
Odd Cycles (1,3,5, 23) - no Rituximab treatment
Even Cycles (2,4,6, .24): Rituximab IV 375 
mg/m2 Day1
Arm E - Rituximab
Odd Cycles (1,3,5, 23) - no Rituximab treatment
Even Cycles (2,4,6, .24): Rituximab IV 375 
mg/m2  Day1
Arm F - Lenalidomide and Rituximab
Cycles 1-13: Lenalidomide 20 mg po Days 1-21
Odd Cycles (1,3,5, 23) - no Rituximab treatment 
Even Cycles (2,4,6, .24): Rituximab IV 375 
mg/m2   Day1
High Risk 
Follicular Lymphoma 
(FLIPI 1 score 3-5
OR
GELF high tumor burden)
Stratification
1. FLIPI 1 STATUS
· Score 0-2*
· Score 3
· Score 4-5
2. GELF Criteria
· Low tumor burden**
· High tumor burden
Rev. 3/13
Rev. 4/13
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1. 
Introduction 
1.1 
Natural History of Indolent Lymphoma 
According to the American Cancer Society, it is estimated that approximately 
66,000 individuals were diagnosed with non-Hodgkin’s lymphoma (NHL) and 
over 19,000 men and women died of the disease in 2008 (1). Cases of follicular 
lymphoma (FL) comprise more than 70% of “low-grade” histologies and 22% of 
all cases of NHL, second only to diffuse large B-cell lymphoma (2,3). The survival 
rates for patients with indolent non-Hodgkin’s lymphoma (NHL) remained 
unchanged from the 1950s through the early 1990s, but recent evidence 
suggests that outcomes are improving (4-6).  Indolent NHL is a particular 
challenge because it is an incurable disease requiring multiple treatments yet 
relatively long survivals elevate the importance of quality of life associated with 
treatment. Advanced stage high tumor burden patients have shorter survivals 
and, even in the rituximab era, high risk patients have significantly shorter PFS. 
1.2 
Treatment for Indolent Lymphoma 
1.2.1 
Background 
Traditional treatment options for low-grade NHL have included 
expectant observation for asymptomatic low tumor burden disease 
and multi-agent cytotoxic chemotherapy for patients who have 
symptomatic, high tumor burden or progressive disease. Biologic 
therapy has become an integral part of therapy and includes agents 
that specifically target B-lymphocytes such as monoclonal anti-CD20 
antibodies and radiolabled anti-CD20 antibodies. Though treatment 
response is high to cytotoxic and biologic therapies initially, relapse is 
inevitable and response rate and duration decline whereas cumulative 
toxicities increase with subsequent treatments.  With a better 
understanding of malignant lymphocyte biology at the cellular level, 
novel agents that target key molecular and cell signaling pathways are 
under investigation.  Investigating new combinations of novel agents 
with biologic and cytotoxic therapies provide the opportunity to 
improve outcomes for patients with indolent NHL. 
1.2.2 
Induction Therapy 
Several randomized phase III trials comparing varied chemotherapy 
combinations (i.e., cyclophosphamide, vincristine, prednisone (CVP), 
cyclophosphamide, adriamycin, vincristine, prednisone (CHOP), 
mitoxantrone, 
chlorambucil, 
prednisone) 
plus 
rituximab 
with 
chemotherapy alone in previously untreated patients have been 
reported and updated (Table 1) (7-18).   The overall response rate 
(ORR) and either median time to treatment failure (TTF) or median 
event-free survival (EFS) were superior in the chemoimmunotherapy 
arm for both chemotherapy-naïve patients and those who have been 
previously treated. Moreover, overall survival (OS) improvements for 
the chemoimmunotherapy arms (versus chemotherapy without 
immunotherapy) are becoming apparent.  


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The ECOG 1496 study randomized responding patients induced with 
CVP to either maintenance rituximab or observation (7). The median 
PFS for patients receiving rituximab maintenance was 5.6 years 
versus 1.8 years for those receiving no maintenance (P=0.0000003; 
hazard ratio, 0.4 [0.3-0.6]), and estimated OS at 3 years was 92% 
versus 83% (P=0.03; one-sided log rank test), favoring the rituximab 
maintenance arm. The German Lymphoma Study Group randomized 
428 patients over age 60 with untreated, advanced-stage FL to CHOP 
alone or CHOP combined with rituximab (R-CHOP) for 6 to 8 cycles 
(10). After a median observation time of 18 months, TTF (P<0.001) 
and OS (P=0.016) were superior in the R-CHOP arm. Patients 
younger than 60 years achieving a partial remission (PR) or complete 
remission (CR) after CHOP or R-CHOP were then randomized to 
long-term interferon or autologous stem cell transplant. Interestingly, 
the benefit of R-CHOP was much less apparent among the patients 
who 
received 
autologous 
stem 
cell 
transplant 
(SCT), 
and 
transplantation did not seem to add to R-CHOP. An updated reported 
showed improved 4-year progression free survival (PFS) and OS for 
patients who received chemoimmunotherapy (14). 
1.2.3 
A new standard induction chemotherapy regimen for high tumor 
burden follicular lymphoma: bendamustine-based therapy. 
A pivotal randomized phase III trial was recently reported by Rummel 
et al that compared bendamustine/rituximab induction chemotherapy 
vs R-CHOP for patients with high tumor burden follicular lymphoma 
(157). Bendamustine is an alkylating agent which contains a 
bifunctional mechlorethamine derivative, a benzimidazole heterocyclic 
ring, and a butyric acid substituent. Mechlorethamine and its 
derivatives develop electrophilic alkyl groups, which form covalent 
bonds resulting in interstrand crosslinks. Bendamustine has 
demonstrated clinical activity in multiple tumor types including chronic 
lymphocytic leukemia (CLL), Hodgkin’s lymphoma, NHL, multiple 
myeloma, breast cancers, and small-cell lung cancers (148). 
Bendamustine has been marketed in Germany for over 30 years, and 
was formally re-approved in 2005 in Germany by the Federal Institute 
for Drug and Medical Devices (BfArM), for the treatment of patients 
with indolent NHL, CLL, or multiple myeloma. Bendamustine 
subsequently received approval in the United States of America 
(USA) in 2008 by the Food and Drug Administration (FDA) for the 
first-line treatment of patients with CLL, and for the treatment of 
patients with advanced indolent B-cell NHL that progressed during or 
within 6 months of treatment with rituximab or a rituximab-containing 
regimen. 
Bendamustine has been shown to be a potent, selective, cytotoxic 
agent against B lymphocytes with synergism between bendamustine 
and rituximab observed in both CD20+ lymphoma cell lines and on ex 
vivo cells from patients with B-CLL or B-cell lymphomas (149). In 
preliminary studies, the efficacy of bendamustine alone and in 
combination with rituximab, has been seen with both a high response 
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indolent NHL which progressed during or after treatment with 
rituximab or a rituximab-containing regimen (151). In these studies, 
bendamustine was well tolerated, with a manageable toxicity profile in 
the setting of fairly durable responses. 
A multicenter Phase 2 study was conducted by the Study Group 
Indolent Lymphomas, Germany (StiL), of patients (n=63) with either 
relapsed/refractory indolent lymphoma (n=47) or mantle cell 
lymphoma (n=16) who were treated with rituximab at 375 mg/m2 on 
day 1 and bendamustine at 90 mg/m2 on days 2 and 3 every 28 days 
for 4 cycles (155). The overall response rate (ORR) was 90%, the CR 
rate was 60%, and the median PFS was 24 months. Bendamustine 
was well tolerated in this study. Leukopenia was the most common 
hematologic adverse event with World Health Organization (WHO) 
grade 3 or grade 4 events occurring in 35 (16%) of 216 cycles. Other 
less frequent grade 3 or grade 4 hematologic adverse events included 
thrombocytopenia (3%) and anemia (1%). Growth factors were not 
administered and no evidence of cumulative myelosuppression was 
observed. The most common nonhematologic toxicity was grade 1 
nausea reported in 43% of cycles.  A second multicenter Phase 2 
study in a similar population of lymphoma patients receiving the same 
combination therapy had comparable results (154). Patients (n=67) 
with either relapsed/refractory indolent lymphoma (n=51) or mantle 
cell lymphoma (n=16) were treated with rituximab at 375 mg/m2 on 
day 1 and bendamustine at 90 mg/m2 on days 2 and 3 of each 28-day 
cycle for 4 to 6 cycles. Patients also received a dose of 375 mg/m2 of 
rituximab 7 days before the first 28-day cycle and 28 days after the 
last cycle of the combination treatment. The ORR was 92% and the 
CR rate was 42%. 
The pivotal, multicenter, randomized Phase 3 study, conducted by the 
StiL, enrolled 549 patients with advanced indolent NHL or MCL to 
treatment with either bendamustine in combination with rituximab (BR) 
or standard R-CHOP in the first-line setting (156,157). Entry criteria 
included stage III or IV disease, a defined need for treatment in all 
patients (except those with mantle cell lymphoma), and no prior 
treatment. The primary objective was to prove non-inferiority of the BR 
regimen compared with the R-CHOP regimen, defined as a difference 
of less than 15% (amended to 10%) in PFS after 3 years but with an 
improved safety profile. Patients in the BR group were treated with 
rituximab at 375 mg/m2 on day 1 and bendamustine at 90 mg/m2 on 
days 1 and 2 of each 28-day treatment cycle. Patients in the R-CHOP 
group were treated with rituximab at 375 mg/m2, cyclophosphamide at 
750 mg/m2, doxorubicin The first interim analysis of 273 evaluable 
patients was reported at the American Society of Hematology (ASH) 
meeting in December 2007 (156). The 2-drug combination (BR) 
appeared as effective as the 5-drug combination (R-CHOP) with an 
ORR of 94% for the BR group (n=139) compared with 93% for the R-
CHOP group (n=134) in this preliminary analysis. The CR rates were 
also similar, slightly favoring the BR combination over R-CHOP, with a 
CR of 51% for BR, compared with 40% for R-CHOP. In terms of 
toxicity, R-CHOP was more toxic compared with BR.  R-CHOP was 


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more frequently associated with serious adverse events (SAE) and 
overall toxicity compared with BR.  
In December 2009, Rummel et al presented the final analysis of the 
randomized phase III STiL study. (157)   A median number of 6 cycles 
was given in both treatment arms each (82% of BR pts and 86% of 
CHOP-R patients received 6 cycles.  Among all patients, response 
was similar between the two patient groups with an ORR for BR of 
92.7% for BR and 91.3% for R-CHOP; however, CR rate was 
improved for BR (40%) compared with R-CHOP (31%).  Among all 
patients, BR was associated with a superior PFS compared with R-
CHOP (BR: 54.9 vs CHOP-R: 34.8 months (median), HR = 0.57 (95% 
CI: 0.43 - 0.76; p = 0.00012) as was the time to next treatment (BR: 
not reached vs CHOP-R: 37.5 months (median), R = 0.52 (95% CI: 
0.38 - 0.70), p = 0.00002).  No differences in OS were noted.  Of 513 
evaluable patients, 179 were high tumor burden follicular lymphoma.  
BR was associated with significantly improved PFS among FL 
patients: BR: not reached vs CHOP-R: 46.7 months (median), HR = 
0.63 (95% CI: 0.42 - 0.95), p = 0.0281.  Among salvage treatments, 
approximately 40% of BR patients received R-CHOP, while 38% of R-
CHOP patients received BR.    
In terms of toxicity, significant differences in hematologic toxicities 
were observed for neutropenia grade 3+4 occurring in 46.5% of R-
CHOP patients vs 10.7% with BR (p< 0.0001).  This was despite more 
GCSF use in R-CHOP (20%) compared with BR (4.0%). Other 
toxicities that were significantly increased with R-CHOP compared 
with BR included: Alopecia (all vs <2% patients, p< 0.0001), 
paresthesias (73 vs 18, < 0.0001), stomatitis (47 vs 16, <0.0001), 
infectious complications (127 vs 96, p=0.0025), sepsis (8 vs 1 pt, 
p=0.0190).  The only side effects more frequent with BR compared 
with R-CHOP were skin/erythema (42 vs 23 p=0.0122) and allergic 
reaction (skin) (40 vs 15, p= 0.0003). In this final analysis, the 
combination of BR improved PFS and CR rates, while showing a 
better tolerability profile. These results strongly suggest that BR may 
be the new standard first-line treatment for patients with high tumor 
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Table 1.  Randomized Trials Comparing Chemoimmunotherapy With Chemotherapy in Follicular Lymphoma 
 
Series 
Year 
No. Patients Arms 
Conclusions 
 
Hochster (7,15) 
2005 
401 
CVP vs CVP with rituximab post-
induction maintenance 
Improved PFS (median with rituximab 5.6 
years vs 1.8 with no maintenance, 
P=0.0000003) and OS (88% vs 72%, 
p0.03) with post-induction rituximab 
 
Hiddeman (10) 
and Buske (14) 
2005 
and 
2006 
428 
8 cycles each CHOP vs R-CHOP (all 
patients then randomized to interferon 
maintenance vs autologous HSCT) 
4-year PFS: CHOP 28% vs R-CHOP 62% 
(p< 0.0001) 4-year OS: CHOP 81 %  vs. 
R-CHOP 90% versus (p=0.039)      
 
Marcus (11,12) 
2006 
321 
8 cycles each CVP vs R-CVP 
At 53-month median follow up, median 
TTF: CVP 15 months vs R-CVP 34 
months; OS improved for R-CVP 
(p=0.029, log rank; hazard ratio 0.60) 
 
Foussard  (18) 
and Salles (8) 
2006 
358 
CHVP x 12 cycles over 18 months vs. 6 
cycles R-CHVP over 6 months (both 
arms treated with concurrent interferon-
alpha x 18 months) 
Median 5-year follow-up, EFS: CHVP 
37% vs. R-CHVP 53% (p<0.0001); 
Median OS: CHVP 79% vs. R-CHVP 84% 
(p=not significant)  
 
Herold (13) 
2007 
358 
8 cycles each of MCP vs R-MCP (both 
followed by interferon-alpha) 
Median EFS (p=0.001) and median OS 
(p=0.0096) improved with R-MCP 
 
Forstpointner (16) 
2006 
125  
(relapsed) 
4 cycles each FCM vs R-FCM with 2nd 
randomization of rituximab maintenance 
(4 weekly doses at 3 and 9 months) vs 
observation 
Response duration significantly prolonged 
by R-maintenance after R-FCM 
 
 
Van Oers (17) 
2006 
465  
(relapsed) 
6 cycles each CHOP vs R-CHOP 
induction followed by 2nd randomization 
to rituximab maintenance (one dose q3 
months x 24 months) vs observation 
Improved PFS with R maintenance after 
CHOP induction (HR, 0.30; P < .001) and 
R-CHOP induction (HR, 0.54; P  0.004) 
 
Rummel (157) 
2009 
564 
6 cycles each of R-CHOP vs 
bendamustine/rituximab (BR) 
 
Significantly improved PFS with BR 
induction (BR: not reached vs CHOP-R: 
46.7 months (median), HR = 0.63 (95% 
CI: 0.42 - 0.95), p = 0.0281) and 
significantly less toxicity with BR 
compared with R-CHOP 


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1.2.4 
Post-Induction (Continuation) CD20 Antibody Therapy 
To improve the response rate, duration of response, and potentially 
prolong OS, additional doses of rituximab have been administered as 
post-remission or “maintenance therapy.” Median EFS has been 
shown to be prolonged with this approach, following chemotherapy 
induction (15-17) or after rituximab alone therapy (19,20). Two of the 
most commonly applied maintenance (or continuation) rituximab 
approaches following “induction” are the following: 1) rituximab given 
as a single dose every 2 to 3 months (17,19) and 2) 4 weekly doses of 
rituximab given every 6 months for 2 years (7, 16, 20). 
Prior pharmacokinetic data have shown that the administration of a 
single dose of rituximab every 3 to 4 months maintains effective blood 
levels (21), while preliminary pharmacokinetic data from an ECOG 
trial in lymphoma patients with low tumor burden who received single 
rituximab dose every 3 months showed that 47% of patients had 
rituximab blood levels ≤ 25 mcg/mL at 12 weeks (22). Therefore, 
rituximab maintenance therapy may have to be administered at more 
frequent intervals (e.g., every 2 months). 
1.2.5 
Importance of Achieving Complete Remission (CR) 
The achievement of a CR with induction therapy in low-grade NHL is 
important, especially if the ultimate goal is to administer post-
remission therapy (e.g., monoclonal antibody) that is likely to be most 
effective in the presence of quantitative t(14;18). In order to study the 
importance of induction treatment for untreated low-grade lymphoma, 
a recent meta-analysis analyzed the clinical outcome of patients with 
a focus on CR rate and its relation to disease progression. Thirty-two 
induction/treatment regimens from 25 publications (2001-2006) with 
2,421 patients were studied by Saville et al (23). Therapies were 
induction and/or consolidation therapy, excluding trials with rituximab 
maintenance. Treatment categories were chemotherapy combinations 
without fludarabine, rituximab as a single-agent or in combination with 
chemotherapy, fludarabine as a single-agent or in combination, and 
ibritumomab tiuxetan or tositumomab as single agents or in 
combination. There was a highly significant linear correlation between 
the CR rate and event rate for disease progression with all treatments 
(rho= -0.79; 95% CI: -0.57 to -0.91; P<0.001). The analysis showed 
that a higher CR rate correlated with a lower hazard of disease 
progression.   
As discussed above in Section 1.2.2 (and Table 1), the ECOG 1496 
low-grade lymphoma randomized trial showed a significant advantage 
for patients who received maintenance rituximab (MR) after CVP 
induction with a median PFS of 5.6 years versus 1.8 years for those 
who did not receive maintenance (P=0.0000003; hazard ratio, 0.4 
[0.3-0.6]) (7).  In terms of prognostic analysis for patients who 
received MR following CVP induction (n=158), several factors were 
examined in univariate and Cox proportional hazard models.  There 
was a significantly better outcome/benefit with MR for patients who 
had quantitative t(14;18) after CVP induction compared with gross 


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disease (quantitative t(14;18) defined as <10% marrow involvement, 
no lymph node >2 cm, and reduction of a bulky nodal mass by >75%). 
Median PFS was not reached for minimal disease MR patients 
compared to 3 years for those with gross disease after CVP (HR=0.4, 
[0.2,0.6], p=0.001). In addition to quantitative t(14;18), CR rate 
(p=0.04) also predicted for longer PFS (96% v 71% at 2 years). In 
multivariate analysis for PFS, only quantitative t(14;18) after CVP was 
significant (RR 0.5, p=0.009). For OS there was a strong trend 
favoring MR among high tumor burden patients (one-sided p=0.03). 
Therefore, an important strategy in the current randomized trial is to 
incorporate novel therapeutic approaches in an attempt to achieve 
quantitative t(14;18) with increased CR rate following induction 
therapy and through continuation therapy immediately following 
induction. 
1.3 
Defining High-Risk Follicular Lymphoma 
1.3.1 
High-Risk Follicular Lymphoma 
We hypothesize that alternate methods of defining tumor burden and 
response to treatment are superior to current clinical methods, such 
as the FLIPI score and Revised Response Criteria, in predicting high 
risk lymphoma. High risk lymphomas have shorter lower complete 
response rates and lower disease-free survival rates, and, most 
importantly, shorter progression-free and overall survivals. Currently, 
there is no gold standard to define high risk follicular lymphoma, 
although a number of methods are in clinical use including the FLIPI 
risk score, the original (33,34) and revised Groupe D’Etude des 
Lymphomes Follicularies (GELF) criteria, (8) British National 
Lymphoma Investigation (BNLI) criteria (35), the German Lymphoma 
Study Group (10), the East German Study Group Criteria (13),  and 
the M.D. Anderson tumor score (36). Advanced stage and higher 
initial tumor burden have long been recognized to confer inferior 
prognosis in cancer. Notably, these criteria are rather crude in NHL, 
with an Ann Arbor staging system more than 40 years old. Further, 
the enumeration of nodal sites and definition of bulk is inconsistent.  
1.3.1.1 
Groupe D’Etude des Lymphomes Follicularies (GELF) 
Tumor Burden 
The GELF criteria were established in the late 1990’s as 
clinical criteria that separated follicular lymphoma patients 
into low and high tumor burden (33,34). The criteria were 
used to define patient populations who warranted initiation 
of 
cytotoxicic 
chemotherapy 
based 
on 
symptoms 
attributable to their disease/lymphoma or high risk features 
(e.g., compression of vital organs) (34) vs asymptomatic 
patients with low-risk features who were included in “watch 
and wait” (no immediate cytotoxics) randomized trials 
(33,35). Further, several of the criteria, such as size of 
nodes (bulky disease) and number of nodal sites, have 
been shown to be associated with increased risk of relapse 
(36). The original GELF criteria included stage II, III, or IV 


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patients with the presence of at least one of the following 
signs: any nodal or extranodal tumor mass with a diameter 
of greater than 7 cm; involvement of at least three nodal 
sites, each with a diameter of greater than 3 cm; any B 
symptom; splenic enlargement with inferior margin below 
the umbilicus line; compression syndrome (ureteral, orbital, 
gastrointestinal) or pleural or peritoneal serous effusion 
(irrespective of cell content); leukemia (> 5.0 x 109/L 
circulating 
malignant 
cells) 
or 
cytopenia 
(polymorphonuclear leukocytes <1.0 x 109/L and/or 
platelets <100 x 109/L). Over the past decade, lymphoma 
groups around the world have used similar, but slightly 
modified criteria (8,10, 53,35-38).  
1.3.1.2 
Follicular Lymphoma International Prognostic Index (FLIPI) 
The FLIPI was developed in order to predict prognosis of 
patients with newly diagnosed follicular lymphoma (FL).  
The five original FLIPI criteria were: age > 60 years, Ann 
Arbor stage III-IV, hemoglobin level < 12 gm/dL, >4 nodal 
areas, and serum LDH level above normal. The original 
FLIPI discriminated between 3 major subgroups of patients 
with FL with regard to OS, carrying a low (0-1 risk factors), 
intermediate (2 risk factors), or high risk (3-5 risk factors) 
(39). However despite the data being derived from FL 
patients who were treated in different treatment regimens 
on varied multicenter study group protocols, none of the 
regimens/patients were treated with rituximab therapy.  An 
updated report examined the importance of the FLIPI 
prognostic score among rituximab-based treated patients 
(9).   Buske et al showed that among 362 patients treated 
with R-CHOP, a modified definition of FLIPI risk groups 
may be warranted of 1 or 2 risk factors (55% of the 
patients), 3 risk factors (27%), and patients with 4 or 5 risk 
factors (18%).  This resulted in a separation of 3 distinct 
risk groups (2-year TTF 90% vs 74% vs 57%, respectively; 
P <0.001). 
1.3.2 
Quantitative t(14;18) in Follicular Lymphoma. 
In follicular lymphomas, about 70% of patients have t (14;18) cells in 
the blood and marrow compartments that can be detected and 
quantified by application of the polymerase-chain reaction (PCR) for 
major and minor breakpoints. Numerous studies have demonstrated 
that patients who achieve quantitative t(14;18), defined as the 
absence of detectable t(14;18) cells, enjoy longer PFS (40-45). This is 
true with chemotherapy (40, 42, 46), high dose therapy and 
transplantation (41, 43, 45), and in the rituximab era including 
radioimmunotherapy (42, 44-46). Importantly, a higher proportion of 
patients (~75%) are able to achieve quantitative t(14;18) with chemo-
immunotherapy, suggesting that the rate of decline of PCR-positive 
cells may be a more precise predictor. Further, the cumulative body of 
data indicate that the marrow aspirate is a somewhat more sensitive 


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compartment for establishment of quantitative t(14;18), such that 
decline in circulating PCR-positive cells should be a convenient and 
reliable way to determine rate of change whereas a marrow sample is 
optimal for establishing absolute quantitative t(14;18) at the end of 
treatment. Because the distribution of FL is variable among patients, 
with some manifesting relatively bulky disease with no or minimal 
marrow disease and others manifesting smaller, widespread 
adenopathy with greater marrow disease, the determination of 
quantitative t(14;18) could vary by disease pattern. Despite the wealth 
of data regarding PCR status in FL, associations with disease pattern 
have largely not been done. Further, there is an observation that the 
marrow compartment, which was often the last to clear in the 
rituximab era, is more susceptible to rituximab and, in fact, the ability 
to achieve quantitative t(14;18) has increased substantially. These 
observations indicate the need to complement the t (14;18) analyses 
with sensitive imaging of the lymph node compartments. 
1.4 
Bortezomib 
1.4.1 
Bortezomib Background 
The ubiquitin proteasome pathway has become an attractive target for 
pharmacological blockade in the treatment of lymphoproliferative 
malignancies because it plays a central regulatory role in cell survival, 
cell-cycle progression, and cell homeostasis in eukaryotic cells. 
Through the degradation of intracellular proteins, the ubiquitin-
proteasome pathway regulates key signaling pathways such as 
transcription 
activation, 
apoptosis, 
and 
pathways 
that 
direct 
angiogenesis, cell trafficking, and metastasis (47). Specific proteins 
degraded by the proteasome include the growth regulatory proteins 
p21 and p27, the p53 tumor suppressor, and the transcription factor 
nuclear factor kappa B (NF-kB) (48-52). Preclinical models have 
demonstrated that inhibition of the ubiquitin-proteasome pathway 
induces apoptosis in a variety of tumor-derived cell lines (53-55).  
Proteasome inhibition is of particular interest in NHL due to its 
mitigating 
effects 
on 
nuclear 
factor 
kappa 
B  
(NF-kB) through degradation of the NF-kB inhibitor protein, IkB.  NF-
kB activates pro-survival genes and proteins such as bcl-2, an anti-
apoptotic protein that is over-expressed in follicular lymphoma.  
Preclinical data has shown that proteasome inhibition results in 
phosphorylation and the subsequent cleavage and inactivation of bcl-
2 (56).  
1.4.2 
Single-agent Bortezomib Lymphoma Clinical Trials 
Bortezomib is a potent, selective, and reversible proteasome inhibitor 
that was first approved by the FDA for the treatment of relapsed and 
refractory multiple myeloma and for patients with myeloma who have 
received at least one prior therapy (57,58). Bortezomib was also 
approved for the treatment of newly diagnosed multiple myeloma in 
the United States as of June 2008. In December 2006, bortezomib 
received FDA approval for the treatment of patients with mantle cell 
lymphoma (MCL) who have received at least one prior therapy (59-


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61). Two single-agent phase 2 bortezomib lymphoma studies included 
small numbers of indolent non-Hodgkin lymphoma (NHL). Goy and 
colleagues (60) treated 27 patients with B-cell lymphomas (including 
diffuse large B-cell lymphoma (DLBCL) and indolent NHLs) of which 
only 4 attained a response (1 complete remission (CR), 1 CR 
unconfirmed (CRu), 2 partial remissions (PR)).  The one CRu 
occurred in a patient with follicular lymphoma (FL), while the CR was 
in a patient with small lymphocytic lymphoma (SLL), and the PRs in 
one patient with DLBCL, and one in Waldenstroms. Interestingly, the 
response in FL occurred only after a protocol amendment allowing 
more protracted schedules of administration, following earlier protocol 
versions that required patients to be removed from study after two 
cycles if they had no response.  In a study by Straus and colleagues 
(62), 11 FL were assessed. Two of the 11 patients responded to 
therapy (18%), which interestingly occurred 3 months after the end of 
treatment.  This study, like the one reported by Goy et al (60), also 
removed patients from study for absence of response after 1 or 2 
cycles of therapy.  It is has been shown that responses to bortezomib 
therapy in indolent lymphoma can be delayed. 
In the largest single-agent bortezomib indolent lymphoma study 
conducted to date, O’Connor and colleagues showed an overall 
response rate (ORR) of 50% in the subset of patients with FL (63,64). 
In a 33 patient multicenter study, patients with relapsed or refractory 
FL, marginal zone lymphoma SLL, and Waldenstroms were eligible 
and patients continued on treatment if no progression of disease 
occurred.  The median number of prior therapies for all patients was 
3.  The ORR for the entire population was 39% (35% on an intention 
to treat) including 4 CRs.  Of the 18 patients with FL, four achieved a 
CR and 5 achieved PR for an ORR of 50%.  The median time to 
response for patients with FL was 11 to 12 weeks, while the median 
time to treatment response for patients with MCL was 4 weeks.  
Interestingly, among all responding patients, the progression-free 
survival (PFS) with bortezomib was equivalent to the PFS seen with 
the line of chemotherapy given prior to study (12.3 months for both), 
which was identical for patients with FL alone. 
This single-agent response rate of 50% for FL is among the highest 
reported for a non-chemotherapeutic drug in the relapsed/refractory 
setting. Further, preliminary data is available from David and 
colleagues in a multicenter study using rituximab/bortezomib therapy 
in untreated “high tumor burden” indolent lymphoma (65).  Expected 
ORR using single-agent rituximab in “low tumor burden” FL is 72%-
73% (with 20%-36% CR) (37,66). Investigators at Northwestern 
University are conducting a Simon 2-stage phase II trial for untreated 
“high tumor burden” indolent lymphoma and reported on the pre-
planned interim analysis (65). All patients were required to have “high 
tumor burden” as defined by GELF criteria.  Twenty-seven pts have 
enrolled, of whom 17 were in the first stage. Fourteen patients had FL, 
2 MZL, and 1 SLL. The median Follicular Lymphoma International 
Prognostic Index (FLIPI) was 3, while the median follow-up was 12 
months (range 1-24 months). Induction therapy consisted of 3 cycles: 


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bortezomib given at 1.6 mg/m2 days 1, 8, 15, and 22 q35 days for 3 
cycles and rituximab at 375 mg/m2 x 4 weekly doses for cycle 1, then 
day 1 only for cycles 2 and 3.  Abbreviated consolidation therapy was 
subsequently given with 1 dose of each drug q2 months x 8 months.  
After cycle 1, the ORR was only 29% (no CRs) with 71% stable 
disease (SD). The best ORR, seen after 3 cycles of induction and 8 
months of maintenance therapy was 71% (with CR 35%) in this high 
tumor burden patient population. According to histology, the best ORR 
among FL patients was 86% (CR 42%).  Therapy was overall well 
tolerated. The conversion of ORR of 29% (CR 0%) following 4 weeks 
of rituximab/bortezomib to an ORR of 86% (CR 42%) is suggestive of 
clinical benefit from bortezomib therapy. 
1.4.3 
Bortezomib/Rituximab Lymphoma Clinical Data 
Two bortezomib/rituximab treatment regimens were evaluated in a 
randomized phase II study for patients with relapsed, refractory low 
grade NHL (67).  Treatment Arm A treated patients with bortezomib 
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 bortezomib 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. To date, 81 patients 
have 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 bortezomib), and 18% of patients on 
Arm B (weekly bortezomib), 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 preliminary data the response rate is 51% in 
Arm A and 54% in Arm B. 
1.4.4 
Bortezomib/Chemotherapy Data 
Preclinical data has shown that bortezomib induced synergistic 
apoptosis when combined with rituximab and cyclophosphamide in 
lymphoma cells in vitro and in vivo SCID mice (68). This cell death 
occurred through caspase-dependent mechanisms.  Clinically, 
bortezomib has also been combined with combination chemotherapy 
programs such as CHOP and CVP.  Gerecitano et al incorporated 
bortezomib into R-CVP replacing oncovin (vincristine) of CVP with 
bortezomib (R-CBP) for 16 pts with relapsed or refractory FL, 
CLL/SLL, marginal zone lymphoma, WM, or MCL (69).  Bortezomib 
was escalated from 1.1 to 1.8 mg/m2 given days 2 and 8 with 
escalating cyclophosphamide from 750 mg/m2 to 1,000 mg/m2 given 
day 1.  Therapy was overall well tolerated and no dose limiting toxicity 
had been reached at bortezomib 1.8 mg/m2 and cyclophosphamide of 
1,000 mg/m2.  Of 12 evaluable patients ORR is 58% with 2 CRs (17%, 
including 1 MCL, 1 FL) and 5 PRs (42%, including 2 FL, 1 MCL, 1 
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1.4.5 
Bortezomib/BR (BVR) Lymphoma Combination Clinical Trials 
Data has been presenting from 2 prospective clinical trials combining 
bortezomib with BR (BVR) for the treatment of lymphoma.  Fowler et 
al reported results on 49 patients with relapsed/refractory FL (150). 
Patients received therapy as 35-day cycles with bortezomib dosed at 
1.6 mg/m2 (days 1, 8, 15, 22), bendamustine 90 mg/m2 (days 1, 2), 
and rituximab 375 mg/m2 (days 1, 8, 15, 22, cycle 1; d 1, cycles 2–5) 
for up to 5 cycles. They showed that BVR had an ORR of 84% with a 
CR rate of 47%.  Overall BVR was well tolerated.   Non-hematologic 
grade 3/4 AEs that occurred in more than one patient included 
syncope (n=2; 3%) and peripheral neuropathy. Grade 3/4 neutropenia, 
thrombocytopenia, and anemia were seen in 25%, 6%, and 3% of pts, 
respectively. Treatment-related serious AEs were reported in 17 
(27%) patients, including 3 (5%) with febrile neutropenia and 1 (2%) 
with grade 3 herpes zoster who did not receive antiviral prophylaxis 
and discontinued therapy. Of the 17 (27%) patients with treatment-
related peripheral neuropathy, only 4 (6%) had grade 3 (2 
discontinued therapy; no grade 4); peripheral neuropathy has 
resolved in 5 (29%) patients to date. 
Friedberg et al reported results using the same combination therapy 
(i.e., BVR), but they used a different treatment schedule (152). 
Treatment consisted of bendamustine 90 mg/m2 days 1 and 4; 
rituximab 375 mg/m2 day 1 and bortezomib 1.3 mg/m2 day 1, 4, 8, 11. 
Six 28-day cycles of therapy were planned. Thirty-one patients were 
enrolled; median age was 64 yrs (range 44-84). Histology included 16 
FL, 7 MCL, 3 marginal zone NHL, 3 SLL and 2 lymphoplasmacytic 
NHL. Patients were heavily pretreated with a median of 4 prior 
regimens, including anthracycline containing chemotherapy (n=19), 
purine analog chemotherapy (n=6), stem cell transplant (n=6), and 
radioimmunotherapy (n=9).  Of 25 patients evaluable for response, 
ORR was 84%. Best response following therapy was CR/CRu: 13 
(52%); PR: 8 (32%); SD: 1(4%); PD: 3 (12%). Interestingly, 11/11 
patients with FL responded to treatment (including 7 (64%) CR/CRu). 
Common expected toxicities included thrombocytopenia, fatigue, 
fever, anemia, neutropenia and infusion reactions. Peripheral 
neuropathy was reported in 18 patients, including 2 with grade 3 
neurotoxicity; additionally 14 patients reported constipation. There 
were 5 patients who developed varicella zoster reactivation (no 
prophylaxis given). These resulted were deemed promising and 
warranting additional evaluation of this B-RB regimen in de novo 
disease. A randomized trial would be necessary to determine the 
degree to which bortezomib adds efficacy to the BR combination. 
1.4.6 
Subcutaneous bortezomib. 
A randomized Phase 1 pilot study in 24 subjects with multiple 
myeloma demonstrated that both the IV and SC routes of VELCADE 
administration have similar systemic drug exposure and proteasome 
inhibition. Importantly, SC and IV administration of VELCADE 
appeared to result in similar efficacy profiles (ie, response rate) and 
similar safety profiles. The pilot study also provided preliminary 
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evidence of good local tolerance for SC injection of VELCADE, when 
administered at 1 mg/mL concentration1.  
The data from the Phase 1 pilot study formed the basis of the design 
of a randomized, Phase 3 study that compared the efficacy and safety 
of subcutaneous versus intravenous bortezomib at the approved 1.3 
mg/m(2) dose and twice per week schedule in patients with relapsed 
multiple myeloma.  222 patients were randomly assigned in a 2:1 ratio 
to receive either subcutaneous (n=148) or intravenous (n=74) 
bortezomib. The response-evaluable population consisted of 145 
patients in the subcutaneous group and 73 in the intravenous group. 
Patients received a median of eight cycles (range one to ten) in both 
groups. The ORR (CR+PR) after 4 cycles of treatment was 42 % in 
both the SC and IV treatment groups for the response-evaluable 
population. The ORR after 4 cycles in the IV arm was consistent with 
what was observed in historical single-agent VELCADE trials with 
relapsed multiple myeloma subjects. The study met the noninferiority 
objective (p-value for the noninferiority hypothesis was 0.00201).  
The median TTP (Kaplan-Meier estimate) was 10.4 months in the SC 
treatment group and 9.4 months in the IV treatment group. The 
hazard ratio was 0.839 with 95% CI (0.564, 1.249), and the p=0.3866 
(stratified log-rank test), indicating similar results between the SC and 
IV arm. The median PFS (Kaplan-Meier estimate) was 10.2 months in 
the SC treatment group and 8.0 months in the IV treatment group. 
After a median follow-up of 11.8 months, the 1-year survival rate was 
72.6% in the SC arm and 76.7% in the IV arm. The p-value for the 
difference in 1-year survival rate was 0.5037, indicating similar results 
between the SC and IV arm. The median time to first response 
(Kaplan-Meier estimate) was 3.5 months for both the SC and IV 
treatment groups. Among the responders, the median duration of 
response (Kaplan-Meier estimate) was 9.7 months in the SC 
treatment group, compared with 8.7 months in the IV treatment group. 
Overall, similar efficacy results were observed in the SC and IV 
treatment groups, and the study demonstrated that VELCADE SC 
administration is not inferior to VELCADE IV administration. 
From a safety standpoint, the safety profile between the SC and IV 
treatment groups in general was comparable in most System Organ 
Classes (SOCs), a difference in incidence in certain safety 
parameters in favor of the SC treatment group was noted. One 
hundred and forty (95%) subjects in the SC treatment group and 73 
(99%) subjects in the IV treatment group reported at least 1 treatment-
emergent adverse event. In the SC treatment group, there was a 
lower incidence of Grade 3 adverse events as compared with the IV 
treatment group (57% vs. 70%, respectively); a lower incidence of 
adverse events leading to treatment discontinuations (22% in the SC 
treatment group and 27% in the IV treatment group); and a lower 
incidence of adverse events leading to dose modifications in the SC 
group: dose reduction (33% in the SC treatment group compared with 
45% in the IV treatment group); dose withholding (30% in the SC 
treatment group compared with 39% in the IV treatment group); or 


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cycle delay (20% in the SC treatment group compared with 34% in the 
IV treatment group). Serious adverse events were similar between the 
2 treatment groups (36% in the SC treatment group and 35% in the IV 
treatment group).  
The SC treatment group reported a lower incidence in several 
adverse events associated with VELCADE toxicity. The incidence of 
peripheral neuropathy events (all Grades) was 38% in the SC 
treatment group and 53% in the IV treatment group; the incidence of 
Grade 2 peripheral neuropathy events was 24% in the SC treatment 
group and 41% in the IV treatment group; and the incidence of Grade 
3 peripheral neuropathy event was 6% in the SC treatment group 
and 16% in the IV treatment group. There also appeared to be a trend 
towards lower incidence in gastrointestinal adverse events (37% for 
SC and 58% for IV, predominantly due to differences in Grade 1-2 
abdominal pain, diarrhea, and dyspepsia); as well as a 5% difference 
in incidence of Grade 3 and 4 hematology laboratory results in the SC 
treatment group compared with the IV treatment group for WBC (8% 
in the SC treatment group compared with 18% in the IV treatment 
group), neutrophil count (22% in the SC treatment group compared 
with 28% in the IV treatment group) and platelets (18% in the SC 
treatment group compared with 23% in the IV treatment group). 
Local tolerability of SC administration was acceptable. Nine (6%) 
subjects reported a local reaction to SC administration as an adverse 
event. Eighty-five (58%) subjects in the SC treatment group reported 
at least 1 local injection site reaction. The most common local 
injection site reaction was redness, which was reported in 84 (57%) 
subjects. The majority of subjects with worst injection site reactions 
were assessed as mild (38%) or moderate (18%). Only 2 (1%) 
subjects were reported as having severe injection site reactions. All 
local site reactions resolved completely and rarely led to treatment 
modifications. 
In conclusion, the SC administration of VELCADE has good local 
tolerance. The systemic safety profile for the SC administration of 
VELCADE was associated with a lower incidence of Grade 3 
adverse events, and treatment modifications (discontinuations and 
dose reductions). In particular, there was a lower incidence of 
peripheral neuropathy NEC reported. 
1.5 
Lenalidomide 
1.5.1 
Background 
Lenalidomide is a member of a class of pharmaceutical agents known 
as immunomodulatory drugs. It offers potential benefit over the first 
commercially available immunomodulatory compound, thalidomide, in 
terms of both safety and efficacy in human subjects (72). The key to 
its therapeutic potential lies in the fact that it has multiple mechanisms 
of action, which act to produce both anti-inflammatory and anti-tumor 
effects. These effects are thought to be contextual in that they depend 
on both the cell type and the triggering stimulus. To date, lenalidomide 


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has been associated with TNF-α inhibitory, T-cell costimulatory, and 
antiangiogenic activities (72).  Lenalidomide is marketed in the United 
States for the treatment of subjects with transfusion-dependent 
anemia due to low- or intermediate-1-risk Myelodysplastic Syndrome 
(MDS) associated with a deletion 5-q cytogenetic abnormality with or 
without additional cytogenetic abnormalities and in combination with 
dexamethasone for subjects with previously treated multiple myeloma. 
Lenalidomide is also approved and marketed, in combination with 
dexamethasone, for the treatment of patients with multiple myeloma 
who had been treated with at least one prior therapy. 
Lenalidomide is being investigated as treatment for various 
hematological and oncologic indications. It is also being explored as a 
treatment for inflammatory conditions, including chronic regional pain 
syndrome. While many of the studies are ongoing, results from 
controlled and uncontrolled studies in subjects with multiple myeloma 
and MDS are available. Lenalidomide as well as thalidomide have 
demonstrated activity in multiple myeloma, another B cell malignancy. 
Increased angiogenesis has been described in NHL (72-75). 
Immunomodulatory drugs such as lenalidomide directly kill certain 
types of tumor cells or induce cell-cycle arrest. They also possess 
potent anti-angiogenic activity in vitro and this is likely to contribute to 
their anti-tumor effects. Immunomodulatory drugs help to minimize 
metastasis by reducing the expression of pro-angiogenic cytokines, 
such as vascular endothelial growth factor, decreasing blood vessel 
cytokines, density and affecting cell adhesion molecules. In addition, 
immunomodulatory drugs co-stimulate T-cells and enhance antitumor 
immunity, which is mediated by T-helper-1 type cytokines, such as 
interferon-γ and interleukin-2 (IL-2). Immunomodulatory drugs also co-
stimulate T-cells and enhance other innate immune cells such as 
natural killer cells, which can enhance tumor cell death (76,77). In 
addition, a recent manuscript demonstrated remarkable activity of 
thalidomide when combined with rituximab for relapsed mantle cell 
NHL (78). Preclinical experiments have noted that in the Burkitt 
lymphoma derived Namalwa cells, single agent lenalidomide inhibits 
proliferation in a concentration dependent manner (~30% inhibition at 
30 mM). Single agent dexamethasone also inhibits Namalwa cell 
growth in a concentration dependent manner with IC50 >1000 nM. 
When used in combination with lenalidomide (10~100 mM), the IC50 
for dexamethasone is 2.0-6.3 nM, indicating an additive effect of 
Lenalidomide 
and 
dexamethasone. 
 
Furthermore, 
in 
mouse 
models/studies, significant enhancement of rituximab-mediated ADCC 
was seen when used in combination with lenalidomide (79).  This was 
associated with recruitment of NK cells and stimulation of dendritic 
cells. In addition, an antiangiogenic effect was seen following 
lenalidomide/rituximab treatment in these studies. 
1.5.2 
Single-Agent Lymphoma Clinical Data 
Witzig 
and 
colleagues 
reported 
data 
on 
43 
patients 
with 
relapsed/refractory 
indolent 
lymphoma 
using 
single-agent 
Lenalidomide (80). Patients received lenalidomide 25 mg orally once 


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daily on days 1-21 on a 28-day cycle and continued therapy for 52 
weeks as tolerated or until disease progression. The median age of 
patients was 63 years (range, 43–89) and the median number of prior 
treatment regimens was 3 (range, 1–15). Histology included SLL 
(n=18), FL (n=22), nodal marginal B-cell lymphoma (n=2) and 
extranodal marginal zone B-cell lymphoma of MALT type (n=1). 
Eleven of the 43 patients (26%) exhibited an objective response (2 
CR, 1 CRu, 8 PR), 15 had SD, while 13 had PD (4 not evaluable). 
Responses included 4/18 SLL (22%) and 7/22 FL (32%), while median 
time to response was 3.6 months for all patients (range 1.7–4.1). PFS 
was 4.6 months for all patients and 7.7+ months (range 4.4-13.5+) for 
responding patients and ongoing. Therapy was well tolerated with the 
most common grade 4 adverse event being neutropenia (14%) and 
the most common grade 3 adverse events of neutropenia (21%) and 
thrombocytopenia (12%). 
Data from two phase II studies of single-agent lenalidomide in patients 
with relapsed or refractory aggressive NHL have been presented 
(81,82). In the first trial, 49 patients received lenalidomide 25 mg 
orally once daily on days 1 to 21 on a 28-day cycle (82). Histology 
included DLBCL (n=26), FL grade 3 (n=5), MCL (n=15) and 
transformed DLBCL (n=3). Median time from original diagnosis was 
2.7 years (range, 0.4-32 years) and median number of prior treatment 
regimens was 4 (1-8). Nearly all patients had received prior rituximab 
and 63% were rituximab-refractory. Seventeen patients (35%) 
exhibited an objective response (2 CR, 4 CRu and 11 PR). Response 
was the similar for patients who were refractory to rituximab or not. 
The median duration of response was 10.4 months. Multivariate 
analysis identified only time since last rituximab and tumor burden as 
correlated with response.  A follow-up phase II study was recently 
reported following accrual of 83 patients with relapsed/refractory 
aggressive lymphoma with the same treatment plan as above (81). 
Histology included 22 MCL, 49 DLBCL, 6 FL grade 3, and 6 
transformed DLBCL. Median age was 63 years (range, 21-86) with 
median time from original diagnosis of 2.2 years (0.4-12), median time 
from last therapy of 4.2 months (range, 1.2-66), and median prior 
treatment regimens of 3 (range, 1-13). An objective response was 
documented in 24/83 patients (29%) with 5 CR/CRu, 19 PR, and 16 
SD.  Therapy was overall well tolerated with the most common grade 
3/4 adverse events were neutropenia (24%), thrombocytopenia 
(16%), leukopenia (9%), anemia (6%), dehydration (5%), and fatigue 
(5%). 
Habermann et al reported on the safety of lenalidomide through the 
combined analyses of 2 phase II clinical trials of patients with 
relapsed/refractory aggressive NHL (NHL-002 and NHL-003) (83). 
Lenalidomide monotherapy was shown to have a favorable safety 
profile. Using the intent-to-treat population, 136 patients were studied. 
The most common (≥10%) adverse events were fatigue, neutropenia, 
rash, thrombocytopenia, constipation, anemia, diarrhea, pyrexia, 
nausea, peripheral edema, decreased white blood cell count, 
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were neutropenia (21%) and thrombocytopenia (15%), while serious 
adverse events (≥ 2% of patients) were disease progression, febrile 
neutropenia, pyrexia, and pneumonia in 4%, and back pain, deep vein 
thrombosis, dehydration, and diarrhea in 2%. No events of tumor lysis 
syndrome were reported. 
1.5.3 
Combined Lenalidomide/Rituximab Lymphoma Data 
Wang et al reported the results of a phase I/II examining dose 
escalation of lenalidomide days 1-21 on a 28 day cycle (starting dose 
5mg orally qd) in combination with rituximab 375 mg/m2 weekly for 4 
weeks for patients with relapsed/refractory MCL (84). Fifteen patients 
were treated on a 3+3 Fibonacci design with median age 73 and 
12/15 had received prior rituximab-hyperCVAD/MA therapy. Two dose 
limiting toxicities (DLT's) that occurred at 25mg lenalidomide; one 
patient had grade 3 hypercalcemia and the other had grade 4 
neutropenic fever and died of sepsis (G5) during the first cycle.  
Therefore maximal tolerated dose with rituximab in this patient 
population was determined to be 20mg.  In terms of response, no 
responses were seen at 10mg or 15mg.  However of 10 evaluable 
patients, 3 PR’s and 3 CR’s were documented at 20mg. 
The above pre-clinical and clinical trial data support the study schema 
adding lenalidomide consolidation therapy following R-chemotherapy 
induction. Consolidation therapy consists of lenalidomide 20 mg orally 
days 1-21 of a 28 day cycle for 1 year, given with rituximab 375 mg/m2 
given one dose every 2 months for 2 years.  This will be compared 
with the standard treatment arm of single agent rituximab 375 mg/m2 
one dose every 2 months for 2 years.  
1.5.4 
Lenalidomide Consolidation/Maintenance Clinical Data 
Lenalidomide has been well studied in multiple myeloma as a part 
induction therapy as well as consolidative and maintenance treatment 
(i.e., post-induction) (85-88). Palumbo et al recently reported on 86 
patients who received 4 cycles of induction chemotherapy 
(bortezomib, liposomal doxorubicin, dexamethasone), followed by 2 
cycles of high-dose cyclophosphamide for stem cell collection, and 
then 2 autologous stem cell transplants (i.e., tandem); patients then 
received lenalidomide-based consolidation and maintenance therapy. 
After the 2nd transplant, patients received lenalidomide 25 mg/day 
(days 1-21 on 28-day cycle) combined with prednisone 50mg qod for 
4 cycles. This was followed by long-term lenalidomide maintenance 
treatment (10mg daily) (85). Overall, lenalidomide post-induction 
therapy was well tolerated with one DVT seen and one patient who 
discontinued therapy.  
Zonder et al evaluated lenalidomide-based post-induction therapy in a 
randomized phase III trial for 198 patients with newly diagnosed 
multiple myeloma (86). Patients were randomized to dexamethasone 
alone induction followed by dexamethasone alone maintenance 
therapy vs combined dexamethasone with lenalidomide (25mg daily 
on 28 of 35 days) x 3 cycles followed by maintenance with 
dexamethasone with lenalidomide  (25mg daily days 21 of 28).  


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Lenalidomide-based 
maintenance 
was 
given 
until 
disease 
progression.  The trial was stopped early due to improved clinical 
benefit for lenalidomide/dexamethasone arm.  Toxicities were 
manageable, including increased thrombosis in the combined arm vs 
dexamethasone alone (27% and 9%, respectively) and grade 3-4 
neutropenia (14% and 2%, respectively), and grade 3-5 infections 
(51% and 28%, respectively). Of note, the incidence of thrombosis 
related to immunomodulatory drugs has been shown to be increased 
when combined with steroids and/or chemotherapy (89).  
Anderson et al studied lenalidomide-based maintenance among 43 
patients with relapsed/refractory multiple myeloma (88). After 8 cycles 
of induction therapy (lenalidomide 15mg, days 1-14, bortezomib 
1.0mg/m2, days 1, 4, 8, 11, and dexamethasone 10/20mg (cycles 1-4 
and 5-8) on days of and after bortezomib), stable or responding 
disease patients received maintenance therapy with: lenalidomide 
days 1-14, bortezomib days 1 and 8 (at doses tolerated at end of 
cycle 8) along with dexamethasone 10 mg, d ays 1, 2, 8, and 9. 
Toxicities were reported to be consisting mainly of grade 1-2 
myelosuppression. Attributable non-hematologic toxicities included 
DVT (2 patients), grade 3 peripheral neuropath (1 patient), and grade 
3 atrial fibrillation (2 patients). 
In addition, Coleman et al studied immunomodulatory drugs in 
combination with rituximab for patients with relapsed/refractory CLL, 
SLL, and MCL (90). They administered rituximab weekly x 4 every 6 
months along with daily alternating thalidomide (50mg) and 
lenalidomide (10mg). Overall therapy was tolerated well.  No 
significant neurologic toxicity or thromboembolic events were seen 
and cytopenias were modest.  The above pre-clinical and clinical trial 
data support the study schema adding lenalidomide consolidation 
therapy following rituximab-chemotherapy induction. Post-induction 
therapy will consist of lenalidomide at 20mg orally days 1-21 on 28-
day cycles for 12 months along with rituximab 375 mg/m2 given one 
dose every 2 months for 24 months.  This will be compared with the 
standard treatment arms of rituximab alone 375 mg/m2 one dose 
every 2 months for 24 months. 
1.6 
Quality of Life in Lymphoma 
1.6.1 
Background and Significance 
Few clinical trials have examined quality of life in NHL, especially 
indolent disease (91). This protocol provides an opportunity to 
prospectively 
examine 
the 
trajectory 
of 
treatment-emergent 
symptoms, the impact of novel treatment approaches on patients’ 
well-being and functional status, and symptom palliation from 
treatment for patients who are likely to have several physical 
symptoms due to their disease in addition to a high level of subjective 
distress associated with their long-term prognosis. The assessment of 
health-related quality of life (HRQL) among patients with indolent 
lymphoma has been infrequently examined in prospective clinical 
trials.  ECOG, in a recent phase III study for patients with untreated 


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low tumor burden indolent lymphoma, integrated HRQL analyses as a 
key component of correlative studies (E4402, the RESORT trial). This 
group of low tumor burden patients largely have few physical 
symptoms associated with their illness; therefore the focus of quality 
of life studies had emphasis on subjective distress, psychological 
functioning, and physical and functional wellbeing.  
We are seeking to build on ECOG-ACRIN’s experience with 
measuring HRQL among adults with lymphoma by including HRQL 
endpoints in the proposed trial, thus expanding this research to 
include NHL patients with high tumor burden. Given the paucity of 
HRQL among adults with lymphoma, we anticipate that these findings 
will represent a major contribution to clinical research through 
enhancing our understanding of patients’ functioning and well-being 
throughout treatment.  
Prior quality of life research in lymphoma has demonstrated an 
association between diagnosis, treatment, relapse and disease 
progression with impairments in HRQL (physical, functional, emotional 
and social well-being) and increased anxiety (92-94). A prospective 
quality of life analysis was performed in elderly Italian patients with 
aggressive lymphoma treated with different anthracycline-containing 
chemotherapy regimens (93). They showed that baseline quality of life 
correlated with IPI score and with anemia.  They found that at the end 
of treatment that no functional scale was worse and that a significant 
improvement was seen for sleep, appetite, pain, and global health.  
Moreover, when comparing the quality of life results for patients in CR 
versus PR or less, only patients in CR had a benefit with respect to 
emotional state (0.10), role function (0.05), constipation (0.04), and 
global quality of life (0.05).  While patients in PR or less had no quality 
of life parameter that was significantly improved at the end of therapy. 
The majority of other quality of life lymphoma data has been collected 
through uncontrolled studies. In a retrospective analysis, Webster and 
Cella showed that diagnosis and disease recurrences were 
associated with a negative psychological impact (91). While 
Montgomery and colleagues showed that among a variety of leukemia 
and lymphoma patients that 51% had clinically significant anxiety, 
27% reported poor mental adjustment to their illness, 51% had 
moderate distress, and 14% had severe distress (95,96).    
1.6.2 
Quality of Life Design 
We will prospectively measure HRQL (physical, functional, emotional 
and social well-being) using the Functional Assessment of Cancer 
Therapy – General (FACT-G) (67). Disease-related symptoms and 
concerns specific to lymphoma will be assessed using the FACT-
Lymphoma subscale (FACT-Lym) (97-99). While limited research has 
examined HRQL among patients with NHL, emotional function is 
significantly impacted and is therefore an important endpoint for this 
trial. Fatigue and neurotoxicity are anticipated to be the most 
commonly 
experienced 
side 
effects 
from 
bortezomib 
and 
lenalidomide. Treatment-emergent symptoms will be assessed using 


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the FACT-Fatigue subscale and neurotoxicity will be assessed using 
the FACT/GOG-Neurotoxicity subscale.  
1.7 
Rationale and Importance of Current Study 
Despite unchanged survival rates for patients with indolent NHL from the 1950s 
through the 1990s, several recent randomized phase III clinical trials have shown 
significantly improved PFS as well improved OS rates, especially with the 
incorporation of rituximab monoclonal antibody therapy (7,10,11,13,16,18). We 
intend to build off of this recent clinical success by incorporating the novel 
targeted therapeutic agents, bortezomib and lenalidomide, both with known 
single-agent efficacy and safety in NHL (see Sections 1.3 and 1.4 above).   
We will achieve maximal cytoreduction in higher risk (increased tumor burden) 
follicular NHL through improved CR rates with bortezomib incorporated into 
chemoimmunotherapy induction and through the addition of lenalidomide to 
rituximab post-induction therapy. This hypothesis is based on strong prior clinical 
trial data (E1496), which showed that the significant benefit of post-induction 
rituximab therapy was most effective in patients with quantitative t(14;18) 
following induction treatment (see Section 1.2.4 above).  Better cytoreduction will 
result in improved PFS and, potentially, OS for patients with high tumor burden 
indolent NHL. In addition, we will collect specimens for future investigations for 
biomarkers for response and survival and also examine the importance and 
impact of different induction chemoimmunotherapy induction regimens and 
rituximab-based consolidation /maintenance therapy among patients’ HRQL. 
1.8 
Gender and Ethnicities Statement 
As there is no a priori reason to expect different treatment effects by gender or 
ethnicity, entry to this study is not restricted to these categorizations. Subgroup 
analyses will be conducted to detect any gender and/or ethnicity treatment 
effects, and any interactions between treatment and these factors. On a recent 
ECOG trial in low-grade lymphoma (E1496), 56% of the patients are male and 
5% are members of minority ethnic groups. It is anticipated that a similar 
proportion of patients on this study will be males and members of minority ethnic 
groups. 
1.9 
Overall Summary/Hypothesis  
Our hypothesis is that enhanced induction therapy and/or improved continuation 
treatment (post-induction) will improve tumor cytoreduction as assessed by 
achievement of increased CR rates and prolonged DFS for patients with high 
tumor burden low-grade lymphoma. Furthermore, these new novel therapeutic 
combinations will be safe and well tolerated among this patient population.  This 
hypothesis is based on our own strong prior clinical trial data (E1496), which 
showed that the benefit of post-remission rituximab therapy was most significant 
in patients with quantitative t(14;18) following induction therapy and the 
achievement of quantitative t(14;18) was the only significant factor for PFS in 
multivariate analysis. Further, achievement of CR with CVP on the E1496 trial 
resulted in significantly different PFS at two years (96% v 71%). An important 
strategy in the current randomized trial is to incorporate novel therapeutic 
approaches in an attempt to achieve quantitative t(14;18) with increased CR rate 
following induction therapy and through consolidative therapy immediately 
following induction. Our hypothesis will be tested in a 3-arm randomized phase II 


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clinical trial comparing standard therapy of BR induction followed by rituximab 
continuation vs BVR induction followed by rituximab continuation and vs BR 
induction followed by lenalidomide/rituximab continuation. 
 
 
 


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2. 
Objectives 
2.1 
Primary Objectives 
2.1.1 
To compare the complete remission (CR) rate of BR versus BVR as 
induction therapy.  
2.1.2 
To compare the 1-year post-induction disease-free survival (DFS) rate 
with rituximab plus lenalidomide to rituximab alone as continuation 
therapy. 
2.2 
Secondary Objectives 
2.2.1 
To determine the 3-year progression-free survival (PFS) and the 5-
year overall survival (OS) with BR, BVR, lenalidomide plus rituximab, 
and rituximab alone. 
2.2.2 
To evaluate patient-reported outcomes at baseline and during 
treatment to determine differences in symptom palliation, treatment-
related symptoms and overall health-related quality of life (HRQL) 
according to treatment arm. 
2.2.3 
To examine the association between baseline FLIPI information and 
outcome (CR, DFS, PFS, and OS). 
2.2.4 
To examine the association between baseline  and end-of-treatment 
patient co-morbidities assessed by the Cumulative Illness Rating 
Scale (CIRS) and outcome (CR, DFS, PFS, and OS). 
2.2.5 
To create an image and tissue bank including serial PET/CT scans, 
diagnostic paraffin-embedded tissue, germline DNA, and serial blood 
and bone marrow samples sufficient to support proposed and future 
studies of tumor and host characteristics that may predict for clinical 
outcome, including treatment arm effects, and enhance existing 
prognostic indices. 
2.2.6 
To evaluate the rate of peripheral neuropathy associated with 
subcutaneous and intravenous VELCADE  (bortezomib).  
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3. 
Selection of Patients 
Each of the criteria in the checklist that follows must be met in order for a patient to be 
considered eligible for this study. Use the checklist to confirm a patient’s eligibility. For 
each patient, this checklist must be photocopied, completed and maintained in the 
patient’s chart.  
In calculating days of tests and measurements, the day a test or measurement is 
done is considered Day 0. Therefore, if a test is done on a Monday, the Monday 
four weeks later would be considered Day 28.  
ECOG-ACRIN Patient No. 
 
 
Patient’s Initials (L, F, M) 
 
 
Physician Signature and Date 
 
NOTE: All questions regarding eligibility should be directed to the study chair or study 
chair liaison. 
NOTE: Institutions may use the eligibility checklist as source documentation if it has 
been reviewed, signed, and dated prior to registration/randomization by the 
treating physician. 
3.1 
Randomization to Induction (Step 1) 
3.1.1 
Patient must have a histologically confirmed (biopsy-proven) 
diagnosis of follicular B-cell non-Hodgkin lymphoma (World Health 
Organization classification:  follicular center grades 1, 2, and 3a), with 
no evidence of transformation to large cell histology. 
Patients having both diffuse and follicular architectural elements will 
be considered eligible if the histology is predominantly follicular (i.e. ≥ 
50% of the cross-sectional area), and there is no evidence of 
transformation to a large cell histology. If the interval since tissue 
diagnosis of low-grade malignant lymphoma is > 24 months, 
diagnostic confirmation using either core needle or excisional lymph 
node biopsy is required to confirm that the histology remains in one of 
the eligible categories. Bone marrow biopsy alone is not acceptable. 
3.1.2 
Patient must meet criteria for High Tumor Burden (higher risk) as 
defined by either the Groupe D’Etude des Lymphomes Follicularies 
(GELF) criteria OR the follicular lymphoma international prognostic 
index (FLIPI):  
3.1.2.1 
To meet GELF criteria, a patient must have at least one 
criterion (please answer yes or no for each criterion): 
3.1.2.1.1 
Nodal or extranodal mass > 7 cm (please 
also document here the largest/longest 
single nodal or extranodal mass diameter). 
Largest size:__________ 
3.1.2.1.2 
At least 3 nodal masses: all > 3.0 cm in 
diameter. 
_______
_______
_______
_______
_______


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3.1.2.1.3 
Systemic symptoms due to lymphoma or B 
symptoms. 
3.1.2.1.4 
Splenomegaly with spleen > 16 cm by CT 
scan. 
3.1.2.1.5 
Evidence of compression syndrome (e.g., 
ureteral, orbital, gastrointestinal) or pleural 
or peritoneal serous effusion due to 
lymphoma (irrespective of cell content). 
3.1.2.1.6 
Leukemic presentation (> 5.0 x 109/L 
malignant circulating follicular cells). 
3.1.2.1.7 
Cytopenias (polymorphonuclear leukocytes 
< 1.0 X 109/L, hemoglobin < 10gm/dL, 
and/or platelets <100 x 109/L). 
OR 
3.1.2.2 
To meet FLIPI criteria (see Appendix IV for lymph node 
diagram), a patient must have a score of 3, 4, or 5 (per 
FLIPI-1, one point each for below criterion; please answer 
yes or no for each criterion): 
3.1.2.2.1 
Age > 60 years 
3.1.2.2.2 
Ann Arbor stage III-IV 
3.1.2.2.3 
Hemoglobin level < 12 mg/dL 
3.1.2.2.4 
> 4 nodal areas (see Appendix IV for nodal 
diagram) 
3.1.2.2.5 
Serum LDH level above normal  
3.1.3 
Patient must have stage II, III or IV disease (Modified Ann Arbor 
Staging – see Appendix XI). 
3.1.4 
Baseline measurements and evaluations (PET and CT) must be 
obtained within 6 weeks of randomization to the study. Combined 
PET/CT will be sufficient if the PET/CT is performed with oral and 
intravenous contrast; if PET/CT is without oral and intravenous 
contrast, then separate CTs (in addition to PET/CT) must be 
obtained. Patient must have at least one objective measurable 
disease parameter. Measurable disease in the liver is required if the 
liver is the only site of lymphoma. Please see Section 6 for definition 
of measurable disease. 
NOTE: CTs of neck, chest, abdomen and pelvis must be obtained   
≤ 6 weeks prior to randomization. PET scans must be done 
≤ 8 weeks prior to randomization. 
3.1.5 
Patient must have had no prior chemotherapy, radiotherapy or 
immunotherapy for lymphoma. For purposes of this trial, prednisone 
or other corticosteroids used for non-lymphomatous conditions will not 
be considered as prior chemotherapy. In addition, a prior/recent short 
course (< 2 weeks) of steroids for symptom relief of lymphoma-related 
symptoms will not make a patient ineligible. 
_______
_______
_______
_______
_______
_______
_______
_______
_______
_______
_______
_______
_______
_______
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3.1.6 
HIV positive patients are not excluded, but to enroll, must meet all of 
the below criteria: 
3.1.6.1 
HIV is sensitive to antiretroviral therapy 
3.1.6.2 
Must be willing to take effective antiretroviral therapy if 
indicated 
3.1.6.3 
No history of CD4 prior to or at the time of lymphoma 
diagnosis  < 300 cells/mm3 
3.1.6.4 
No history of AIDS-defining conditions 
3.1.6.5 
If on antiretroviral therapy, must not be taking zidovudine 
or stavudine 
3.1.6.6 
Must be willing to take prophylaxis for Pneumocystis 
jiroveci pneumonia (PCP) during therapy and until at least 
2 months following the completion of therapy or until the 
CD4 cells recover to over 250 cells/mm3, which ever 
occurs later. 
3.1.7 
Patient must have no recent history of malignancy except for 
adequately treated basal cell or squamous cell skin cancer, in situ 
cervical cancer, or other cancer for which the patient has been 
disease-free for at least 2 years. 
3.1.8 
Patient must have adequate organ function as measured by the 
following criteria, obtained without growth factor and/or transfusion, 
within 4 weeks of randomization:  
3.1.8.1 
ANC > 1500 /mm3 (includes neutrophils and bands) 
ANC: _____ Date of Test: ______ 
 
3.1.8.2 
Platelet count > 100,000 /mm3. 
Platelet count: _____ Date of Test: _____ 
NOTE: 
Patients with documented marrow involvement (with 
lymphoma) at the time of randomization are not 
required to meet the above hematologic parameters. 
3.1.8.3 
AST and ALT < 5 x the upper limit of normal. 
AST: _____ Date of Test: ____ ULN: ____ 
ALT: _____ Date of Test: ____  ULN: ____ 
3.1.8.4 
Alkaline phosphatase < 5 x the upper limit of normal. 
Alkaline phosphatase: ____ Date of Test: ____ ULN: 
____ 
3.1.8.5 
Total bilirubin < 1.5 x the upper limit of normal. 
Total Bilirubin: ____ Date of Test: ____ ULN: ____ 
NOTE: 
Patients with known Gilbert’s disease should contact 
the study PI. 
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3.1.8.6 
Creatinine < 2.0 mg/dL. Creatinine: _____ Date of Test: 
_____ 
NOTE: 
Determination of renal function classified by either 
measured CLcr, or CLcr estimated by Cockcroft-Gault 
method. 
3.1.9 
ECOG performance status 0-2.  ECOG PS status: ____  
3.1.10 
Patient must have no active, uncontrolled infections (afebrile for > 48 
hours off antibiotics). 
3.1.11 
Patients must not have ≥ Grade 2 neuropathy. 
3.1.12 
Patient must not have myocardial infarction within 6 months prior to 
registration or have New York Heart Association (NYHA) Class III or 
IV heart failure, uncontrolled angina, severe uncontrolled ventricular 
arrhythmias, or electrocardiographic evidence of acute ischemia or 
active conduction system abnormalities. Prior to randomization entry, 
any ECG abnormality at screening has to be documented by the 
investigator as not medically relevant. 
3.1.13 
Patient must not have serious medical or psychiatric illness likely to 
interfere with participation in this clinical study 
3.1.14 
Patients must not have known hypersensitivity to boron or mannitol. 
3.1.15 
Patients must be tested for hepatitis B surface antigen within 6 weeks 
of randomization. Patients who are chronic carriers of Hepatitis B 
Virus with + Hepatitis surface antigen (HBsAg +) are excluded, as 
chemotherapy and B-cell depleting therapy have been associated with 
virus reactivation and fulminant hepatitis. 
Date of Test ____________ Result ___________  
NOTE:  
Patients with prior history of Hepatitis B infection, but 
immune, with only IgG Hepatitis core antibody + (HBcAb +) 
must receive anti-viral prophylaxis (e.g., lamivudine 100mg 
po daily) for at least 1 week prior to cycle 1 and throughout 
induction and continuation therapy and for at least 12 
months after the last rituximab dose.  In addition, 
consultation with a hepatologist is recommended. 
3.1.16 
Age 18 years or older. 
 
3.1.17 
Patient agrees that if randomized to Arm C and proceed onto Arm F 
they must register into the mandatory RevAssist® program, and be 
willing and able to comply with the requirements of RevAssist®. 
3.1.18 
For patients randomized to Arms A and B- Women must not be 
pregnant or breast-feeding due to the use of chemotherapy and/or 
other therapeutic agents used in this protocol. 
All females of childbearing potential must have a blood test or urine 
study within 2 weeks prior to registration to rule out pregnancy. A 
female of childbearing potential is any woman, regardless of sexual 
orientation or whether they have undergone tubal ligation, who meets 
the following criteria: 1) has not undergone a hysterectomy or bilateral 
_______
_______
_______
_______
_______
_______
_______
_______
Rev. 10/11 
Rev. 10/11 
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oophorectomy; or 2) has not been naturally postmenopausal for at 
least 24 consecutive months (i.e., has had menses at any time in the 
preceding 24 consecutive months). 
Female? ______  (Yes or No)         
Date of blood test or urine study: __________ 
3.1.19 
For patients randomized to Arms A and B- Women of childbearing 
potential and sexually active males must be strongly advised to use 
an accepted and effective method of contraception.  
3.1.20 
Patients randomized to Arm C and proceeding to Arm F 
3.1.20.1 
Women must not be pregnant or breast-feeding due to use 
of chemotherapy and experimental treatment agents in this 
protocol.  Females of childbearing potential (FCBP)† must 
have a negative serum or urine pregnancy test with a 
sensitivity of at least 25 mIU/mL within 10 – 14 days prior 
to and again within 24 hours of prescribing lenalidomide 
(prescriptions must be filled within 7 days) and must either 
commit to continued abstinence from heterosexual 
intercourse or begin TWO acceptable methods of birth 
control, one highly effective method and one additional 
effective method AT THE SAME TIME, at least 28 days 
before she starts taking lenalidomide.  FCBP must also 
agree to ongoing pregnancy testing.  Men must agree to 
use a latex condom during sexual contact with a FCBP 
even if they have had a successful vasectomy.  See 
Appendix VII - Risks of Fetal Exposure, Pregnancy Testing 
Guidelines and Acceptable Birth Control Methods.  
Female of childbearing potential?___ (Yes or No) 
Date of blood or urine study?_____ 
3.1.20.2 
Females of childbearing potential (FCBP) must agree to 
use two reliable forms of contraception simultaneously or 
to practice complete abstinence from heterosexual 
intercourse during the following time periods related to this 
study/lenalidomide: 1) for at least 28 days before starting 
lenalidomide; 2) while participating in the study; and 3) for 
at 
least 
28 
days 
after 
discontinuation/stopping 
lenalidomide. The two methods of reliable contraception 
must include one highly effective method (i.e. intrauterine 
device (IUD), hormonal [birth control pills, injections, or 
implants], tubal ligation, partner’s vasectomy) and one 
additional effective (barrier) method (i.e. latex condom, 
diaphragm, cervical cap). FCBP must be referred to a 
qualified provider of contraceptive methods if needed. 
3.1.20.3 
Women must agree to abstain from donating blood during 
study participation and for at least 28 days after 
discontinuation from protocol treatment. 
Males 
must 
agree to abstain from donating blood, semen, or sperm 
______
______
______ 
_____
Rev. 10/11 
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during study participation and for at least 28 days after 
discontinuation from protocol treatment. 
All males, regardless of whether they have undergone a 
successful vasectomy, must agree to use a latex condom 
during sexual contact with a female of childbearing 
potential, or to practice complete abstinence from 
heterosexual intercourse with any female of childbearing 
potential during all cycles of study treatment and for at 
least 28 days following discontinuation of protocol 
treatment.  
3.1.20.4 
Patients must be willing to take DVT prophylaxis as all 
patients 
randomized 
to 
the 
lenalidomide/rituximab 
continuation arm will be required to have deep vein 
thrombosis (DVT) prophylaxis. Subjects with a history of a 
thrombotic vascular event will be required to have full 
anticoagulation, therapeutic doses of low molecular weight 
heparin or warfarin to maintain an INR between 2.0 – 3.0, 
or any other accepted full anticoagulation regimen (e.g. 
direct thrombin inhibitors or Factor Xa inhibitors) with 
appropriate monitoring for that agent. Subjects without a 
history of a thromboembolic event are required to take a 
daily aspirin (81 mg or 325 mg) for DVT prophylaxis. 
Subjects who are unable to tolerate aspirin should receive 
low molecular weight heparin therapy or warfarin treatment 
or another accepted full anticoagulation regimen. 
3.2 
Registration to Continuation Therapy (Step 2) 
3.2.1 
Patient must have improved their response or have had no interval 
change in their tumor measurements with restaging from Induction 
cycle 3 to 6 as determined at Cycle 6 restaging. 
3.2.2 
Patient must have adequate organ function as measured by the 
following criteria, obtained without growth factor and/or transfusion, 
within 4 weeks of registration:  
3.2.2.1 
ANC > 1000/mm3 (includes neutrophils and bands) 
ANC: _____ Date of Test: ______ 
3.2.2.2 
Platelet count > 100,000 /mm3. 
Platelet count: _____ Date of Test: _____ 
NOTE:  
Patients with documented marrow involvement (with 
lymphoma) at the time of registration are not required to 
meet the above hematologic parameters. 
3.2.2.3 
AST and ALT < 5 x the upper limit of normal. 
AST: _____ Date of Test: ____ ULN: ____ 
ALT: _____ Date of Test: ____  ULN: ____ 
_______
_______
_______
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3.2.2.4 
Alkaline phosphatase < 5 x the upper limit of normal. 
Alkaline phosphatase: ____ Date of Test: ____ ULN: ____ 
3.2.2.5 
Total bilirubin < 1.5x the upper limit of normal. 
Total Bilirubin: ____ Date of Test: ____ ULN: ____ 
NOTE:  
Patients with known Gilbert’s disease should 
contact the study PI. 
3.2.2.6 
Creatinine < 2.0 mg/dL. Creatinine: _____ Date of Test: 
_____ 
NOTE: 
Determination of renal function classified by 
either measured CLcr, or CLcr estimated by 
Cockcroft-Gault method. 
3.2.3 
ECOG performance status 0-2.  ECOG PS status: ____  
3.2.4 
Patient must have no active, uncontrolled infections (afebrile for > 48 
hours off antibiotics). 
3.2.5 
Patients must not have ≥ Grade 2 neuropathy (Arm F only). 
3.2.6 
Patients with prior history of Hepatitis B infection, but immune, with 
only IgG Hepatitis core antibody + (HBcAb +) must receive anti-viral 
prophylaxis (e.g., lamivudine 100mg po daily) for at least 1 week prior 
to cycle 1 and throughout induction and continuation therapy and for 
at least 9 months after the last rituximab dose.  In addition, 
consultation with a hepatologist is recommended. 
3.2.7 
Additional Requirements for Arm C Induction patients registering to 
Step 2 (Arm F Lenalidomide/Rituximab): 
3.2.7.1 
Patients must be willing to take deep vein thrombosis 
(DVT) prophylaxis. Subjects with a history of a thrombotic 
vascular event will be required to have full anticoagulation, 
therapeutic doses of low molecular weight heparin or 
warfarin to maintain an INR between 2.0 – 3.0, or any 
other accepted full anticoagulation regimen (e.g. direct 
thrombin inhibitors or Factor Xa inhibitors) with appropriate 
monitoring for that agent. Subjects without a history of a 
thromboembolic event are required to take a daily aspirin 
(81 mg or 325 mg) for DVT prophylaxis. Subjects who are 
unable to tolerate aspirin should receive low molecular 
weight heparin therapy or warfarin treatment or another 
accepted full anticoagulation regimen. 
3.2.7.2 
Women must not be pregnant or breast-feeding due to use 
of chemotherapy and experimental treatment agents in this 
protocol.  Females of childbearing potential (FCBP)† must 
have a negative serum or urine pregnancy test with a 
sensitivity of at least 25 mIU/mL within 10 – 14 days prior 
to and again within 24 hours of prescribing lenalidomide 
(prescriptions must be filled within 7 days) and must either 
commit to continued abstinence from heterosexual 
intercourse or begin TWO acceptable methods of birth 
_______
_______
_______
_______
_______
_______
Rev. 10/11 
Rev. 10/11 
Rev. 10/11 
_______
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control, one highly effective method and one additional 
effective method AT THE SAME TIME, at least 28 days 
before she starts taking lenalidomide.  FCBP must also 
agree to ongoing pregnancy testing.  Men must agree to 
use a latex condom during sexual contact with a FCBP 
even if they have had a successful vasectomy.  See 
Appendix VII - Risks of Fetal Exposure, Pregnancy Testing 
Guidelines and Acceptable Birth Control Methods.  
Female of childbearing Potential?___ (Yes or No) 
Date of blood or urine study?_____ 
3.2.7.2.1 
A female of childbearing potential (FCBP) is 
any woman, regardless of sexual orientation 
or whether they have undergone tubal 
ligation, who meets the following criteria: 1) 
has not undergone a hysterectomy or 
bilateral oophorectomy; or 2) has not been 
naturally postmenopausal for at least 24 
consecutive months (i.e., has had menses 
at any time in the preceding 24 consecutive 
months). 
3.2.7.3 
Females of childbearing potential (FCBP) must agree to 
use two reliable forms of contraception simultaneously or 
to practice complete abstinence from heterosexual 
intercourse during the following time periods related to this 
study/lenalidomide: 1) for at least 28 days before starting 
lenalidomide; 2) while participating in the study; and 3) for 
at 
least 
28 
days 
after 
discontinuation/stopping 
lenalidomide. The two methods of reliable contraception 
must include one highly effective method (i.e. intrauterine 
device (IUD), hormonal [birth control pills, injections, or 
implants], tubal ligation, partner’s vasectomy) and one 
additional effective (barrier) method (i.e. latex condom, 
diaphragm, cervical cap). FCBP must be referred to a 
qualified provider of contraceptive methods if needed.  
Patient must agree to abstain from donating blood during 
study participation and for at least 28 days after 
discontinuation from protocol treatment. 
3.2.7.4 
All males, regardless of whether they have undergone a 
successful vasectomy, must agree to use a latex condom 
during sexual contact with a female of childbearing 
potential, or to practice complete abstinence from 
heterosexual intercourse with any female of childbearing 
potential during the cycles of continuation therapy of which 
lenalidomide are taken and for at least 28 days after 
discontinuation/stopping lenalidomide. 
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Patient must agree to abstain from donating blood, semen, 
or sperm during study participation and for at least 28 days 
after discontinuation from protocol treatment. 
3.2.7.5 
Patients registering to Arm F must register into the 
mandatory RevAssist® program, and be willing and able to 
comply with the requirements of RevAssist®. 
_______


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Version Date: June 15, 2016 
 
NCI Update Date: January 23, 2015 
38 
4. 
Registration and Randomization Procedures 
CTEP Investigator Registration Procedures 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI)  
policy require all investigators participating in any NCI-sponsored clinical trial to register 
and to renew their registration annually. 
Registration requires the submission of: 
· 
a completed Statement of Investigator Form (FDA Form 1572) with an original 
signature 
· 
a current Curriculum Vitae (CV) 
· 
a completed and signed Supplemental Investigator Data Form (IDF) 
· 
a completed Financial Disclosure Form (FDF) with an original signature 
Fillable PDF forms and additional information can be found on the CTEP website at 
<http://ctep.cancer.gov/investigatorResources/investigator_registration.htm>. For 
questions, please contact the CTEP Investigator Registration Help Desk by email at 
<pmbregpend@ctep.nci.nih.gov>. 
CTEP Associate Registration Procedures / CTEP-IAM Account 
The Cancer Therapy Evaluation Program (CTEP) Identity and Access Management 
(IAM) application is a web-based application intended for use by both Investigators (i.e., 
all physicians involved in the conduct of NCI-sponsored clinical trials) and Associates 
(i.e., all staff involved in the conduct of NCI-sponsored clinical trials). 
Associates will use the CTEP-IAM application to register (both initial registration and 
annual re-registration) with CTEP and to obtain a user account. 
Investigators will use the CTEP-IAM application to obtain a user account only. (See 
CTEP Investigator Registration Procedures above for information on registering with 
CTEP as an Investigator, which must be completed before a CTEP-IAM account can be 
requested.) 
An active CTEP-IAM user account will be needed to access all CTEP and CTSU 
(Cancer Trials Support Unit) websites and applications, including the CTSU members’ 
website. 
Additional information can be found on the CTEP website at 
<http://ctep.cancer.gov/branches/pmb/associate_registration.htm>.  For questions, 
please contact the CTEP Associate Registration Help Desk by email at 
<ctepreghelp@ctep.nci.nih.gov>. 
CTSU Registration Procedures 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
IRB Approval: 
Each investigator or group of investigators at a clinical site must obtain IRB 
approval for this protocol and submit IRB approval and supporting documentation 
to the CTSU Regulatory Office before they can be approved to enroll patients. 
Study centers can check the status of their registration packets by querying the 
Regulatory Support System (RSS) site registration status page of the CTSU 
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members’ web site by entering credentials at https://www.ctsu.org. For sites 
under the CIRB initiative, IRB data will automatically load to RSS. 
Requirements for E2408 site registration: 
· 
CTSU IRB Certification 
· 
CTSU IRB/Regulatory Approval Transmittal Sheet 
Submitting Regulatory Documents 
Submit completed forms along with a copy of your IRB Approval and Model Informed 
Consent to the CTSU Regulatory Office, where they will be entered and tracked in the 
CTSU RSS.  
CTSU Regulatory Office 
1818 Market Street, Suite 1100 
Philadelphia, PA 19103 
PHONE: 1-866-651-2878 
FAX: (215) 569-0206 
EMAIL: CTSURegulatory@ctsu.coccg.org (for regulatory document 
submission only) 
Required Protocol Specific Regulatory Documents 
 
1.  
CTSU Regulatory Transmittal Form. 
 
2.  
Copy of IRB Informed Consent Document. 
 
NOTE:  Any deletion or substantive modification of information 
concerning risks or alternative procedures contained in the 
sample informed consent document must be justified in writing by 
the investigator and approved by the IRB. 
 
3.  
A.  
CTSU IRB Certification Form. 
 
 
 
Or  
 
 
 
 
 
B.  
Signed HHS OMB No. 0990-0263 (replaces Form 310). 
 
 
 
Or  
C.  
IRB Approval Letter 
 
 
 
 
 
NOTE: The above submissions must include the following details: 
•  Indicate all sites approved for the protocol under an assurance 
number. 
•  OHRP assurance number of reviewing IRB 
•  Full protocol title and number 
•  Version Date 
•  Type of review (full board vs. expedited) 
•  Date of review. 
•  Signature of IRB official 
4. 
Pharmacy License and Investigator Statement (Appendix XV) 
In order to ship bendamustine, E2408 has a protocol-specific requirement to 
collect a site pharmacy license.  For sites who do not utilize a pharmacy, a 
signed Investigator Statement (see Appendix XV) is required. This form only 
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needs to be submitted by the Principal Investigator at each institution, it does not 
have to be submitted for each sub-investigator. 
Before submission of the Investigator Statement, confirm the following: 
· 
All fields are complete 
· 
The form has been signed by the Principal Investigator 
Checking Your Site’s Registration Status: 
Check the status of your site’s registration packets by querying the RSS site 
registration status page of the members’ section of the CTSU website.  (Note: 
Sites will not receive formal notification of regulatory approval from the CTSU 
Regulatory Office.) 
· 
Go to https://www.ctsu.org and log in to the members’ area using your CTEP-
IAM username and password 
· 
Click on the Regulatory tab at the top of your screen 
· 
Click on the Site Registration tab 
· 
Enter your 5-character CTEP Institution Code and click on Go 
Patients must not start protocol treatment prior to randomization. 
Treatment should start within seven working days after randomization.  
Patient registration can occur only after pre-treatment evaluation is 
complete, eligibility criteria have been met, and the study site is listed as 
‘approved’ in the CTSU RSS.  Patients must have signed and dated all 
applicable consents and authorization forms.   
Patient enrollment will be facilitated using the Oncology Patient Enrollment 
Network (OPEN). OPEN is a web-based registration system available on a 24/7 
basis.  To access OPEN, the site user must have an active CTEP-IAM account 
(check at < https://eapps-ctep.nci.nih.gov/iam/index.jsp >) and a 'Registrar' role 
on either the LPO or participating organization roster. 
All site staff will use OPEN to enroll patients to this study. It is integrated 
with the CTSU Enterprise System for regulatory and roster data. OPEN can 
be accessed at https://open.ctsu.org or from the OPEN tab on the CTSU 
members’ side of the website at https://www.ctsu.org. 
Prior to accessing OPEN site staff should verify the following: 
· 
All eligibility criteria has been met within the protocol stated 
timeframes. 
· 
All patients have signed an appropriate consent form and HIPAA 
authorization form (if applicable).  
NOTE: 
The OPEN system will provide the site with a printable 
confirmation of registration and treatment information. Please 
print this confirmation for your records.  
NOTE: 
To receive site reimbursement for specific tests and/or bio-
specimen submissions, completion dates must be entered in the 
OPEN Funding screen post registration. Please refer to the 
protocol specific funding page on the CTSU members’ website for 
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additional information. Timely entry of completion dates is 
recommended as this will trigger site reimbursement. 
Further instructional information is provided on the OPEN tab of the CTSU 
members’ side of the CTSU website at https://www.ctsu.org or at 
https://open.ctsu.org. For any additional questions contact the CTSU Help 
Desk at 1-888-823-5923 or ctsucontact@westat.com. 
4.1 
Randomization (Step 1)  
Patients must not start protocol treatment prior to randomization. 
Treatment should start within seven working days after registration. 
The following information will be requested at time of randomization: 
4.1.1 
Protocol Number  
4.1.2 
Investigator Identification  
4.1.2.1 
Institution and affiliate name (Institution CTEP ID) 
4.1.2.2 
Investigator’s name (NCI number) 
4.1.2.3 
Cooperative Group Credit 
4.1.2.4 
Credit Investigator 
4.1.2.5 
Protocol specific contact information 
4.1.3 
Patient Identification  
4.1.3.1 
Patient’s initials (first and last) 
4.1.3.2 
Patient’s Hospital ID and/or Social Security number 
4.1.3.3 
Patient demographics 
4.1.3.3.1 
Gender 
4.1.3.3.2 
Birth date 
4.1.3.3.3 
Race 
4.1.3.3.4 
Ethnicity 
4.1.3.3.5 
Nine-digit ZIP code 
4.1.3.3.6 
Method of payment 
4.1.3.3.7 
Country of residence 
4.1.4 
Eligibility Verification  
Patients must meet all of the eligibility requirements listed in Section 
3.1.  An eligibility checklist has been appended to the protocol.  A 
confirmation of registration will be forwarded by the ECOG-ACRIN 
Operations Office - Boston. 
4.1.5 
Classification/Stratification Factors 
4.1.5.1 
FLIPI-1score (3 groups): 0 or 1 or 2 factors vs. 3 factors vs. 
4 or 5 factors. 
4.1.5.2 
GELF tumor burden: low vs high. 
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4.1.6 
Additional Requirements 
4.1.6.1 
Patients must provide a signed and dated, written informed 
consent form. 
NOTE: Copies of the consent are not collected by the 
ECOG-ACRIN Operations Office - Boston. 
4.1.6.2 
PET/CT and CT scans must be submitted for central 
review as outlined in Section 11. 
4.1.6.3 
Quality of life forms are to be submitted as indicated in 
Section 6.1.2. 
4.1.6.4 
Pathology materials must be submitted for central review 
per Section 10. 
 
4.1.6.5 
Additional specimens are to be submitted for laboratory 
studies and/or banking as indicated in Sections 10 and 11 
per patient consent. 
NOTE: Submitted scans and specimens must be entered 
and tracked via the ECOG-ACRIN Sample 
Tracking System (STS). See Section 10.4  
4.1.6.6 
Arm C female patients of child-bearing potential:  At 
the start of cycle 6 of induction therapy, female patients of 
child-bearing potential are to initiate abstinence from or 
utilize adequate contraception methods during 
heterosexual intercourse. 
4.1.6.7 
RevAssist® Program  
Lenalidomide will be provided to patients on Arm F 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 RevAssist® program of 
Celgene 
Corporation.  
Per 
standard 
RevAssist® 
requirements all physicians who prescribe lenalidomide for 
research subjects enrolled into this trial, and all research 
subjects randomized to Arm C who then proceed on to 
Arm F of this trial, must be registered in and comply with all 
requirements of the RevAssist® program.  Refer to Section 
8.4.9 of the protocol for complete information on the 
RevAssist® Program. 
4.1.7 
Instructions for Patients who Do Not Start Assigned Protocol 
Treatment  
If a patient does not receive any assigned protocol treatment, baseline 
and follow-up data will still be collected and must be submitted 
according to the instructions in the E2408 Forms Packet. Document 
the reason for not starting protocol treatment on the off-treatment 
form. Also report the date and type of the first non-protocol treatment 
that the patient receives. 
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4.2 
Registration (Step 2) 
Patients should not start protocol treatment prior to step 2 registration. 
Treatment should start per instructions in Section 5. 
NOTE: 
Patients for arms D and E should register to step 2 prior to cycle 1, 
even though no treatment is scheduled for that time period. 
The following information will be requested at time of randomization: 
4.2.1 
Protocol Number  
4.2.2 
Investigator Identification  
4.2.2.1 
Institution and affiliate name (Institution CTEP ID) 
4.2.2.2 
Investigator’s name (NCI number) 
4.2.2.3 
Cooperative Group Credit 
4.2.2.4 
Credit Investigator 
4.2.2.5 
Protocol specific contact information 
4.2.3 
Patient Identification  
4.2.3.1 
Patient’s initials (first and last) 
4.2.3.2 
Patient’s Hospital ID and/or Social Security number 
4.2.3.3 
Patient demographics 
4.2.3.3.1 
Gender 
4.2.3.3.2 
Birth date 
4.2.3.3.3 
Race 
4.2.3.3.4 
Ethnicity 
4.2.3.3.5 
Nine-digit ZIP code 
4.2.3.3.6 
Method of payment 
4.2.3.3.7 
Country of residence 
4.2.4 
Eligibility Verification  
Patients must meet all of the eligibility requirements listed in Section 
3.2.  An eligibility checklist has been appended to the protocol.  A 
confirmation of registration will be forwarded by the ECOG-ACRIN 
Operations Office - Boston. 
4.2.5 
Classification Factors 
4.2.5.1 
Induction Treatment: Arm A vs. Arm B vs. Arm C 
4.2.6 
Additional Requirements 
4.2.6.1 
PET/CT and CT scans must be submitted for central 
review as outlined in Section 11. 
4.2.6.2 
Quality of life forms are to be submitted as indicated in 
Section 6.1.2. 
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4.2.6.3 
Additional specimens are to be submitted for laboratory 
studies and/or banking as indicated in Sections 10 and 11, 
per patient content. 
NOTE: Submitted scans and specimens must be entered 
and tracked via the ECOG-ACRIN Sample 
Tracking System (STS). See Section 10.4. 
4.2.6.4 
Arm C/Arm F patients must enroll in RevAssist® and agree 
to comply with the requirements of the RevAssist® 
program. It is recommended that patients register for the 
program no later than the beginning of Cycle 6 of 
Induction. 
4.2.6.5 
RevAssist® Program  
Lenalidomide will be provided to patients on Arm F 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 RevAssist® program of 
Celgene 
Corporation.  
Per 
standard 
RevAssist® 
requirements all physicians who prescribe lenalidomide for 
research subjects enrolled into this trial, and all research 
subjects randomized to Arm C who then proceed on to 
Arm F of this trial, must be registered in and comply with all 
requirements of the RevAssist® program.  Refer to Section 
8.4.9 of the protocol for complete information on the 
RevAssist® Program. 
4.2.7 
Instructions for Patients who Do Not Start Assigned Protocol 
Treatment  
If a patient does not receive any assigned protocol treatment, follow-
up data will still be collected and must be submitted according to the 
instructions in the E2408 Forms Packet. Document the reason for not 
starting protocol treatment on the off-treatment form. Also report the 
date and type of the first non-protocol treatment that the patient 
receives. 
4.3 
Investigator’s Drug Brochure and Safety Alerts 
The Investigator Drug Brochures (IDBs) for bortezomib , lenalidomide and 
bendamustine are available for download from the ECOG webpage. The IDBs 
provide relevant and current scientific information about the investigational 
product. The IDBs should be submitted to your IRB/EC according to GCP 
regulations. The IDB and any correspondence to the Institutional Review Board 
(IRB)/Ethics Committee (EC) should be kept in the E2408 regulatory files.  
Should any SAE report on this study qualify as a safety alert report requiring 
expedited reporting, the SAE report will be sent by the respective pharmaceutical 
company to regulatory authorities globally (including the FDA) and ECOG-
ACRIN. If applicable, ECOG-ACRIN will disseminate these safety alert reports to 
all ECOG-ACRIN investigators in the bimonthly group mailings. These reports 
should be forwarded to your IRB/EC within 90 days of receipt for review. 
Reporting instructions are provided with each safety alert. These safety alerts 
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and any correspondence to your IRB/EC should be maintained in your E2408 
study files. 
4.4 
IND Status 
When used in this protocol, bortezomib, lenalidomide and bendamustine are 
each classified as an “unapproved use of an approved agent” and by definition 
considered investigational agents. However, while it is not an indication currently 
approved by the FDA, the use of bortezomib, lenalidomide and bendamustine in 
this protocol is exempt from the requirements of an IND and described under 
Title 21 CFR 312.2(b). 


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5. 
Treatment Plan 
NOTE: 
Please refer to Section 5.1.5, Table 2 for a detailed outline of the treatment 
schedule for each of the three study arms: (i) R-bendamustine induction 
followed by rituximab continuation OR (ii) RB-bendamustine induction 
followed by rituximab continuation OR (iii) R-bendamustine induction followed 
by lenalidomide/rituximab continuation. 
NOTE:  
Patients with prior history of Hepatitis B infection, but immune, with only 
Hepatitis core antibody + (HBcAb +) (i.e., HBsAg and HBV DNA testing must 
be negative) are allowed to receive treatment on this trial. Additionally, these 
patients must receive anti-viral prophylaxis (e.g., lamivudine 100mg po daily) 
for at least 1 week prior to cycle 1 and throughout induction and continuation 
therapy and for 12 months beyond the last dose of rituximab. In addition, 
consultation with a hepatologist is recommended.  
NOTE: 
See Section 5.4.1 for dose modifications for Rituximab. 
NOTE: 
PET/CT scan imaging requirements for central review are outlined in Section 
11.1 and Appendix VI. 
NOTE: 
For all drugs and continuing cycles of therapy, BSA does not need to be re-
calculated unless there is a greater than 5% change in weight. 
5.1 
Arm A - BENDAMUSTINE-RITUXIMAB (BR) INDUCTION FOLLOWED BY 
RITUXIMAB CONTINUATION (ARM D) 
5.1.1 
Arm A - BR Induction 
Agent 
Dose 
Route 
Day 
    Cycle Length** 
Rituximab* 
375 mg/m2 
IV 
1 
Every 28 days 
Bendamustine 
90 mg/m2 
IV 
1 and 2 
Every 28 days 
All doses are based on actual body weight. 
*  
Rituximab may be rounded to the nearest 50 mg.  
**  Cycle length may be altered to 26 days (-2 days) or to 31 days (+3 
days), for holidays or other extenuating scheduling situations.  
NOTE:  
Prophylactic filgrastim or pegfilgrastim may be used in any 
cycle according to ASCO guidelines (101). 
5.1.1.1 
Premedication 
5.1.1.1.1 
Acetaminophen (650 or 1000 mg orally) and 
diphenhydramine (25 or 50 mg oral or 
intravenous) is to be administered 30 to 60 
minutes prior to starting each infusion of 
rituximab. Since transient hypotension may 
occur during rituximab infusion, 
consideration should be given to withholding 
anti-hypertensive medications 12 hours 
prior to rituximab infusion. 
5.1.1.1.2 
Standard anti-emetic therapy may be given 
to patients prior to administration of each 
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BR treatment: including 5-HT3 serotonin 
receptor antagonists (e.g., ondansetron 8-
16 mg) +/– steroids (e.g., dexamethasone). 
5.1.1.2 
Administration Schedule 
The following are to be administered in the order indicated 
(1 cycle = 28 days). 
5.1.1.2.1 
Rituximab 375 mg/m2 IV Day 1. The 
rituximab dose may be rounded to the 
nearest 50 mg.  See Section 5.4.1.1 
regarding rituximab infusion rates. 
5.1.1.2.2 
Bendamustine will be administered to 
patients by IV infusion on days 1 and 2 of 
each 28-day cycle. The infusions are given 
over a 60-minute period and on day 1 will 
be administered to patients after the 
administration of rituximab. 
NOTE:  See Sections 5.5 and 5.6 regarding supportive 
care recommendations (for HIV negative and HIV 
positive patients). 
NOTE: Dose modifications – BR See Section 5.4.2 for 
dose modifications (due to toxicity). 
5.1.1.3 
Restaging and Length of Therapy 
5.1.1.3.1 
Repeat cycles every 28 days for a total of 6 
cycles. Patients may be evaluated in the 
office more frequently if needed at physician 
discretion. 
5.1.1.3.2 
Patients will be restaged after 3 cycles of 
therapy.  Patients who are in at least stable 
disease (SD, PR, or CR) after 3 cycles will 
receive 3 subsequent cycles. Patients who 
have improved their response or have had 
no interval change in their tumor 
measurements with restaging from cycle 3 
to 6 will then proceed to continuation 
therapy. Patients who have progressive 
disease (PD) will discontinue protocol 
treatment. 
5.1.1.4 
Arm D -Rituximab Continuation 
Agent 
Dose 
Route 
Day 
    Cycle Length  
Rituximab* 
375 mg/m2 
IV 
1 
Every 8 weeks (56 days)** 
Dosing is based on actual body weight. 
* The first dose of rituximab continuation should be given 8 
weeks after the start of cycle 6 of induction (i.e., to start week 29 
as in Section 5.1.5). The first dose of rituximab must not be 
delayed longer than 4 weeks from the scheduled time point. 
** May be given +/- 1 week (i.e., at 7 or 9 week interval). 
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5.1.1.4.1 
Premedication 
5.1.1.4.1.1 
Acetaminophen (650 or 1000 
mg) and diphenhydramine 
(25 or 50 mg) is to be 
administered 30 to 60 
minutes prior to starting each 
infusion of rituximab. 
5.1.1.4.1.2 
Since transient hypotension 
may occur during rituximab 
infusion, consideration 
should be given to 
withholding anti-hypertensive 
medications 12 hours prior to 
rituximab infusion. 
5.1.1.4.2 
Administration Schedule 
Rituximab 375 mg/m2 IV Day 1. The 
rituximab dose may be   rounded to the 
nearest 50 mg.  
NOTE: The first dose/infusion of rituximab 
continuation should be given 8 
weeks after the start of cycle 6 of 
induction. 
5.1.1.5 
Length of Therapy 
Repeat rituximab dosing every 8 weeks for 2 years (a total 
of 12 rituximab  doses). 
5.1.1.6 
Dose Modifications: Toxicity Grading 
All toxicities should be graded according to the Common 
Terminology   Criteria for Adverse Events. 
5.1.1.7 
Dose Modifications – Rituximab 
See Section 5.4.1. 
5.1.2 
Arm B - BENDAMUSTINE, RITUXIMAB-BORTEZOMIB (BVR) 
INDUCTION FOLLOWED BY RITUXIMAB CONTINUATION (ARM E) 
5.1.2.1 
Arm B - BVR Induction 
Agent 
Dose 
Route*** 
Days 
    Cycle Length**  
Rituximab* 
375 mg/m2 
IV 
d 1 
Every 28 days 
Bortezomib 
1.3 mg/m2 
IV or SQ 
d 1, 4, 8, and 11 
Every 28 days 
Bendamustine 
90 mg/m2 
IV 
d 1 and 4 
Every 28 days 
All doses are based on actual body weight. 
*  
Rituximab may be rounded to the nearest 50 mg vial. 
**  
Cycle length may be altered to 26 days (-2 days) or to 31 days (+3 days), 
for holidays or other extenuating scheduling situations. 
***  
See Section 8.3 for key differences between IV and SQ administration. 
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NOTE:  Prophylactic filgrastim or pegfilgrastim may be used 
according to ASCO guidelines (101). 
NOTE: Anti-viral prophylactic therapy (e.g., acyclovir 400 mg orally 
BID or valacyclovir 500 mg orally QD) is strongly 
recommended throughout induction on Arm B and continuing 
for at least 6 weeks after the last cycle. 
5.1.2.1.1 
Premedication 
5.1.2.1.1.1 
Acetaminophen (650 or 1000 
mg) and diphenhydramine 
(25 or 50 mg) is to be 
administered 
30 
to 
60 
minutes prior to starting each 
infusion of rituximab. Since 
transient hypotension may 
occur 
during 
rituximab 
infusion, 
consideration 
should 
be 
given 
to 
withholding anti-hypertensive 
medications 12 hours prior to 
rituximab infusion. 
5.1.2.1.1.2 
Standard anti-emetic therapy 
should be given to patients 
prior to administration of 
each 
BVR 
treatment: 
including 
5-HT3 
serotonin 
receptor antagonists (e.g., 
ondansetron 8-16 mg) +/– 
steroids 
(e.g., 
dexamethasone). 
5.1.2.2 
Administration Schedule 
The following are to be administered in the order indicated 
(1 cycle = 28 days). 
5.1.2.2.1 
Bortezomib 1.3 mg/m2 IV or SQ Days 1, 4, 
8, and 11 (four total doses per cycle). 
5.1.2.2.2 
Rituximab 375 mg/m2 IV Day 1. The 
rituximab dose may be rounded to the 
nearest 50 mg. See Section 5.4.1 regarding 
rituximab infusion rates. 
5.1.2.2.3 
Bendamustine will be administered to 
patients by IV infusion on days 1 and 4 of 
each 28-day cycle. The infusions are given 
over a 60-minute period and on day 1 will 
be administered to patients after the 
administration of rituximab.  
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NOTE:  
See Sections 5.5 and 5.6 regarding supportive 
care recommendations (for HIV negative and 
HIV positive patients). 
NOTE: 
Dose Modifications – BVR: See Section 5.4.3 for 
dose modifications (due to toxicity). 
5.1.2.3 
Restaging and length of therapy 
5.1.2.3.1 
Repeat cycles every 28 days for a total of 6 
cycles. Patients may be evaluated in the 
office more frequently if needed at physician 
discretion. 
5.1.2.3.2 
Patients will be restaged after 3 cycles of 
therapy.  Patients who are in at least stable 
disease (SD, PR, or CR) after 3 cycles will 
receive 3 subsequent cycles. Patients who 
have improved their response or have had 
no interval change in their tumor 
measurements with restaging from cycle 3 
to 6 will then proceed to rituximab 
continuation as below in Section 5.1.2.4. 
Patients who have progressive disease 
(PD) will discontinue protocol treatment. 
5.1.2.4 
Arm E - Rituximab Continuation 
Agent 
Dose 
Route 
Day 
    Cycle Length  
Rituximab* 
375 mg/m2 
IV 
1 
Every 8 weeks (56 
days)** 
Dosing is based on actual body weight. 
* The first dose of rituximab continuation should be given 8 weeks after 
the start of cycle 6 of induction (i.e., to start week 29 as in Section 
5.1.5). The first dose of rituximab must not be delayed more than 4 
weeks from the scheduled time point. 
** May be given +/- 1 week (i.e., at 7 or 9 week interval). 
5.1.2.4.1 
Premedication 
Acetaminophen (650 or 1000 mg) and 
diphenhydramine (25 or 50 mg) is to be 
administered 30 to 60 minutes prior to 
starting each infusion of rituximab. 
Since transient hypotension may occur 
during rituximab infusion, consideration 
should be given to withholding anti-
hypertensive medications 12 hours prior to 
rituximab infusion. 
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5.1.2.4.2 
Administration Schedule 
Rituximab 375 mg/m2 IV Day 1. The 
rituximab dose may be rounded to the 
nearest 50 mg.  
NOTE: The first dose/infusion of rituximab 
continuation should be given 8 
weeks after the start of cycle 6 of 
induction. 
5.1.2.4.3 
Length of Therapy 
Repeat rituximab dosing every 8 weeks for 
2 years (a total of 12 rituximab doses). 
5.1.2.4.4 
Dose Modifications: Toxicity Grading 
All toxicities should be graded according to 
the    Common     Terminology Criteria for 
Adverse Events (version 4.0). 
5.1.2.4.5 
Dose Modifications – Rituximab 
See Section 5.4.1. 
5.1.3 
Arm C - BENDAMUSTINE-RITUXIMAB (BR) INDUCTION 
FOLLOWED BY LENALIDOMIDE AND RITUXIMAB CONTINUATION 
(ARM F) 
5.1.3.1 
Arm C - BR Induction 
Agent 
Dose 
Route 
Day 
    Cycle Length** 
Rituximab* 
375 mg/m2 
IV 
1 
Every 28 days 
Bendamustine 
90 mg/m2 
IV 
1 and 2 
Every 28 days 
All doses are based on actual body weight. 
*  
Rituximab may be rounded to the nearest 50 mg vial. 
**  
Cycle length may be altered to 26 days (-2 days) or to 31 days (+3 days), 
for holidays or other extenuating scheduling situations. 
NOTE:  
Prophylactic filgrastim or pegfilgrastim may be used according 
to ASCO guidelines (101). 
5.1.3.2 
Premedication 
5.1.3.2.1 
Acetaminophen (650 or 1000 mg) and 
diphenhydramine (25 or 50 mg) is to be 
administered 30 to 60 minutes prior to 
starting each infusion of rituximab. Since 
transient hypotension may occur during 
rituximab infusion, consideration should be 
given 
to 
withholding 
anti-hypertensive 
medications 12 hours prior to rituximab 
infusion. 
5.1.3.2.2 
Standard anti-emetic therapy may be given 
to patients prior to administration of each 


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52 
treatment: 
including 
5-HT3 
serotonin 
receptor antagonists (e.g., ondansetron 8-
16 mg) +/– steroids (e.g., dexamethasone).  
 
5.1.3.3 
Administration Schedule 
The following are to be administered in the order indicated 
(1 cycle = 28 days). 
5.1.3.3.1 
Rituximab 375 mg/m2 IV Day 1. The 
rituximab dose may be rounded to the 
nearest 50 mg. See Section 5.4.1 regarding 
rituximab infusion rates. 
5.1.3.3.2 
Bendamustine will be administered to 
patients by iv infusion on days 1 and 2 of 
each 28-day cycle. The infusions are given 
over a 60-minute period and on day 1 will 
be administered to patients after the 
administration of rituximab. 
NOTE:  
See Sections 5.5 and 5.6 regarding supportive 
care recommendations (for HIV negative and 
HIV positive patients). 
NOTE: 
Dose Modifications – BR:  See Section 5.4.2 for 
dose modifications (due to toxicity). 
5.1.3.4 
Restaging and Length of Therapy 
5.1.3.4.1 
Repeat cycles every 28 days for a total of 6 
cycles. Patients may be evaluated in the 
office more frequently if needed at physician 
discretion. 
5.1.3.4.2 
Patients will be restaged after 3 cycles of 
therapy. Patients who are in at least stable 
disease (SD, PR, or CR) after 3 cycles will 
receive 3 subsequent cycles. Patients who 
have improved their response or have had 
no 
interval 
change 
in 
their 
tumor 
measurements with restaging from cycle 3 
to 6 will then proceed to continuation 
therapy. Patients who have progressive 
disease (PD) will discontinue protocol 
treatment. 
5.1.4 
Arm F - Lenalidomide/Rituximab Continuation 
Agent 
Dose* 
Route 
Day 
    Cycle Length  
Lenalidomide** 
20 mg 
PO 
1 through 21 
Every 28 days 
Rituximab*** 
375 mg/m2 
IV 
1 
Every 8 weeks (56 
days) 
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*  
See Section 5.4.4 regarding dose reductions of lenalidomide. 
**  
The first cycle of Lenalidomide should start 4 weeks after the start of cycle 6 
of induction (i.e., to start week 25 as in Section 5.1.5).  Also, please see 
Appendix V for the pill diary that must be filled out for each cycle/dose of 
lenalidomide therapy. The first dose of lenalidomide must not be delayed 
more than 6 weeks from the scheduled time point. 
***  The first dose of rituximab continuation should be given 8 weeks after the 
start of cycle 6 of induction (i.e., to start week 29 as in Section 5.1.5). 
Rituximab therapy will be given every 8 weeks (every 56 days) “on 
schedule” regardless of potential delay or withdrawal of lenalidomide. In 
addition, rituximab may be given +/- 1 week (i.e., at 7 or 9 week interval). 
The first dose of rituximab must not be delayed more than 4 weeks from the 
scheduled time point. 
 
For a patient that discontinues lenalidomide after undergoing all three 
dose reductions, they are able to remain on-study and continue with 
rituximab maintenance. 
In 
addition, 
if 
a 
patient 
is 
unable 
to 
tolerate lenalidomide and the treating physician discontinues lenalidomide 
prior to undergoing all three dose reductions, they may stay on study 
and continue with rituximab maintenance, however this must be discussed 
with the study PI. 
NOTE: 
Missed or delayed doses of lenalidomide will not be given 
or made up. Any missed or delayed dose should be 
recorded in the patient pill diary as missed or delayed. 
5.1.4.1 
Lenalidomide fertility instructions 
NOTE: Please also see Appendix VIII “Risks of Fetal 
Exposure, Pregnancy Testing Guidelines and 
Acceptable Birth Control Methods.” 
Before starting study drug: 
All study participants must be registered into the 
mandatory RevAssist® program, and be willing and able to 
comply with the requirements of RevAssist®. Females of 
childbearing potential (FCBP) must have a negative serum 
or urine pregnancy test with a sensitivity of at least 25 
mIU/mL within 10 – 14 days prior to and again within 24 
hours of prescribing lenalidomide (prescriptions must be 
filled within 7 days) and must either commit to continued 
abstinence from heterosexual intercourse or begin TWO 
acceptable methods of birth control, one highly effective 
method and one additional effective method AT THE 
SAME TIME, at least 28 days before she starts taking 
lenalidomide.  FCBP must also agree to ongoing 
pregnancy testing.  Men must agree to use a latex condom 
during sexual contact with a FCBP even if they have had a 
successful vasectomy.  See Appendix VIII: Risks of Fetal 
Exposure, Pregnancy Testing Guidelines and Acceptable 
Birth Control Methods. 
NOTE: A female of childbearing potential (FCBP) is any 
woman, regardless of sexual orientation or 
Rev. 10/11 
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whether they have undergone tubal ligation, who 
meets the following criteria: 1) has not undergone 
a hysterectomy or bilateral oophorectomy; or 2) 
has not been naturally postmenopausal for at 
least 24 consecutive months (i.e., has had 
menses at any time in the preceding 24 
consecutive months). 
5.1.4.2 
Anticoagulation 
All 
subjects 
randomized 
to 
lenalidomide/rituximab 
continuation therapy will be required to have deep vein 
thrombosis (DVT) prophylaxis during lenalidomide therapy. 
Subjects with a history of a thrombotic vascular event are 
required to have full anticoagulation, therapeutic doses of 
low molecular weight heparin or Coumadin to maintain an 
INR between 2.0–3.0, or any other accepted full 
anticoagulation regimen (e.g. direct thrombin inhibitors or 
Factor Xa inhibitors) with appropriate monitoring for that 
agent. All subjects without a history of a thromboembolic 
event are required to take a daily aspirin (81mg or 325 mg) 
for DVT prophylaxis. Subjects who are unable to tolerate 
aspirin should receive low molecular weight heparin 
therapy or Coumadin treatment or another accepted full 
anticoagulation regimen. 
Of note, if platelets decline to < 50,000/mm3, prophylactic 
anti-coagulation should be stopped (in addition to holding 
lenalidomide 
as 
below 
in 
Section 
5.7.5). 
If/when 
lenalidomide is restarted (with return of platelet toxicity to < 
Grade 2 as in Table 7 in Section 5.4.4), then prophylactic 
anti-coagulation should also be restarted. 
5.1.4.3 
Rituximab Premedication. 
· 
Acetaminophen 
(650 
or 
1000 
mg) 
and 
diphenhydramine (25 or 50 mg) is to be 
administered 30 to 60 minutes prior to starting each 
infusion of rituximab. Since transient hypotension 
may occur during rituximab infusion, consideration 
should be given to withholding anti-hypertensive 
medications 12 hours prior to rituximab infusion. 
5.1.4.4 
Administration Schedule 
a.  Lenalidomide 20mg PO days 1 through 21 on a 28-
day cycle. 
NOTE: The first cycle of Lenalidomide will start 4 
weeks after the start of cycle 6 of induction.  
See Table in Section 5.1.5. 
NOTE: Prior to starting lenalidomide continuation, the 
ANC must be > 1000 cells/mm3 (1.0 x 109/L) 
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and the platelet count must be > 75,000 
cells/mm3 (75 x 109/L). 
NOTE: Creatinine clearance should be calculated 
prior to the first dosing of lenalidomide. 
NOTE: See Appendix V for the lenalidomide pill diary 
that must be filled out for each cycle/dose of 
lenalidomide therapy. 
b.  Rituximab 375 mg/m2 IV Day 1. The rituximab dose may 
be rounded to the nearest 50 mg.  
NOTE: The first dose of rituximab continuation 
should be given 8 weeks after the start of 
cycle 6 of induction. 
NOTE: All patients receiving Lenalidomide based 
continuation therapy must complete the 
Lenalidomide pill diary for each cycle/dose of 
Lenalidomide (see Appendix V). 
5.1.4.5 
Length of Therapy 
5.1.4.5.1 
Repeat rituximab dosing every 8 weeks for 
2 years (a total of 12 rituximab doses). 
5.1.4.5.2 
Lenalidomide therapy is given every 4 
weeks for a total of 13 cycles. 
5.1.4.6 
Dose Modifications: Toxicity Grading 
The descriptions and grading scales found in the revised 
NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0 will be utilized for AE reporting. All 
appropriate treatment areas should have access to a copy 
of the CTCAE version 4.0. A copy of the CTCAE version 
4.0 can be downloaded from the CTEP web site 
(http://ctep.cancer.gov). 
5.1.4.7 
Dose Modifications- Rituximab 
See Section 5.4.1 
5.1.4.8 
Dose Modifications- Lenalidomide 
See Section 5.4.4 
5.1.5 
Overall Treatment Plan 
Table 2 
Treatment schedule/timing 
NOTE: Restage after every three (3) Rituximab 
treatments. 


ECOG-ACRIN 
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RANDOMIZATION (STEP 1)  
stratification factors:  GELF tumor burden (Low vs High) and FLIPI (0-2 vs. 3 vs. 4-5) 
 
BR Induction  
(Arm A) 
BVR Induction (Arm B) 
BR Induction  
(Arm C) 
6 cycles of Induction  
BR Induction 
BVR Induction 
BR Induction 
Cycle = 28 days 
1: Wk 1-4 
BR #1 
BVR #1 
 BR #1 
2: wk 5-8 
BR #2 
BVR #2 
BR #2 
3: wk 9-12 
BR #3 
BVR  #3 
BR #3 
 
RESTAGE #1 
4: wk13-16 
BR #4 
BVR #4 
BR #4 
5: wk17-20 
BR #5 
BVR  #5 
BR #5 
6: wk21-24 
BR #6 
BVR #6 
BR #6 
 
RESTAGE #2 
REGISTRATION (STEP 2)* Prior to Week 25 
Year 1 of Continuation          (52 
weeks) 
Rituximab 
Continuation 
(Arm D) 
Rituximab Continuation 
(Arm E) 
Lenalidomide/Rituxi
mab Continuation 
(Arm F) 
Cycle = 28 days 
 
C1: w 25-28 
No treatment 
No treatment  
Lenalidomide #1  
2: wk29-32 
Rituximab #1 
Rituximab #1 
Rituximab #1 and 
Lenalidomide #2   
3: wk33-36 
No treatment 
No treatment  
Lenalidomide #3  
4: wk37-40 
Rituximab #2 
Rituximab #2 
Rituximab #2 and 
Lenalidomide #4  
 
5: wk41-44 
No treatment 
No treatment  
Lenalidomide #5  
6: wk45-48 
Rituximab #3 
Rituximab #3 
Rituximab #3 and 
Lenalidomide #6  
7: wk49-52 
No treatment 
No treatment  
Lenalidomide #7  
 
RESTAGE #3 Prior to Week 53 
8: wk53-56 
Rituximab #4 
Rituximab #4 
Rituximab #4 and 
Lenalidomide #8   
9: wk57-60 
No treatment 
No treatment  
Lenalidomide #9  
10: wk61-64 
Rituximab #5 
Rituximab #5 
Rituximab #5 and 
Lenalidomide #10  
11: wk65-68 
No treatment 
No treatment  
Lenalidomide #11  
12: wk69-72 
Rituximab #6 
Rituximab #6 
Rituximab #6 and 
Lenalidomide #12  
13: wk73-76 
No treatment 
No treatment  
Lenalidomide #13  
 
RESTAGE #4 After Week 76 
Year 2 of Continuation         
Rituximab (alone) continuation- all patients 
Cycles 14-18 
 Rituximab to continue every 8 weeks for 3 doses (given Cycles 14, 16, 18) 
Odd Cycles: no Treatment  
 
RESTAGE #5 Prior to start of Cycle 20 
Cycles 20-24 
Rituximab to continue every 8 weeks for 3 doses (given Cycles 20, 22, 
24) 
Odd Cycles: no Treatment 
 
RESTAGE #6 
* Rituximab therapy to be given every 8 weeks “on schedule” regardless of potential delay (or withdrawal) 
of Lenalidomide. Rituximab may be given +/- 1 week (i.e., at 7 or 9 week interval). 
Rev. 4/13 
Rev. 4/13 
Rev. 4/13 
Rev. 4/13 
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5.2 
Adverse Event Reporting Requirements 
5.2.1 
Purpose 
Adverse event data collection and reporting, which are required as 
part of every clinical trial, are done to ensure the safety of patients 
enrolled in the studies as well as those who will enroll in future studies 
using similar agents. Adverse events are reported in a routine manner 
at scheduled times during a trial (please refer to the E2408 Forms 
Packet for the list of forms with directions for routine adverse event 
reporting).  Additionally, certain adverse events must be reported in 
an expedited manner for more timely monitoring of patient safety and 
care. The following sections provide information about expedited 
reporting. 
5.2.2 
Determination of Reporting Requirements 
Reporting requirements may include the following considerations: 1) 
whether the patient has received an investigational or commercial 
agent; 2) the characteristics of the adverse event including the grade 
(severity), the relationship to the study therapy (attribution), and the 
prior experience (expectedness) of the adverse event; 3) the phase 
(1, 2, or 3) of the trial; and 4) whether or not hospitalization or 
prolongation of hospitalization was associated with the event. 
Commercial agents are those agents not provided under an IND but 
obtained instead from a commercial source. The NCI, rather than a 
commercial distributor, may on some occasions distribute commercial 
agents for a trial. 
Steps to determine if an adverse event is to be reported in an 
expedited manner: 
Step 1: Identify the type of event: The descriptions and grading 
scales found in the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0 will be 
utilized for AE reporting.  All appropriate treatment areas 
should have access to a copy of the CTCAE version 4.0. A 
copy of the CTCAE version 4.0 can be downloaded from the 
CTEP web site (http://ctep.cancer.gov). 
Step 2: Grade the event using Version 4.0 of the NCI CTCAE. 
Step 3: Determine whether the adverse event is related to the 
protocol therapy (investigational or commercial). Attribution 
categories are as follows: Unrelated, Unlikely, Possible, 
Probable, and Definite. 
Step 4: Determine the prior experience of the adverse event. 
Expected events are those that have been previously 
identified as resulting from administration of the agent. An 
adverse event is considered unexpected, for expedited 
reporting purposes only, when either the type of event or the 
severity of the event is NOT listed in:  
· 
Arm A, B, C, D, E, and F – the drug package insert, Investigator 
Brochure,  or protocol  
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Step 5: Review Section 5.2.6 for E2408 and/or ECOG-ACRIN 
specific requirements for expedited reporting of specific 
adverse events that require special monitoring. 
NOTE: For general questions regarding expedited reporting 
requirements, please contact the AEMD Help Desk at 
aemd@tech-res.com or  301-897-7497. 
5.2.3 
Reporting Methods 
Arms A, B, C, D, E and F- This study requires that expedited adverse 
event reporting use CTEP’s Adverse Event Reporting System (CTEP-
AERS). CTEP’s guidelines for CTEP-AERS can be found at 
http://ctep.cancer.gov. A CTEP-AERS report must be submitted 
electronically to ECOG-ACRIN and the appropriate regulatory 
agencies via the CTEP-AERS Web-based application located at 
http://ctep.cancer.gov. 
In the rare event when Internet connectivity is disrupted a 24-hour 
notification is to be made by telephone to  
· 
the FDA (800-332-1088) and  
· 
the AE Team at ECOG-ACRIN (617-632-3610) 
An electronic report MUST be submitted immediately upon re-
establishment of internet connection. 
Supporting and follow up data:  Any supporting or follow up 
documentation must be faxed to ECOG-ACRIN (617-632-2990), 
Attention: AE within 48-72 hours.  In addition, supporting or follow up 
documentation must be faxed to the FDA (800-332-0178) in the same 
timeframe.  
NCI Technical Help Desk:  For any technical questions or system 
problems regarding the use of the CTEP-AERS application, please 
contact the NCI Technical Help Desk at ncictephelp@ctep.nci.nih.gov 
or by phone at 1-888-283-7457. 
5.2.4 
When to Report an Event in an Expedited Manner 
When an adverse event requires expedited reporting, submit a full 
CTEP-AERS report within the timeframes outlined in Section 5.2.6 
NOTE: Adverse events that meet the reporting requirements in 
Section 5.2.6 and occur within 30 days of the last dose of 
protocol treatment must be reported on an expedited 
adverse event report form (using CTEP-AERS). For any 
adverse events that occur more than 30 days after the last 
dose of treatment, only those that have an attribution of 
possibly, probably, or definitely AND meet the reporting 
requirements in Section 5.2.6 must be reported on an 
expedited adverse event report form (using CTEP-AERS). 
5.2.5 
Other Recipients of Adverse Event Reports 
ECOG-ACRIN will forward CTEP-AERS reports to the appropriate 
regulatory agencies and pharmaceutical company, if applicable. 
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Adverse events determined to be reportable must also be reported by 
the institution, according to the local policy and procedures, to the 
Institutional Review Board responsible for oversight of the patient. 
A drug supporter representative may call a site for additional 
information regarding a serious adverse event.  Any additional written 
AE information requested by the drug supporter MUST be submitted 
to BOTH ECOG-ACRIN and the drug supporter. 
5.2.6 
Expedited Reporting for Commercial Agents 
Commercial reporting requirements are provided below. The 
commercial agents used in arms Arm A, B, C, D, E, and F of this 
study are Rituximab, Bortezomib, Lenalidomide and Bendamustine. 
Expedited reporting requirements for adverse events experienced by patients on arm(s) with commercial agents 
only – Arms A, B, C, D, E, and F 
Attribution 
Grade 4 
Grade 5a 
ECOG-ACRIN and 
Protocol-Specific 
Requirements 
Unexpected 
Expected 
Unexpected 
Expected 
See footnote  
(b) for special 
requirements. 
d 
Unrelated or 
Unlikely 
 
 
7 calendar 
days 
7 calendar 
days 
Possible,  
Probable,  
Definite 
7 calendar 
days 
 
7 calendar 
days 
7 calendar 
days 
7 Calendar Days: 
Indicates a full CTEP-AERS report is to be submitted within 7 calendar days of learning 
of the event. 
a 
This includes all deaths within 30 days of the last dose of treatment regardless of attribution. NOTE:  Any 
death that occurs > 30 days after the last dose of treatment and is attributed possibly, probably, or 
definitely to the treatment must be reported within 7 calendar days of learning of the event.   
b 
Protocol-specific expedited reporting requirements: The adverse events listed below also require expedited 
reporting for this trial: 
Serious Events: Any event following treatment that results in persistent or significant disabilities/incapacities, 
congenital anomalies, or birth defects must be reported via CTEP-AERS within 7 calendar days 
of learning of the event.  For instructions on how to specifically report these events via CTEP-
AERS, please contact the AEMD Help Desk at aemd@tech-res.com or 301-897-7497. This will 
need to be discussed on a case-by-case basis. 
Pregnancy:  
Pregnancies and suspected pregnancies (including a positive or inconclusive pregnancy test regardless of age 
or disease state) occurring while the subject is onprotocol treatment, or within 28 days of the subject’s last 
dose of protocol treatment, are considered immediately reportable events. The pregnancy, suspected 
pregnancy, or positive/inconclusive pregnancy test must be reported via CTEP-AERS within 24 hours 
of the Investigator’s knowledge.   
Please refer to Appendix XVI for detailed instructions on how to report the occurrence of a pregnancy 
as well as the outcome of all pregnancies. 
5.2.7 
Reporting Second Primary Cancers 
All cases of second and secondary malignancies [including acute 
myeloid leukemia (AML) and myelodysplastic syndrome (MDS)], 
regardless of attribution, that occur following treatment on NCI-
sponsored trials must be reported as follows: 
1. Submit a completed Second Primary Form within 30 days to 
ECOG-ACRIN at: 
Rev. 10/11 
Rev. 5/11 
Rev. 2/14 
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ECOG-ACRIN Operations Office - Boston 
FSTRF 
900 Commonwealth Avenue 
Boston, MA 02215 
2. Report the diagnosis via CTEP-AERS, regardless of 
attribution, at http://ctep.cancer.gov 
Report under a.) leukemia secondary to oncology 
chemotherapy, 
b.) 
myelodysplastic 
syndrome, 
c.) 
treatment 
related 
secondary 
malignancy, 
or 
d.) 
Neoplasm Other, malignant (grade 3 or 4) 
3. Submit a copy of the pathology report to ECOG-ACRIN and 
NCI/CTEP confirming the diagnosis. 
4. If the patient has been diagnosed with AML/MDS, submit a 
copy of the cytogenetics report (if available) to ECOG-
ACRIN and NCI/CTEP. 
NOTE: All new malignant tumors must be reported through 
CTEP-AERS whether or not they are thought to be 
related to either previous or current treatment.  All 
new malignancies should be reported including solid 
tumors (including non-melanoma skin malignancies), 
hematologic malignancies, Myelodysplastic Syndrome 
(MDS)/Acute Myelogenous Leukemia (AML), and in situ 
tumors. 
Whenever possible, the CTEP-AERS report should include the 
following:  
· 
tumor pathology 
· 
history of prior tumors 
· 
prior treatment/current treatment including duration 
· 
any associated risk factors or evidence regarding how long the 
tumor may have been present 
· 
when and how the tumor was detected 
· 
molecular characterization or cytogenetics or the original tumor (if 
available) and of any new tumor 
· 
tumor treatment and outcome (if available).   
NOTE: The Second Primary Form and the CTEP-AERS report 
should not be used to report recurrence or development of 
metastatic disease. 
NOTE: If a patient has been enrolled in more than one NCI-
sponsored study, the Second Primary Form must be 
submitted for the most recent trial. ECOG-ACRIN must be 
provided with a copy of the form and the associated 
pathology report and cytogenetics report (if available) even if 
ECOG-ACRIN was not the patient's most recent trial. 
NOTE: Once data regarding survival and remission status are no 
longer required by the protocol, no follow-up data should be 
submitted via CTEP-AERS or by the Second Primary Form. 


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5.3 
Comprehensive Adverse Events and Potential Risks List (CAEPR) 
5.3.1 
Comprehensive Adverse Events and Potential Risks List (CAEPR) for 
Bortezomib 
The Comprehensive Adverse Events and Potential Risks List 
(CAEPR) provides a thorough and single list of reported and/or 
potential adverse events (AE) associated with an agent using a 
uniform presentation of events by body system.  The CAEPRS 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 
2084 patients. Below is the CAEPR for bortezomib (PS-341). 
Version 2.5, June 30, 20141 
 
 Adverse Events with Possible  
 Relationship to PS-341 (Bortezomib, Velcade) 
 (CTCAE 4.0 Term) 
[n= 2084] 
 
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
 
Anemia 
 
 
 
CARDIAC DISORDERS 
 
 
 
Heart failure 
 
GASTROINTESTINAL DISORDERS 
 
 
Abdominal pain 
 
 
Constipation 
 
 
 
Diarrhea 
 
 
 
 
Dyspepsia 
 
 
 
Gastrointestinal hemorrhage2 
 
 
 
 
 Gastrointestinal perforation3 
 
 
Ileus 
 
 
Nausea 
 
 
 
Vomiting 
 
 
 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
 
 
Chills 
 
 
 
Edema limbs 
 
 
Fatigue 
 
 
 
Fever 
 
 
 
INFECTIONS AND INFESTATIONS 
 
Infection4 
 
 
 
INVESTIGATIONS 
 
 
Neutrophil count decreased 
 
 
Platelet count decreased 
 
 
 
 
Weight loss 
 
 
METABOLISM AND NUTRITION DISORDERS 
 
Anorexia 
 
 
 
 
Dehydration 
 
 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
 
 
Arthralgia 
 
 
Rev. 5/12, 9/14 
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Back pain 
 
 
 
Bone pain 
 
 
 
Musculoskeletal and connective 
tissue disorder - Other (muscle 
spasms) 
 
 
 
Myalgia 
 
 
 
Pain in extremity 
 
 
NERVOUS SYSTEM DISORDERS 
 
 
Dizziness 
 
 
 
Headache 
 
 
 
 
Leukoencephalopathy 
 
 
Neuralgia 
 
 
 
Paresthesia 
 
 
Peripheral motor neuropathy 
 
 
 
Peripheral sensory neuropathy 
 
 
 
 
 
Reversible posterior 
leukoencephalopathy syndrome 
 
PSYCHIATRIC DISORDERS 
 
 
Anxiety 
 
 
 
Insomnia 
 
 
RENAL AND URINARY DISORDERS 
 
 
 
Acute kidney injury 
 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
 
 
 
Adult respiratory distress syndrome 
 
 
Cough 
 
 
 
Dyspnea 
 
 
 
Pharyngeal mucositis 
 
 
 
 
Pulmonary hypertension 
 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
 
 
Rash maculo-papular 
 
 
VASCULAR DISORDERS 
 
 
Hypotension 
 
 
1 This 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 e-mail. 
2 Gastrointestinal 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. 
3 Gastrointestinal perforation includes Colonic perforation, Duodenal perforation, Esophageal 
perforation, Gastric perforation, Ileal perforation, Jejunal perforation, Rectal perforation, and 
Small intestinal perforation under the GASTROINTESTINAL DISORDERS SOC. 
4 Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC. 
Also reported on PS-341 (bortezomib, Velcade) trials but with the relationship to PS-341 
(bortezomib, Velcade) still undetermined: 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system disorders - 
Other (hematocrit low); Blood and lymphatic system disorders - Other (lymphadenopathy); 


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Disseminated intravascular coagulation; Febrile neutropenia; Hemolytic uremic syndrome; 
Leukocytosis 
CARDIAC DISORDERS - Acute coronary syndrome; Asystole; Atrial fibrillation; Atrial flutter; 
Atrioventricular block complete; Cardiac arrest; Cardiac disorders - Other (cardiac amyloidosis); 
Cardiac disorders - Other (cardiomegaly); Chest pain - cardiac; Left ventricular systolic 
dysfunction; Mobitz type I; Myocardial infarction; Palpitations; Pericardial effusion; Pericardial 
tamponade; Pericarditis; Right ventricular dysfunction; Sinus bradycardia; Sinus tachycardia; 
Supraventricular tachycardia; Ventricular arrhythmia; Ventricular fibrillation; Ventricular 
tachycardia 
EAR AND LABYRINTH DISORDERS - External ear inflammation; Hearing impaired; Tinnitus 
ENDOCRINE DISORDERS - Hypothyroidism 
EYE DISORDERS - Blurred vision; Conjunctivitis; Dry eye; Extraocular muscle paresis; Eye 
disorders - Other (chalazion); Eye disorders - Other (choroidal effusion); Eye disorders - Other 
(conjunctival hemorrhage); Eye disorders - Other (retinal hemorrhage with bilateral vision 
impairment); Keratitis; Watering eyes 
GASTROINTESTINAL DISORDERS - Abdominal distension; Ascites; Bloating; Colitis; Dry 
mouth; Duodenal ulcer; Dysphagia; Enterocolitis; Esophagitis; Flatulence; Gastritis; 
Gastroesophageal reflux disease; Gastrointestinal disorders - Other (colonic wall thickening); 
Gastrointestinal disorders - Other (early satiety); Gastrointestinal disorders - Other (eructation); 
Gastrointestinal disorders - Other (ileitis); Gastrointestinal disorders - Other (ischemic bowel); 
Gastrointestinal disorders - Other (mouth/tongue ulceration); Gastrointestinal disorders - Other 
(retching); Gastrointestinal pain; Gingival pain; Hemorrhoids; Mucositis oral; Oral pain; 
Pancreatitis; Small intestinal obstruction; Typhlitis 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Edema face; Flu like 
symptoms; Gait disturbance; General disorders and administration site conditions - Other 
(catheter related complication);General disorders and administration site conditions - Other 
(hepato-renal syndrome); Hypothermia; Injection site reaction; Malaise; Multi-organ failure; Non-
cardiac chest pain; Pain; Sudden death NOS 
HEPATOBILIARY DISORDERS - Hepatic failure; Hepatobiliary disorders - Other (hepatitis); 
Hepatobiliary disorders - Other (portal vein thrombosis); Hepatobiliary disorders - Other (VOD) 
IMMUNE SYSTEM DISORDERS - Allergic reaction; Anaphylaxis; Cytokine release syndrome 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Bruising; Fall; Fracture; 
Vascular access complication 
INVESTIGATIONS - Activated partial thromboplastin time prolonged; Alanine aminotransferase 
increased; Alkaline phosphatase increased; Aspartate aminotransferase increased; Blood 
bilirubin increased; CD4 lymphocytes decreased; CPK increased; Carbon monoxide diffusing 
capacity decreased; Cardiac troponin I increased; Cardiac troponin T increased; Cholesterol 
high; Creatinine increased; Ejection fraction decreased; GGT increased; INR increased; 
Investigations - Other (albumin); Investigations - Other (BUN); Investigations - Other (low 
chloride); Investigations - Other (pancytopenia); Lipase increased; Lymphocyte count 
decreased; Serum amylase increased; Weight gain; White blood cell decreased 
METABOLISM AND NUTRITION DISORDERS - Acidosis; Hypercalcemia; Hyperglycemia; 
Hyperkalemia; Hyperuricemia; Hypoalbuminemia; Hypocalcemia; Hypoglycemia; Hypokalemia; 
Hypomagnesemia; Hyponatremia; Hypophosphatemia; Metabolism and nutrition disorders - 
Other (failure to thrive); Metabolism and nutrition disorders - Other (hypoproteinemia); Tumor 
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MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthritis; Avascular 
necrosis; Buttock pain; Chest wall pain; Generalized muscle weakness; Joint range of motion 
decreased; Muscle weakness lower limb; Musculoskeletal and connective tissue disorder -  
Other (cramping); Osteonecrosis of jaw 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - 
Tumor pain 
NERVOUS SYSTEM DISORDERS - Acoustic nerve disorder NOS; Akathisia; Ataxia; Cognitive 
disturbance; Depressed level of consciousness; Dysesthesia; Dysgeusia; Dysphasia; Edema 
cerebral; Encephalopathy; Facial muscle weakness; Facial nerve disorder; Hypersomnia; 
Intracranial hemorrhage; Ischemia cerebrovascular; Lethargy; Memory impairment; Nervous 
system disorders - Other (autonomic neuropathy); Nervous system disorders - Other (Bell's 
palsy); Nervous system disorders - Other (cranial palsy); Nervous system disorders - Other 
(dysautonomia); Nervous system disorders - Other (L sided facial droop); Nervous system 
disorders - Other (paralysis); Nervous system disorders - Other (polyneuropathy); Nervous 
system disorders - Other (spinal cord compression); Nervous system disorders - Other (tongue 
paralysis); Presyncope; Seizure; Somnolence; Stroke; Syncope; Tremor; Vasovagal reaction 
PSYCHIATRIC DISORDERS - Agitation; Confusion; Delirium; Depression; Personality change; 
Psychosis 
RENAL AND URINARY DISORDERS - Bladder spasm; Chronic kidney disease; Cystitis 
noninfective; Hematuria; Proteinuria; Renal and urinary disorders - Other (bilateral 
hydronephrosis); Renal and urinary disorders - Other (calculus renal); Renal and urinary 
disorders - Other (glomerular nephritis proliferative); Urinary frequency; Urinary incontinence; 
Urinary retention; Urinary tract pain 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Allergic rhinitis; Aspiration; 
Atelectasis; Bronchopulmonary hemorrhage; Bronchospasm; Epistaxis; Hiccups; Hypoxia; 
Laryngeal edema; Mediastinal hemorrhage; Pharyngolaryngeal pain; Pleural effusion; Pleuritic 
pain; Pneumonitis; Postnasal drip; Pulmonary edema; Respiratory failure; Respiratory, thoracic 
and mediastinal disorders - Other (obstructive airways disease); Respiratory, thoracic and 
mediastinal disorders - Other (pleurisy); Respiratory, thoracic and mediastinal disorders - Other 
(respiratory distress); Respiratory, thoracic and mediastinal disorders - Other (tachypnea); 
Tracheal mucositis; Tracheal stenosis; Voice alteration 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Bullous dermatitis; Dry skin; 
Erythema multiforme; Erythroderma; Hyperhidrosis; Pain of skin; Palmar-plantar 
erythrodysesthesia syndrome; Pruritus; Purpura; Rash acneiform; Skin and subcutaneous 
tissue disorders - Other (angioedema); Skin and subcutaneous tissue disorders - Other 
(leukoclastic vasculitis); Skin and subcutaneous tissue disorders - Other (Skin lesion NOS); 
Urticaria 
VASCULAR DISORDERS - Capillary leak syndrome; Flushing; Hematoma; Hypertension; 
Thromboembolic event; Vascular disorders - Other (trach site); Vasculitis 
NOTE: PS-341 (bortezomib; Velcade) 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. 


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5.3.2 
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 2.6, December 24, 20151 
 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 
 
 
CARDIAC DISORDERS 
 
 
Myocardial infarction2 
ENDOCRINE DISORDERS 
 
 Hypothyroidism 
 
GASTROINTESTINAL DISORDERS 
Constipation 
 
 
Diarrhea 
 
 
 
Nausea 
 
 
 
Pancreatitis 
 
Vomiting 
 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
 
Chills 
 
 
Edema limbs 
 
Fatigue 
 
 
 
Fever 
 
HEPATOBILIARY DISORDERS 
 
 
Hepatic failure 
IMMUNE SYSTEM DISORDERS 
 
 
Anaphylaxis 
 
 
Immune system disorders - Other (graft vs. host 
disease)3 
INFECTIONS AND INFESTATIONS 
 
Infection4 
 
INVESTIGATIONS 
 
 
Lipase increased 
 
Lymphocyte 
count 
decreased 
 
Neutrophil count decreased 
 
 
Platelet count decreased 
 
 
 
Weight loss 
 
 
White blood cell decreased 
 
Rev. 10/11, 9/13 
10/14, 7/16 


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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 
 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) 
 
 
Leukemia 
secondary 
to 
oncology 
chemotherapy5 
 
 
Myelodysplastic syndrome5 
 
 
Neoplasms benign, malignant and unspecified 
(incl cysts and polyps) - Other (tumor flare)6 
 
 
Treatment related secondary malignancy5 
NERVOUS SYSTEM DISORDERS 
 
Dizziness 
 
 
Headache 
 
 
 
Stroke2 
 
 
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 
subcutaneous 
tissue 
disorders 
- 
Other 
(pyoderma gangrenosum) 
 
 
 
Stevens-Johnson syndrome 
 
 
Toxic epidermal necrolysis 
SURGICAL AND MEDICAL PROCEDURES 
 
 
Surgical and medical procedures - Other 
(impaired stem cell mobilization)7 
VASCULAR DISORDERS 
 
Thromboembolic event8 
 
1 This 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 e-mail. 
2 Myocardial infarction and cerebrovascular accident (stroke) have been observed in multiple myeloma 
patients treated with lenalidomde and dexamethasone. 
3 Graft vs. host disease has been observed in subjects who have received lenalidomide in the setting of 
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4 Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC. 
5 There 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. 
6 Serious tumor flare reactions have been observed in patients with chronic lymphocytic leukemia (CLL) 
and lymphoma. 
7 A decrease in the number of stem cells (CD34+ cells) collected from patients treated with >4 cycles of 
lenalidomide has been reported. 
8 Significantly increased risk of deep vein thrombosis (DVT), pulmonary embolism (PE), and arterial 
thrombosis has been observed in patients with multiple myeloma receiving lenalidomide with 
dexamethasone. 
9 Gastrointestinal 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. 
10 Gastrointestinal 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. 
11 Osteonecrosis 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 developmental 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. 
Adverse events reported on Lenalidomide (CC-5013)trials, but for which there is 
insufficient evidence to suggest that there was a reasonable possibility that 
Lenalidomide (CC-5013) caused the adverse event: 
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; Palpitations; Pericarditis; Sinus bradycardia; Sinus tachycardia; 
Supraventricular tachycardia; Ventricular tachycardia 
EAR AND LABYRINTH DISORDERS - Tinnitus 
ENDOCRINE DISORDERS - Cushingoid; Hyperthyroidism 
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 


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(pale feces); Gastrointestinal hemorrhage9; Gastrointestinal obstruction10; 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 
IMMUNE SYSTEM DISORDERS - Allergic reaction; Immune system disorders - Other 
(angioedema) 
INFECTIONS AND INFESTATIONS - Infections and infestations - Other (Opportunistic infection 
associated with >=grade 2 lymphopenia) 
INJURY, POISONING AND PROCEDURAL 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 jaw11; 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 cerebral; 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 
RENAL AND URINARY DISORDERS - 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 


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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. 
 


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5.3.3 
Comprehensive Adverse Events and Potential Risks List (CAEPR) for 
Rituximab (NSC 687451) 
The Comprehensive Adverse Event and Potential Risks list (CAEPR) 
provides a single list of reported and/or potential adverse events (AE) 
associated with an agent using a uniform presentation of events by 
body system.  They are developed and continuously monitored by the 
CTEP Investigational Drug Branch (IDB).  The information listed in the 
CAEPR(s) below, as well as the other resources described in the 
'Determination of reporting requirements' part of the Adverse Event 
Reporting section in this 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. 
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) 
 
 
Febrile neutropenia 
 
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 simplex, West Nile virus) 
 


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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 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
 
Arthralgia 
 
 
Back pain 
 
 
Myalgia 
 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL 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 subcutaneous tissue disorders - 
Other (angioedema) 
 
 
 
Stevens-Johnson syndrome 
 
 
Toxic epidermal necrolysis 
 
Urticaria 
 
VASCULAR DISORDERS 
 
Flushing 
 
 
Hypertension 
 
 
Hypotension 
 


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1 This 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 e-mail. 
2 Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC. 
3 Gastrointestinal 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. 
4 Gastrointestinal perforation includes Colonic perforation, Duodenal perforation, Esophageal 
perforation, Gastric perforation, Ileal perforation, Jejunal 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 
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. 
 


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5.4 
Dose Modifications 
All toxicities should be graded according to the NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0. All appropriate treatment areas 
should have access to a copy of the CTCAE version 4.0. A copy of the CTCAE 
version 4.0 can be downloaded from the CTEP web site (http://ctep.cancer.gov). 
5.4.1 
Dose Modifications – Rituximab 
NOTE: There is no dose reduction for rituximab, only infusion rate 
adjustment or discontinuation. 
5.4.1.1 
Hypersensitivity and Infusion Reactions and Rituximab 
Infusion Rates 
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. 
Rituximab should be administered intravenously through a 
dedicated line at an initial rate of 50 mg/hr.  Rituximab 
administration schedules should be followed as per the 
standard of care at each institution. In general, if 
hypersensitivity or infusion-related events do not occur, 
escalate the infusion rate in 50 mg/hr increments every 30 
minutes, to a maximum of 300 mg/hr.  If hypersensitivity or 
infusion-related events develop, the infusion should be 
temporarily slowed or interrupted.  The patient should be 
treated according to the appropriate standard of care.  The 
infusion can be continued at one-half the previous rate 
when symptoms abate.  Subsequent rituximab infusions 
can be administered at an initial rate of 100 mg/hr, and 
increased at 30-minute intervals by 100 mg/hr increments 
to a maximum of 400 mg/hr. 
NOTE:  In addition, alternative Rituximab infusion rates 
(i.e., “rapid rituximab infusion”) can be used per 
institutional guidelines as long as the total number 
of milligrams of Rituximab is the same and that 
“rapid infusion” is not administered with the 
patients first rituximab cycle. Further, a rituximab 
infusion time should never be given over less than 
90 minutes (common infusion time for “rapid 
infusion” is 20% of the bag volume over 30 
minutes, and then 80% of the remaining bag 
volume over 60 mintues). 


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Table 3. Rituximab Infusion Rate Adjustments. 
Infusion 
Rate 
Fever 
 
 
Rigors 
 
 
Mucosal 
Congestion/ 
Edema 
 
 
Hypotension 
 
(or) 
 
(or) 
 
 
 
 
Decrease ½ >38.0ºC  
Mild 
 
Mild 
 
Mild 
Interrupt 
>39.0ºC 
 
Moderat
e 
 
Moderate 
 
Mild to Moderate 
During the rituximab infusion, the patient's vital signs (blood 
pressure, pulse, respiration, temperature) should be monitored at 
least every 15 minutes x 4 and then hourly until the infusion is 
discontinued.  Following the antibody infusion, the intravenous 
line should be maintained for medications as needed. If there are 
no complications after one hour of observation, the intravenous 
line may be discontinued. If/once the patient is transitioned to 
rapid rituximab infusion (i.e. 90 minute infusion), vital signs, 
observation and related care may be done according to 
institutional standards. 
5.4.1.2 
Cardiovascular 
Infusions should be discontinued in the event of serious or 
life-threatening cardiac arrhythmias. Patients who develop 
clinically significant arrhythmias should undergo cardiac 
monitoring during and after subsequent infusions of 
rituximab. Patients with preexisting cardiac conditions 
including arrhythmias and angina have had recurrences of 
these events during rituximab therapy and should be 
monitored throughout the infusion and immediate post-
infusion period. 
5.4.1.3 
Tumor Lysis Syndrome  
Rituximab rapidly decreases benign and malignant CD20 
positive cells.  Tumor lysis syndrome has been reported to 
occur within 12 to 24 hours after the first rituximab infusion 
in patients with high numbers of circulating malignant 
lymphocytes. Patients with high tumor burden (bulky 
lesions) may also be at risk.  Patients at risk of developing 
tumor lysis syndrome should be followed closely and 
appropriate laboratory monitoring performed.  Appropriate 
medical therapy should be provided for patients who 
develop tumor lysis syndrome.   
5.4.2 
Dose Modifications –  BR 
NOTE: Bendamustine-related infusion reactions can be treated 
according to the appropriate standard of care. 
5.4.2.1 
Bendamustine treatment modifications, ie, dose delays and 
dose reductions, are permitted for patients who are unable 
Rev. 10/11 
Rev. 2/14 


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to tolerate the protocol-specified dosing schedule. Dose 
modifications will be made according to the guidelines 
described below. All toxicity (both hematologic and 
nonhematologic) must resolve to grade 0 or 1 or the grade 
at baseline before beginning the next treatment cycle. 
Toxicity is measured using the National Cancer Institute 
Common Terminology Criteria for Adverse Events. 
5.4.2.2 
Hematologic 
At the start of each cycle, ANC must be at least 1000/mm3 
and platelet count must be at least 75000/mm3 to proceed 
with treatment (unless the patient has documented marrow 
involvement with lymphoma suppressing bloodcounts). 
Routine granulocyte-colony stimulating factor (G-CSF) 
support is not required but in the case of severe or life 
threatening (grade 3 or 4) neutropenia, G-CSF is 
recommended. It is recommended that cycles be delayed 
in 1-week increments for a maximum of 4 weeks until 
hematologic parameters allow the next cycle of BR to be 
administered (eg, ANC > 1 x 109/L, platelets > 75 x109/L). 
5.4.2.3 
Dose Reductions 
5.4.2.3.1 
If thrombocytopenia of grade 2 or higher or 
neutropenia of grade 3 or higher persists for 
2 weeks, a reduction in the dose of 
bendamustine will be required (as described 
below) and will be implemented for all 
subsequent cycles once the neutrophil and 
platelet counts return to an acceptable level. 
NOTE:  
If there is a delay of more than 28 
days 
due 
to 
bendamustine-
related toxicity, treatment with 
bendamustine 
should 
be 
discontinued. 
 
5.4.2.3.2 
Patients who experience bendamustine-
related grade 4 hematologic or grade 3 or 4 
non-hematologic toxicity at a dose of 90 
mg/m2 (except for alopecia or grade 3 
nausea or vomiting) will have their dose of 
bendamustine decreased to 75 mg/m2/day. 
Similarly, patients who experience grade 2 
or greater thrombocytopenia or neutropenia 
who require a dose delay of 2 weeks at 90 
mg/m2/day 
will 
have 
their 
dose 
of 
bendamustine decreased to 75 mg/m2/day 
in the subsequent cycle (Table 4).  
NOTE: In the case of neutropenia only, G-
CSF support should be used 
before 
considering 
a 
dose 


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reduction. 
G-CSF 
should 
be 
administered 
to 
the 
patient 
according to local and ASCO 
guidelines 
(see 
http:/www.asco.org). If neutropenia 
occurs despite G-CSF support, 
then 
a 
dose 
reduction 
of 
bendamustine 
should 
be 
implemented. The patient should 
receive further G-CSF support for 
all subsequent treatment cycles.  
5.4.2.3.3 
If a patient again experiences study-drug–
related grade 4 hematologic toxicity, grade 
3 or 4 nonhematologic toxicity, or grade 2 or 
greater thrombocytopenia or neutropenia 
(with G-CSF support) requiring another 
dose delay of 2 weeks of bendamustine at 
75 mg/m2/day, the dose will be further 
reduced to 60 mg/m2 (Table 4). 
    Table 4. Bendamustine dose reduction schedule. 
Dose 
Toxicity 
Action 
90 mg/m2 
Grade 3 or 4 non-hematologic toxicity+ 
Reduce dose to 75 mg/m2 
Grade 4 hematologic toxicity 
Reduce dose to 75 mg/m2 
Grade 2 or greater thrombocytopenia or grade 3 or higher 
neutropenia* that requires a dose delay of 2 weeks 
 
Reduce dose to 75 mg/m2 
 
75 mg/m2 
Grade 3 or 4 non-hematologic toxicity+ 
Reduce dose to 60 mg/m2 
Grade 4 hematologic toxicity 
Reduce dose to 60 mg/m2 
Grade 2 or greater thrombocytopenia or  grade 3 or higher 
neutropenia that requires a dose delay of 2 weeks 
Reduce dose to 60 mg/m2 
 
60 mg/m2 
Grade 3 or 4 non-hematologic toxicity+ 
Reduce dose to 45 mg/m2 
Grade 4 hematologic toxicity 
Reduce dose to 45 mg/m2 
Grade 2 or greater thrombocytopenia or grade 3 or higher 
neutropenia that requires a dose delay of 2 weeks 
Reduce dose to 45 mg/m2 
 
45 mg/m2 
Grade 3 or 4 non-hematologic toxicity+ 
Stop bendamustine 
Grade 4 hematologic toxicity 
Stop bendamustine 
Grade 2 or greater thrombocytopenia or grade 3 or higher 
neutropenia that requires a dose delay of 2 weeks 
Stop bendamustine 
*  In the case of neutropenia only, G-CSF support should occur before considering dose 
reduction. 
+  Due to bendamustine; and excluding grade 3 nausea/vomiting 


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5.4.3 
Dose Modifications – BVR 
5.4.3.1 
BR component 
5.4.3.1.1 
Hematologic and non-hematologic (besides 
neurotoxicity): see Section 5.4.2 above. 
5.4.3.2 
Bortezomib 
5.4.3.2.1 
Grade 4 hematologic toxicity and/or Grade 2 
or greater thrombocytopenia and/or grade 3 
or higher neutropenia that requires a dose 
delay of 2 weeks: if patient is receiving 
bendamustine at 90 mg/m2, then only 
bendamustine will be reduced as in Table 4.  
If any of these toxicities re-occur (at a 
bendamustine dose of 75 mg/m2 or lower), 
and if the toxicity returns to Grade 1 or 
better, and bortezomib is to be restarted, 
the dose must be reduced by approximately 
25% as follows (for all days): 
Dose Level 
Dosage 
0 
1.3 mg/m2 
-1 
1 mg/m2 
-2 
0.7 mg/m2 
-3 
Contact the study chair 
5.4.3.2.2 
For grade 3 or grade 4 non-hematologic 
toxicity (besides neurotoxicity- see Section 
5.4.3.2.3 and Table 5) that is considered by 
the investigator to be likely or definitely 
related to bortezomib, then drug is to be 
held. 
For 
non-hematologic 
toxicities, 
bortezomib may be held for up to 3 weeks 
until the toxicity returns to Grade 1 or better.  
If, after bortezomib has been held, the 
toxicity does not resolved as defined above, 
then the drug must be discontinued.  If the 
toxicity returns to Grade 1 or better, and 
bortezomib is to be restarted, the dose must 
be reduced by approximately 25% as follows 
(for all days): 
Dose Level 
Reduce dose to: 
1.3 mg/m2 
1 mg/m2 
1 mg/m2 
0.7 mg/m2 
0.7 mg/m2 
Contact the study chair 


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If the patient was receiving 0.7 mg/m2, the 
case should be discussed with the study 
chair. 
5.4.3.2.3 
Neurotoxicity 
Follow the table immediately below when 
assessing neurotoxicity. Bortezomib dose 
reductions apply to all days (1, 4, 8, and 11) 
dosing of this drug. All dose modification will 
be permanent and no dose re-escalations 
will be attempted. Please contact the study 
chair if uncertainties arise regarding the 
application of Tables 5 and 6 below. Please 
also see the neurotoxicity-directed quality of 
life form (FACT-GOG neurotoxicity) in the 
E2408 Forms packet.  This is an important 
tool for determining the presence and 
intensity 
of 
neuropathic 
pain 
and/or 
peripheral neuropathy from the patients’ 
perspective.  Neuropathic symptoms are 
more prominent than abnormalities on the 
clinical examination.  After the patient 
completes 
the 
neurotoxicity-direct 
questionnaire, the questionnaire should be 
reviewed to assist with the evaluation of the 
onset and intensity of peripheral neuropathy 
and other neurotoxicities that may possibly 
require intervention or dose modification. 
5.4.3.2.4 
Hepatic Impairment 
Patients with mild hepatic impairment 
(bilirubin ≤ 1.5  ULN) do not require a 
starting dose adjustment.  If a patient 
develops moderate or severe hepatic 
impairment with bilirubin ≥ Grade 2 (> 1.5 -
3.0 X ULN) while on study, the investigator 
should hold Bortezomib until the toxicity 
returns to < Grade 2. Restarting Bortezomib 
at the next lower dosed level could be 
considered at the Investigator’s discretion 
and following exclusion of Bortezomib -
induced 
liver 
impairment 
and 
careful 
consideration of liver disease due to other 
causes, such as, but not limited to, active 
infection 
and 
lymphoma-related 
liver 
disease. 
NOTE: Patients with bilirubin levels greater 
than 1.5 ULN  
(> 
1.5) 
are 
excluded 
from 
enrollment in this protocol. 


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Table 5. Dose Modification for Bortezomib-related neuropathic pain and/or 
peripheral sensory neuropathy. 
Severity of Peripheral Neuropathy 
Signs and Symptoms 
Modification of Dose and Regimen 
Grade 1 (paresthesias and/or loss of reflexes) 
without pain or loss of function 
No action 
Grade 1 with pain  
Reduce by one dose level (see Table 6) 
Grade 2 without pain (Moderate symptoms; 
limiting instrumental ADL) 
 
Hold* bortezomib therapy until toxicity improves 
to 
grade 
1 
or 
resolves. 
When 
toxicity 
improves/resolves, re-initiate with a reduction 
by 1 dose level and change treatment schedule 
to once per week (see Table 6) 
Grade 2 with pain or Grade 3 (Severe 
symptoms; limiting self care ADL) 
Hold* bortezomib therapy until toxicity improves 
to 
grade 
1 
or 
resolves. 
When 
toxicity 
improves/resolves, re-initiate with a reduction 
by two dose levels and change treatment 
schedule to once per week (see Table 6) 
Grade 4 (Life-threatening consequences; 
urgent intervention indicated) 
Discontinue bortezomib (permanently) 
ADLs = activities of daily living 
*Hold:  Interrupt bortezomib for up to 3 weeks until the toxicity returns to Grade 1 or 
resolves. 
Activities of Daily Living (ADL):  Instrumental ADL refers to preparing meals, 
shopping for groceries or clothes, using the telephone, managing money, etc.  Self 
care ADL refers to bathing, dressing and undressing, feeding self, using the toilet, 
taking medications, and not bedridden. 
Table 6. Dose level reductions of bortezomib. 
One dose level 
1.3 to 1* 
Two dose levels 
1.3 or 1* to 0.7 mg/m2/dose 
Schedule change 
Change from twice per week (days 1,4,8, and 11) to once per 
week (days 1 and 8);** 
* If the patient is receiving 1 mg/m2/dose biweekly and experiences repeat grade 1 with pain 
then patient should have schedule change to once per week. If grade 1 pain re-occurs on 
weekly dosing, then contact the Principal Investigator. 
** If patient is receiving once weekly bortezomib dosing and experiences grade 1 with pain or 
repeat grade 2 or more toxicity, contact the Principal Investigator. 
5.4.4 
Dose Modifications- Lenalidomide  
Subjects will be evaluated for adverse events at each visit with the 
revised NCI CTCAE version 4.0 used as a guide for the grading of 
severity. The dose of lenalidomide for each subject will be interrupted 
and modified following toxicity as described below. Refer to the table 
below for instructions on dose modifications and Section 5.1.4 for 


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dose reduction instructions for lenalidomide (including fertility 
instructions). 
Any missed or delayed doses of lenalidomide will not be given or 
made up. Any missed or delayed dose should be recorded in the 
patient pill diary as missed or delayed. In addition, rituximab should be 
given "on schedule" regardless of missed lenalidomide doses. 
For a patient that discontinues lenalidomide after undergoing all three 
dose  reductions, they are able to remain on-study and continue with 
rituximab  maintenance. In addition, if a patient is unable to tolerate  
lenalidomide and the treating physician discontinues lenalidomide 
prior to  undergoing all three dose reductions, they may stay on study 
and  continue with rituximab maintenance, however this must be 
discussed with the study PI. 
Table 7. Dose Modifications for Lenalidomide. 
NCI CTCAE Toxicity Grade 
Action Required 
Sustained (≥ 7 days) 
Grade 3 neutropenia or > any Grade 
3 neutropenia associated with fever 
(temperature > 38.5o C) or any Grade 
4 neutropenia 
Hold (interrupt dosing) 
Follow CBC every seven days 
If neutropenia has resolved to ≤ Grade 2 restart at next lower dose level 
Use of growth factors (filgrastim, pegfilgrastim) is permitted at the 
discretion of the investigator 
Thrombocytopenia  
≥ Grade 3 (platelet count <50,000 
cells/mm3 [50 X 109/L]) 
Hold (interrupt dosing) lenalidomide. 
Hold prophylactic anti-coagulation. 
Follow CBC weekly every seven days 
If thrombocytopenia resolves to ≤ Grade 2 restart at next lower dose level 
(and restart prophylactic anti-coagulation) 
Allergic reaction or 
hypersensitivity* 
Grade 2 
 
 
Hold (interrupt) dose. Follow at least every seven days 
Rash should resolve to ≤ grade 1 prior to starting the next cycle of 
therapy. When the toxicity resolves to < Grade 1, restart at next lower 
dose level. 
Grade 3-4 
Discontinue Lenalidomide. 
Desquamating (blistering) rash- any 
Grade  
Discontinue Lenalidomide. 
Venous thrombosis/embolism  
> Grade 3 
· 
Hold (interrupt) lenalidomide and start anticoagulation; restart 
lenalidomide at investigator’s discretion (maintain dose level). 
Omit lenalidomide for remainder of cycle. See Anticoagulation 
Consideration (Section 5.1.4.2) 
Other non-hematologic toxicity > 
Grade 3** 
· 
Hold (interrupt) lenalidomide dose.  Follow at least weekly. 
If the toxicity resolves to ≤ grade 2 prior to Day 21, restart 
lenalidomide and continue through the scheduled end of the cycle.  
Otherwise, omit for remainder of cycle.  Omitted doses are not 
made up.  For toxicity attributed to lenalidomide, reduce the 
lenalidomide dose by 1 dose level when restarting lenalidomide. 
*  These measures should be taken only for those reactions attributed to lenalidomide. 
**  See below section regarding modifications for renal insufficiency. 
Rev. 9/13 
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The next cycle of treatment may begin on the scheduled Day 1 if: 
· 
The ANC is ≥ 1,000 cells/mm3 (1.0 X 109/L); 
· 
The platelet count is ≥ 75,000 cells/mm3 (75 X 109/L); 
· 
Lenalidomide related allergic reaction or hypersensitivity not requiring 
discontinuation have resolved to ≤ Grade 1 severity; 
· 
Any other lenalidomide-related AE not requiring discontinuation has 
resolved to ≤ Grade 2 severity. 
If these conditions are not met on Day 1 of a new cycle, the subject will 
be evaluated once every seven days and a new cycle of lenalidomide will 
not be initiated until the toxicity has resolved as described above. If a new 
cycle is delayed for more than 28 days, the study chair must be notified. 
If lenalidomide dosing was halted during the previous cycle and was 
restarted with a one-level dose reduction without requiring an interruption 
for the remainder of the cycle, then that reduced dose level will be 
initiated on Day 1 of the new cycle. There will be no more than one dose 
reduction from one cycle to the next. 
5.4.4.1 
Lenalidomide Dose Reduction 
The daily oral dose of lenalidomide may be reduced 
successively by one level from the starting dose of 20 mg 
daily on Days 1-21 every 28 days. 
Table 8. Dose Reduction Steps for Adverse Events Related 
to Lenalidomide.     
Dose level 
Dosage 
0 
20 mg daily on Days 1-21, every 28 days 
Level –1 Dose 
15 mg daily on Days 1-21, every 28 days 
Level –2 Dose 
10 mg daily on Days 1-21, every 28 days 
Level –3 Dose* 
5 mg daily on Days 1-21, every 28 days 
NOTE: Once a subject’s dose has been reduced, no dose re-
escalation is permitted.      
*Subjects who cannot tolerate Dose Level –3 are to have 
lenalidomide discontinued permanently. 
5.4.4.2 
Renal insufficiency:  Lenalidomide dosing 
Patients with creatinine clearance of ≥ 60 mL/min will be 
started at lenalidomide 20mg daily on Days 1-21 of each 
28-day cycle as above. No dose adjustments are required 
for patients with CLcr >/= 60 mL/min. 
Patients with creatinine clearance of ≥ 30 mL/min but < 60 
mL/min will be started at lenalidomide 10mg daily (Dose 
modification calculated at 50% rounded down) on Days 1-
21 of each 28-day cycle (these patients could be escalated 
once to 15mg daily on Days 1-21 of each 28-day cycle if 


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they are tolerating lenalidomide well – the escalation will 
occur at the start of a cycle). For these patients who start 
on 10mg daily, de-escalation of one dose level will be 
allowed to 5mg. Further dose de-escalation will be allowed 
to 5mg every other day. Once a subject’s dose has been 
reduced, no dose re-escalation is permitted. 
Patients with creatinine clearance of < 30 mL/min by 
Cockroft-Gault formula should be started at lenalidomide 
5mg daily on Days 1-21 of each 28-day cycle (these 
patients could be escalated once to 10mg daily on Days 1-
21 of each 28-day cycle if they are tolerating lenalidomide 
well – the escalation should occur at the start of a cycle). 
For these patients who start on 5mg daily, de-escalation 
will be allowed to 5mg every other day.  Once a subject’s 
dose has been reduced, no dose re-escalation is 
permitted. 
Patients with a CLcr < 30 mL/min and those on dialysis will 
generally be excluded. 
5.5 
Supportive Care (non-HIV) 
5.5.1 
All supportive measures consistent with optimal patient care will be 
given throughout the study. 
5.5.2 
Filgrastim (Neupogen) or Pegfilgrastim (Neulasta) granulocyte colony 
stimulating factors (G-CSFs) are not recommended for routine use in 
this study. It is recommended that investigators follow the most recent 
ASCO guidelines (101). In the event of neutropenic fever, infection, 
and/or dose delay or reduction, please see Sections 5.4.2 or 5.4.3 
regarding further instructions. 
5.5.3 
Prophylactic antibiotic therapy (e.g. levofloxacin) during induction 
chemotherapy to prevent febrile neutropenia is at the discretion of the 
treating physician as discussed above (Sections 5.4.2 and 5.4.3). 
Some authorities recommend, that patients receive pneumocystis 
prophylaxis during all chemotherapy (e.g., Bactrim DS on Mondays, 
Wednesdays, and Fridays or Dapsone 50 mg orally twice daily for 
subjects allergic to Bactrim) as well as prophylaxis for oral thrush (e.g, 
fluconazole 100 mg daily or oral nystatin).  
5.5.4 
Anti-viral prophylactic therapy (e.g., acyclovir 400mg orally BID or 
valacyclovir 500mg orally QD) is strongly recommended for patients 
who are randomized to receive BVR induction therapy (i.e., Arm B).  
All other patients should be administered treatment at the discrection 
of the treatment physician, but it is recommended for patients with 
recent history of zoster or other HSV infection. 
5.6 
Supportive care therapy for HIV positive patients. 
5.6.1 
HAART (highly active anti-retroviral therapy): In general, HIV-positive 
patients who are on a stable HAART regimen should continue HAART 
while receiving chemotherapy. However, for patients who are newly 
diagnosed with HIV, it is preferable to defer starting HAART until after 
chemotherapy is completed. HAART regimens containing zidovudine 


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and stavudine should be avoided during chemotherapy due to 
concerns for overlapping toxicity with chemotherapy. In addition, the 
protease inhibitor atazanavir (Rayataz™) can cause a physiologically 
unimportant 
hyperbilirubinemia; 
however, 
in 
the 
setting 
of 
chemotherapy, some experts suggest switching that drug for another 
equally effective one. If HAART is withheld during chemotherapy, it 
should be resumed promptly after conclusion of the last cycle of 
chemotherapy. 
5.6.2 
Bactrim (one double strength tablet twice daily three days per week) 
should be given for Pneumocystis and Toxoplasmosis prophylaxis to 
HIV-positive patients during induction chemotherapy (all study arms). 
Dapsone (50 mg orally twice daily), atovaquone, or aerosolized 
pentamidine may be substituted for Pneumocystis prophylaxis in 
subjects allergic to Bactrim. Pneumocystis prophylaxis should be 
continued until the CD4 cells are over 200/mcL. 
5.6.3 
Fluconazole, 100 mg daily, should be given for antifungal prophylaxis 
for patients during induction chemotherapy (all study arms). 
Itraconazole, 200 mg daily, should be substituted for fluconazole for 
histoplasmosis prophylaxis if the CD4 count falls below 150/mcL and 
if the patient lives in an endemic area. 
5.6.4 
Anti-viral prophylactic therapy (e.g., acyclovir 400mg orally BID or 
valacyclovir 500mg orally QD) should be administered at the 
discretion of the treatment physician, but it is recommended for 
patients with recent history of zoster or other HSV infection and is 
strongly recommended for patients randomized to Induction BVR 
therapy (i.e., arm B). 
5.6.5 
Azithromycin, 1,200 mg PO, once weekly, should be given for 
prophylaxis against Mycobacterium avium complex if the CD4 count 
falls below 50/mcL.  
5.6.6 
Administration of granulocyte growth factors (filgrastim, pegfilgrastim, 
sargramostim) is recommended in HIV+ patients during induction 
chemotherapy (e.g. 5 mcg/kg subcutaneously of filgrastim daily) until 
the leukocyte count has recovered to > 1 x 109/L. 
5.7 
Duration of Therapy 
Patients will receive protocol therapy unless: 
5.7.1 
Extraordinary Medical Circumstances: If at any time the constraints of 
this protocol are detrimental to the patient's health, protocol treatment 
should be discontinued. In this event submit forms according to the 
instructions in the E2408 Forms Packet. 
5.7.2 
Patient withdraws consent. 
5.7.3 
Progressive disease. 
5.7.4 
Unacceptable toxicity. 
5.7.5 
Suspected pregnancy. 


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5.8 
Duration of Follow-up 
5.8.1 
For this protocol, all patients, including those who discontinue protocol 
therapy early, will be followed for response until progression, even if 
non-protocol therapy is initiated, and for survival for 15 years from the 
date of registration. All patients must also be followed through 
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6. 
Measurement of Effect 
Non-Hodgkins Lymphoma Response Criteria 
NOTE: These criteria are based upon the criteria from the Revised Response Criteria 
for Malignant Lymphoma (158). 
NOTE: PET-CTs will be reviewed centrally for quality assurance purpose. Please see 
Section 11.2 and Appendix VI for further details regarding QARC central 
review. 
The criteria use the following categories of response: 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, 2.1cm, 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. 
6.1 
Complete Response 
Complete disappearance of all detectable clinical evidence of disease, and 
disease-related symptoms if present prior to therapy. 
6.1.1 
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. 
6.1.2 
If the pretreatment PET scan was negative: all lymph nodes and 
extranodal masses must have regressed on CT to normal size (< 1.5 


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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. 
6.1.3 
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 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. 
6.1.4 
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. 
6.2 
Partial Response (PR) 
The designation of PR requires all of the following: 
6.2.1 
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. 
6.2.2 
No increase in the size of other nodes, liver or spleen. 
6.2.3 
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. 
No new sites of disease. 
6.3 
Stable Disease (SD) 
6.3.1 
Failing to attain the criteria needed for a PR or CR, but not fulfilling 
those for progressive disease (see below).   


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6.3.2 
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. 
6.3.3 
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. 
6.4 
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. 
6.4.1 
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. 
6.4.2 
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. 
6.4.3 
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. 
6.4.4 
Lesions should be PET positive if 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). 
6.4.5 
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 imaging 
studies or physical examination, it is found to be histologically 
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6.5 
Duration of Response 
This is measured from the documented beginning of response (CR or PR) to the 
time of relapse. This is measured in responders.  
6.6 
Survival 
Survival is defined as the date of study entry to the date of death. 
6.7 
Progression-Free Survival 
Progression-free Survival (PFS) is defined as the time from entry onto study until 
lymphoma progression or death from any cause. PFS is often considered the 
preferable endpoint in lymphoma clinical trials, especially those involving 
incurable histologic subtypes (e.g., follicular and low grade, mantle cell 
lymphoma).  PFS reflects tumor growth and, therefore, occurs prior to the 
endpoint of overall survival. In addition, PFS is not confounded by the 
administration of subsequent therapy.  Whether a prolongation of PFS represents 
direct clinical benefit or a surrogate for clinical benefit depends on the magnitude 
of the effect and the risk-benefit ratio of the therapy under investigation.  Unlike 
survival, the precise date of progression is generally unknown.  It may be defined 
as the first date of documentation of a new lesion or enlargement of a previous 
lesion, or the date of the scheduled clinic visit immediately after radiologic 
assessment has been completed.  Where there is missing information, censoring 
of the data may be defined as the last date at which progression status was 
adequately assessed or the first date of unscheduled new anti-lymphoma 
treatment. 
6.8 
Time to Progression 
Time to progression (TTP) is defined as the time from study entry until lymphoma 
progression or death due to lymphoma. In TTP, deaths from other causes are 
censored either at the time of death or at an earlier time of assessment, 
representing a random pattern of loss from the study. TTP is not as useful as 
PFS unless the majority of deaths on a study are unrelated to the lymphoma due 
to the efficacy of the treatment and/or prolonged follow-up. 
6.9 
Time to Treatment Failure 
Time to treatment failure (event-free survival) is measured from the time from 
study entry to any treatment failure including discontinuation of treatment for any 
reason, such as disease progression, toxicity, patient preference, initiation of new 
treatment without documented progression, or death.  This composite endpoint is 
generally not encouraged by regulatory agencies because it combines efficacy, 
toxicity and patient withdrawal. 
6.10 
Disease-Free Survival  
Disease-free survival is measured from the time of occurrence of disease-free 
state (e.g., the adjuvant setting following surgery or radiation therapy) or 
attainment of a complete remission) to disease recurrence or death from 
lymphoma or acute toxicity of treatment.   This definition may be complicated by 
deaths that occur during the follow-up period that are unrelated to the lymphoma 
and there is controversy as to whether such deaths should be considered as 
events or censored at the time of occurrence.  Whereas it is often possible to 


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identify those deaths related to the lymphoma, there is the potential for bias in 
the attribution of deaths. 
6.11 
Disease-Specific Survival  
Disease-specific survival (e.g., lymphoma-specific survival, cause-specific 
survival) is potentially subject to bias because the exact cause of death is not 
always easy to ascertain.  To minimize the risk of bias, the event should be 
recorded as death from lymphoma, or from toxicity from the drug. Death from 
unknown causes should be attributed to the drug. For certain trials, time to next 
lymphoma treatment may be of interest, defined as time from the end of primary 
treatment until the initiation of the next therapy. 
6.12 
Quality of Life Measurement 
6.12.1 
Quality of life materials must be submitted at the time points listed 
below. Please refer to the table below and see the E2408 Forms 
Packet. Failure to submit materials may render the patient 
unevaluable. 
6.12.2 
Hypothesis 
We hypothesize that HRQL will provide a meaningful comparison of 
the different induction and continuation therapies in this randomized 
phase III study and that HRQL data will complement the standard 
assessment of treatment-related toxicity. Please see Section 1.6 
above for more detailed background/significance and hypothesis 
discussion. 
Prospective data will be informative to clinicians and patients in 
providing descriptive data on what to expect with regard to these 
domains during and following treatment. Long-term follow-up will 
provide valuable descriptive data on patients’ HRQL as they transition 
from active treatment to survivorship. In addition, these results will be 
used to identify the most relevant endpoints for follow-up phase III 
trials, to calculate power estimates to adequately address follow-up 
HRQL questions, and to establish minimally important differences to 
evaluate clinically meaningful changes over time and between 
treatment arms. 
6.12.3 
Study Design 
We will prospectively measure HRQL (physical, functional, emotional 
and social well-being) using the Functional Assessment of Cancer 
Therapy – General (FACT-G) (97). Disease-related symptoms and 
concerns specific to lymphoma will be assessed using the FACT-
Lymphoma subscale (FACT-Lym) (97-99). The FACT-Lym used in 
this study will encompass of the parameters of the FACT-G.While 
limited research has examined HRQL among patients with NHL, 
emotional function is significantly impacted and is therefore an 
important endpoint for this trial. 
Fatigue and neurotoxicity are anticipated to be the most commonly 
experienced side effects from bortezomib and lenalidomide. 
Treatment-emergent symptoms will be assessed using the FACT-


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Fatigue subscale and neurotoxicity will be assessed using the 
FACT/GOG-Neurotoxicity subscale. 
Table 9. Quality of Life Studies. 
QOL Form 
Baseline 
Induction 
Continuation 
FACT-Lym 
and FACT-
Fatigue 
X 
At response 
assessment #1  
(prior to cycle 4) 
On day 1 (at start) of continuation;  
at 6 months of continuation; 
at 12 months of continuation; 
at 24 months (end) of continuation 
FACT/GOG 
Neurotoxicity 
X 
Prior to each 
induction cycle 
(starting at cycle 2) 
At the start of each rituximab cycle for 
the first year of continuation. Every 4 
months for the second year. 
6.12.4 
Quality of Life Studies to be Performed 
(1) FACT-Lymphoma subscale (FACT-Lym) - 42 items.   
(2) FACT-Fatigue scale - 13 items. 
(3) FACT/GOG-Neurotoxicity scale - 11 items. 
6.12.5 
Administration Instructions 
6.12.5.1 
The questionnaires must be administered at the timepoints 
listed above. The patient should be instructed to respond 
to the questionnaires in terms of his/her experience during 
the time frame specified on each questionnaire. 
6.12.5.2 
The patient should be asked to read the instructions at the 
beginning of each questionnaire and complete all the 
items. It is permissible to assist the patient with the 
completion of the questionnaires as long as the staff 
person does not influence the patient’s responses. 
6.12.5.3 
The questionnaires must be reviewed by the protocol 
nurse or research coordinator as soon as the patient 
completes them to ensure all items were marked 
appropriately. If more than one answer was marked, the 
patient should be asked to choose the answer which best 
reflects how he/she is feeling. If a question was not 
answered, the patient should be asked if he/she would like 
to answer it. The patient should always have the option to 
refuse. If the patient refuses, it should be indicated on the 
questionnaire that he/she declined to answer the item. 
6.12.5.4 
If the patient cannot complete a questionnaire, or if the 
patient refuses to complete the questionnaire, the reason 
should be noted on the Assessment Compliance Form. 
6.12.5.5 
If a patient misses an appointment on the scheduled date, 
the questionnaires may be completed by telephone on the 
appointed date or they may be completed at the time the 
Rev. 5/12 
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appointment is rescheduled. If the missed scheduled date 
is on a treatment date, the quality of life assessment will be 
done when the patient comes for the rescheduled 
treatment. 
6.12.5.6 
If a patient cannot complete the questionnaire because 
he/she is too sick, this should be documented on the 
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7. 
Study Parameters 
7.1 
Therapeutic Parameters 
1. 
Prestudy scans and x-rays used to assess all measurable or non-
measurable sites of disease must be done ≤ 6 weeks prior to 
randomization. PET scan may be ≤ 8 weeks prior to randomization. 
2. 
If the patient had a bone marrow within the previous 12 months positive for 
lymphoma then the patient does not need a repeat bone marrow performed 
(besides the correlative study bone aspirate with consent- See Section 
11.1.2). All other patients should have a restaging bone marrow biopsy and 
aspirate ≤ 8 weeks prior to registration. 
3. 
Prestudy CBC (with differential and platelet count) should be done ≤ 4 
weeks before randomization.  
4. 
All required prestudy chemistries, should be done ≤ 4 weeks before 
randomization – unless specifically required on Day 1 as per protocol. 
5. 
History & Physical, adverse events, performance status, tumor assessment 
by physical exam, FLIPI  and GELF assessment, and Co-morbidity 
assessments should be done ≤ 2 weeks before randomization. 
See Section 7.2 below regarding biologic sample submissions. 
Rev. 4/13 
Rev. 9/14 
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Table 10. Study Parameters 
 
 
 
Induction (BR or BVR) 
Continuation (rituximab or 
lenalidomide/rituximab) 
Post-Therapy 
Follow-up 
 
Parameter 
Pre-study 
Cycles1 
Restaging 
Cycles2 
Restaging 
 
 
Assignment of FLIPI scores3 
X 
 
 
 
 
 
 
Notation of GELF criteria3 
X 
 
 
 
 
 
 
History and Physical examination 
X 
Every 
cycle 
 
X 
 
X18 
 
Performance Status 
X 
Every 
cycle 
 
X 
 
X18 
 
Tumor Measurements by Physical 
Exam  
(if applicable) 
X 
Every 
cycle 
X 
X 
X 
X18 
 
CBC and Differential4 
X4 
Every 
cycle 
 
X 
 
X18 
 
Serum Chemistries (electrolytes, 
SGOT, SGPT,  total bilirubin, direct 
bilirubin,5 LDH, creatinine, glucose, 
alkaline phos, and calcium) 
X 
Every 
cycle 
 
X 
 
X18 
 
Beta-2-microglobulin 
X 
 
 
X (prior to 1st dose) 
 
 
 
Uric acid 
X 
 
 
 
 
 
Rev. 10/11 
Rev. 9/14 
Bone marrow aspirate biopsy16 
X16 
 
After cycle 66 
 
 
 
 
Pregnancy test (for women of child-
bearing potential)7 
X 
 
 
X8 
 
 
 
Hepatitis B surface antigen and 
core antibody testing 
X9 
 
 
 
 
 
Rev. 1/15 
TSH 
X 
 
 
X14 
Every 6 months 
during 
continuation and 
at completion of 
continuation 
 
 
CD4 count and HIV viral load (HIV 
+ patients only) 
X 
After cycle 
3 and 
after 6 
 
X19 
 


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Creatinine clearance 
X10 
 
 
 
 
 
Rev. 5/12 
CT Neck, Chest, Abdomen, and 
Pelvis12 
X11 
 
After cycle 3 
and after 
611,12 
After cycles 7, 13, 18, 
24 
X12,19 
X18 
Rev. 2/14 
PET/CT Scan12 
X11 
 
After cycle 3 
and after 
611,12 
 
 
 
 
Quality of life studies13 
X 
See 
Section 
6.12 
See Section 
6.12 
See Section 6.12 
See Section 6.12 
 
 
Co-morbidity assessment15 
X 
 
 
 
 
X15 
 
Registration to RevAssist17 
See section 8.4.9 
Rev. 10/11 
Biological Sample Submissions 
See Section 7.2 
1. Cycles are every 28 days. Patients may be evaluated in the office more frequently, if needed, at physician discretion.  
2. Cycles are every 28 days for all arms in continuation therapy, however patients treated in arms D and E of continuation do not need to be 
seen in clinic (or have blood tests/labs done) q 28 days unless clinically warranted.. All patients should be seen in clinic on the first cycle of 
continuation for H&P and completion of HRQL forms. Please refer to treatment schedule in Section 5.1.5. If a delay occurs in lenalidomide, 
rituximab treatment should still be continued “on time.” Any missed or delayed doses of lenalidomide should be recorded in the patient diary 
as missed or delayed. 
3. Yes/No should be entered for each criterion of GELF and FLIPI, as well as absolute calculation of FLIPI-1 and FLIPI-2. (See Section 3.1.2 
and Appendix IV). 
4. At baseline: please record the absolute lymphocyte count.  
5. Direct bilirubin is required only if total bilirubin is elevated. 
6. Repeat biopsy/core and aspirate only if positive at baseline.   Bone marrow biopsy and aspirate should also be obtained at time of relapse. 
7. Within 10-14 days prior to start of induction treatment. See Section 3.1.18 for definition of female of childbearing potential. 
8.  For patients randomized to Arm C and registered to Arm F, pregnancy tests for females of childbearing potential.  A female of childbearing 
potential (FCBP) is a sexually mature female regardless of sexual orientation or whether she has undergone a tubal ligation who: 1) has not 
undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., 
has had menses at any time in the preceding 24 consecutive months). Pregnancy tests must occur within 10 – 14 days and again within 24 
hours prior to prescribing lenalidomide (prescriptions must be filled within 7 days).  FCBP with regular or no menstruation must have a 
pregnancy test weekly for the first 28 days and then every 28 days while on therapy (including breaks in therapy); at discontinuation of 
lenalidomide and at Day 28 post the last dose of lenalidomide.  Females with irregular menstruation must have a pregnancy test weekly for 
the first 28 days and then every 14 days while on therapy (including breaks in therapy), at discontinuation of lenalidomide and at Day 14 and 
Day 28 post the last dose of lenalidomide (see Appendix VIII: Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable Birth 
Control Methods).All patients should receive the Lenalidomide Information Sheet (Appendix XIV) each time lenalidomide is dispensed. 
Rev.4/13, 
9/14 
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9.  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 who receive 
rituximab. Further, consideration should be given to treat patients with anti-viral prophylaxis (e.g., lamuvidine 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. 
10.  Calculate at baseline before induction, and then calculate again at baseline before continuation therapy starts - especially for patients 
randomized to lenalidomide therapy (see Section 5.4), and then repeated thereafter as clinically indicated. 
11. Combined PET/CT scan will be sufficient if the PET/CT is performed with intravenous and oral contrast; if PET/CT is without oral and 
intravenous contrast (it is OK to avoid IV contrast when clinical scenario dictates), then separate/dedicated CTs of 
neck/chest/abdomen/pelvis (in addition to PET/CT) must be obtained. PET/CTs and CTs will be reviewed centrally for quality assurance 
purposes. Please see Section 11.2 and Appendix VI (FDG-PET/CT and CT IMAGING) for further details regarding QARC central review 
guidelines. 
12. It is acknowledged that due to particular circumstances, there may be situations for follow-up scans that both dedicated CT scans with 
contrast and a PET/CT scans will not be able to be obtained; in this circumstance, PET/CTs are the preferred imaging modality. Notably 
however, once a patient enters complete remission, then only CT’s (chest/abdomen/pelvis) should be obtained (not both PET/CT and 
dedicated CTs). 
13. See Section 6.12 and the E2408 Forms Packet for appropriate timing and required forms. 
14. Should be drawn prior to 1st treatment. Further thyroid evaluation/testing (e.g., T3, T4, T3 uptake) to be completed as clinically indicated at 
the discretion of treating physician. 
15. See Section 9.2.3 and Appendix X for further details/methods for completion. Obtain once at baseline (pre-treatment) and then repeat once 
at the end of continuation therapy (at the end of 2 years of continuation). 
16. Bilateral bone marrow biopsies are strongly recommended, but not required.  If the patient had a bone marrow biopsy within the previous 12 
months that was positive for lymphoma, then the patient does not need a repeat bone marrow performed.  However, the correlative pre-
study study bone aspirate with consent is still recommended (See Section 7.2 and Section 11) 
17. After randomization to Arm C and registration to Arm F. Please see Section 8.4.9 for more information. 
18. Patients in follow-up will follow this schedule: 
For scans 
· 
Every 6 months if the patient is between 2 and 5 years from the study entry. 
· 
After 5 years from study entry, at physician discretion. 
For disease progression and survival 
· 
Every 6 months if the patient’s between 2 and 5 years from study enrty. 
· 
Every 12 months if the patient is between 5 and 15 years from the study entry. 
19. Refer to Section 5.1.5 for restaging schedule. 
Rev. 
10/11,
9/14 
Rev. 2/14 
Rev. 10/11,
9/14 
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7.2 
Biological Sample Submissions 
NOTE: Submitted scans and specimens must be entered and tracked via the the ECOG-ACRIN Sample Tracking 
System (STS). See Section 10.4. 
NOTE: An informed consent must be signed prior to the submission of any samples including mandatory diagnostic 
reviews, laboratory studies and/or banking. Samples for laboratory studies and/or banking should be 
submitted only from patients who have given written consent for the use of their samples for these purposes. 
 
 
Baseline 
Induction, 
Cycle 2 
Induction, 
Post -Cycle 
Three (3) 
Restaging 
Prior to  
Start of 
Continuation2 
After Twelve (12) 
Months of 
Continuation2 
End of 
Continuation2 
Relapse 
Ship to: 
 
MANDATORY for Central Review 
Rev. 1/15 
Diagnostic Tumor Biopsy6 
X 
 
 
 
 
 
 
CBPF 
(Section 10 
 
PET/CT and CT Scans3 
X 
 
X 
X7,8 
 
X 
X 
QARC 
(Section 11.1.1) 
 
Submit from patients who answer “Yes” to “I agree to participate in the laboratory research studies that are being done as part of this clinical trial.”  
 
Tumor Tissue 
Any on study biopsy5 
CBPF 
(Section 10) 
 
Peripheral Blood (red top 
tubes) 
X1 
X 
 
X 
X 
X 
 
Mayo Clinic 
Lymphoma 
Laboratory 
(Section 11.1.2) 
 
Peripheral Blood (EDTA 
purple top tubes)9 
X1 
X 
 
X 
X 
X 
 
Rev. 5/12 
Bone Marrow Aspirate 
(EDTA purple top tubes) 
X4,5,10 
 
 
X5 
 
 
 
1. 
Baseline blood should be collected after randomization, prior to treatment. Collect three (3) 10mL EDTA tubes and one (1) 10mL red 
top tube at each time point. 
2. 
Specimens may be collected at time of restaging assessments. Blood specimens may also be collected the day of but prior to the 
next administration of the study drugs, if given. 
3. 
The clinical PET/CTs and CTs performed to determine eligibility and to monitor disease are to be submitted as outlined in Section 
11.1 and Appendix VI (FDG-PET/CT and CT IMAGING) for further details regarding QARC central review guidelines. Scans will be 
reviewed centrally for quality assessment purposes. 
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4. 
Bone marrow from the pre-study assessment may be submitted prior to randomization on the day of collection. Any amount of bone 
marrow will be accepted.  However, for patients with an inaspirable bone marrow (“dry tap”), or if bone marrow has been done 
previously and the patient refuses to have another aspiration done, call Kim Henderson at (507) 284-3805 to discuss the case and 
the possibility for submitting peripheral blood only. 
5. 
Samples are to be submitted from patients who consent to participate in the laboratory research studies OR who answer “Yes” to “I 
agree to provide additional specimens for research.” 
6. 
The original tumor biopsy submitted at baseline will also be used for the optional laboratory studies outlined in Section 11 for those 
patients who have consented to participate. 
7. 
Once a patient enters complete remission, then only CT’s (chest/abdomen/pelvis) will be obtained (no further restaging PET 
scanning); if a patient is not in complete remission at the completion of induction (i.e., stable disease or partial remission), then 
restaging PET scans will be continued (see Table 10). 
8. 
After six (6) cycles. 
9. 
Draw 30mL of blood at baseline and 20mL for all other time points. 
10. Patient must sign consent before submission of bone marrow aspirate.  If submitting initial bone marrow aspirate prior to patient 
enrollment to the trial, please use the Generic Specimen Submission Form (#2981) when sending the bone marrow and label with 
patient identifiers.  Once the patient has been randomized please call Kim Henderson (507) 284-3805 with the ECOG-ACRIN patient 
sequence number and enter the information into the ECOG-ACRIN Sample Tracking System. 
 
Rev. 5/12, 9/14 
Rev. 4/13 
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8. 
Drug Formulation and Procurement 
IND Status 
When used in this protocol, bortezomib, lenalidomide and bendamustine are each 
classified as an “unapproved use of an approved agent” and by definition considered 
investigational agents. However, while it is not an indication currently approved by the 
FDA, the use of bortezomib, lenalidomide and bendamustine in this protocol is exempt 
from the requirements of an IND and described under Title 21 CFR 312.2(b). 
8.1 
Bendamustine (NSC 138783) 
For complete information, please refer to the Investigator Brochure or the 
package insert. 
8.1.1 
Other Names 
Bendamustine hydrochloride, CEP-18083), TREANDA. 
8.1.2 
Classification 
Bendamustine hydrochloride (herein bendamustine) is an alkylating 
agent, which contains a bifunctional mechlorethamine derivative, a 
benzimidazole heterocyclic ring, and a butyric acid substituent. 
8.1.3 
Mode of Action 
Mechlorethamine and its derivatives develop electrophilic alkyl groups 
and form covalent bonds with electron-rich nucleophilic moieties, 
which result in interstrand deoxyribonucleic acid (DNA) crosslinks. 
The bifunctional covalent linkage leads to cell death via several 
pathways; however, the exact mechanism of action of bendamustine 
remains unknown. 
8.1.4 
Storage and Stability 
Description of Drug Substance and Formulation 
Bendamustine (TREANDA) for injection, 100 mg/vial, is a sterile, non-
pyrogenic 
lyophilized 
product 
for 
intravenous 
administration. 
Bendamustine (TREANDA) for injection, 100 mg/vial, contains 100 mg 
of bendamustine (active ingredient) and 170 mg of mannitol. Mannitol 
is a bulking excipient which yields a physically stable and readily re-
dissolvable lyophilized product. 
Intact vials may be stored up to 250C with excursion permitted up to 
300C. Vials should be retained in the original package until time of use 
to protect from light. 
Admixture 
Stability: 
Bendamustine 
(TREANDA) 
contains 
no 
antimicrobial preservative. The admixture should be prepared as 
close as possible to the time of patient administration. 
Once diluted with either 0.9% Sodium Chloride Injection, USP, or 
2.5% Dextrose/0.45% Sodium Chloride Injection, USP, the final 
admixture is stable for 24 hours when stored refrigerated (2-8°C or 
36-47°F) or for 3 hours when stored at room temperature (15-30°C or 
59-86°F) and room light. Administration of bendamustine (TREANDA) 
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8.1.5 
Dose Specifics 
Bendamustine will be administered as a 60-minute IV infusion at a 
dose of 90 mg/m2 on days 1 and 4 of each 28-day cycle. 
8.1.6 
Dosage in Renal or Hepatic Failure 
In a population pharmacokinetic analysis of bendamustine in patients 
receiving 120 mg/m2 there was no meaningful effect of renal 
impairment (CrCL 40 - 80 mL/min, N=31) on the pharmacokinetics of 
bendamustine. Bendamustine has not been studied in patients with 
CrCL < 40 mL/min. These results are however limited, and therefore 
bendamustine should be used with caution in patients with mild or 
moderate renal impairment. Bendamustine should not be used in 
patients with CrCL < 40 mL/min. 
In a population pharmacokinetic analysis of bendamustine in patients 
receiving 120 mg/m2 there was no meaningful effect of mild (total 
bilirubin ≤ ULN, AST ≥ ULN to 2.5 x ULN, and/or ALP ≥ ULN to 5.0 x 
ULN, N=26) hepatic impairment on the pharmacokinetics of 
bendamustine. Bendamustine has not been studied in patients with 
moderate or severe hepatic impairment. These results are however 
limited, and therefore bendamustine should be used with caution in 
patients with mild hepatic impairment. Bendamustine should not be 
used in patients with moderate (AST or ALT 2.5 - 10 x ULN and total 
bilirubin 1.5 - 3 x ULN) or severe (total bilirubin > 3 x ULN) hepatic 
impairment. 
8.1.7 
Preparation 
It will be reconstituted with 20 mL of only Sterile Water for Injection, 
USP. The volume needed of the reconstituted bendamustine should 
be aseptically withdrawn for the required dose (based on 5-mg/mL 
concentration) and immediately transferred to an infusion bag of 0.9% 
Sodium Chloride Injection, USP (normal saline). As an alternative to 
0.9% Sodium Chloride Injection, USP (normal saline), an infusion bag 
of 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, may be 
considered. The resulting final concentration of bendamustine in the 
infusion bag should be within 0.2 and 0.6 mg/mL. For a dose of 
bendamustine in the 50- to 180-mg range, a 250-ml infusion bag may 
be used. For a dose of bendamustine in the 100- to 360-mg range, a 
500-ml infusion bag should be used. The reconstituted solution must 
be transferred to the infusion bag within 30 minutes of reconstitution. 
After transferring, thoroughly mix the contents of the infusion bag. The 
admixture should be a clear and colorless to slightly yellow solution. 
8.1.8 
Administration 
Drug should be administered as an IV infusion over 60 minutes. If 
medical conditions necessitate, e.g., fluid management issues or 
infusion reactions, the infusion may be given over a longer period of 
time. However, the entire infusion time should be < 120 minutes.  In–
line filters are not required for administration.Prime the infusion line 
with drug solution and accurately record infusion start and stop times 
as part of your source documentation.  Unless there are extenuating 


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circumstances, all of the drug should be administered to the patient 
with the exception of what remains in the line.  Be sure to document 
any problems you may encounter with the infusion. If for any reason 
the drug cannot be entirely administered, please measure the 
remaining volume in the infusion bad and record on your source 
documentation.  
8.1.9 
Compatibilities 
No incompatibilities are known (no data is available). 
8.1.10 
Availability 
Drug Orders: 
Initial Orders: Following submission of the required documents and 
patient randomization, a supply of Bendamustine may be ordered 
from Teva Oncology. Institutions must fax the completed E2408 
Bendamustine Drug Request Form (Appendix XIII and available on 
the ECOG Web Site) to Teva Oncology at 610-727-2030. 
Please indicate the number of vials needed on the E2408 
Bendamustine Drug Request Form (Appendix XIII).  Please note that 
vials are packaged in multiples of 10.  Each vial is equal to 100 
mg of bendamustine. 
No Starter Supplies are available for this protocol. 
Institutions should allow 3 business days for receipt of the 
Bendamustine from the date the drug request is received by Teva 
Oncology.  Shipments will be made from Teva Oncology Monday 
through Thursday for delivery onsite Tuesday through Friday. 
There will be no weekend or holiday delivery of drugs. 
Reorders: Institutions should keep in mind that shipments take 3 
business days from the date the drug request is received by Teva 
Oncology.  Reorders using the E2408 Bendamustine Drug Request 
Form (Appendix XIII) should be faxed to Teva Oncology at 610-727-
2030. Once approved by Teva Oncology, the drug will be received on 
site within 3 business days. Shipments will be made from Teva 
Oncology on Monday through Thursday for delivery onsite Tuesday 
through Friday.  Please note that vials are packaged in multiples 
of 10. Each vial is equal to 100 mg of bendamustine. 
There will be no weekend or holiday delivery of drugs. 
Drug Inventory Records: 
Investigational Product Records at Investigational Site(s):It is the 
responsibility of the Investigator to ensure that a current record of 
investigational product disposition is maintained at each study site 
where investigational product is inventoried and disposed. Records or 
logs must comply with applicable regulations and guidelines. 
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Drug Destruction and Return: 
At the completion of the patient’s treatment at your institution, all 
unused drugs, partially used, or empty containers must be destroyed 
at the site according to the institution’s policy for drug destruction. 
Please maintain appropriate records of the disposal, including dates 
and quantities. Sites are required to complete the Certificate of Drug 
Destruction of Clinical Trials located in Appendix VII – Bendamustine 
Reconciliation. A copy of this form should be faxed to Teva Oncology 
at 610-756-2030. 
8.1.11 
Side Effects 
The adverse events specified below are also likely to be of clinical 
importance and may result in bendamustine dose delays or dose 
reductions 
· 
Infection and pneumonia: Infection, including pneumonia and 
sepsis, has been reported and, in rare cases, infection has been 
associated with hospitalization, septic shock, and death. 
Patients 
with 
myelosuppression 
following 
bendamustine 
treatment are susceptible to infections and should be advised to 
contact a physician if they have symptoms or signs of infection, 
including fever or respiratory symptoms. 
· 
Infusion reactions and anaphylaxis: Infusion reactions with 
bendamustine have occurred commonly in clinical studies with 
symptoms that are generally mild and include fever, chills, 
pruritus, and rash. In rare instances, severe infusion reactions, 
described as anaphylactic and anaphylactoid reactions, have 
occurred, particularly in the second and subsequent cycles of 
therapy. Patients should be asked about symptoms suggestive 
of infusion reactions after their first cycle of therapy. Measures 
to 
prevent 
severe 
reactions, 
including 
antihistamines, 
antipyretics, and corticosteroids should be considered in 
subsequent cycles in patients who have previously experienced 
infusion reactions. 
· 
Tumor lysis syndrome: Tumor lysis syndrome has been 
reported with bendamustine, with onset typically within the first 
treatment cycle. Tumor lysis syndrome may lead to acute renal 
failure and death without appropriate medical intervention. 
Preventive measures include maintaining adequate volume 
status, close monitoring of blood chemistry (particularly 
potassium and uric acid levels), and the use of allopurinol during 
the first 1 to 2 weeks of bendamustine treatment. 
· 
Skin reactions: Skin reactions have been reported with the use 
of bendamustine, including non-specific rash, toxic skin 
reactions, and bullous exanthema. The relationship of skin 
reactions to bendamustine administration is often unclear as 
bendamustine is frequently administered with other anti-cancer 
therapies. A case of fatal TEN has been reported in 1 patient 
treated with a combination of bendamustine and rituximab. The 
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TEN was considered possibly related to either agent. The 
relationship of this adverse event to bendamustine remains 
uncertain as TEN has also been reported with single-agent 
rituximab. When skin reactions occur, they may be progressive 
and increase in severity with further treatment. If skin reactions 
are severe or progressive, bendamustine should be withheld or 
discontinued. 
· 
Other 
malignancies: 
Development 
of 
premalignant 
and 
malignant disorders following treatment with bendamustine has 
been 
reported. 
The 
reports 
are 
limited 
and 
included 
development of myelodysplastic syndromes, myeloproliferative 
disorders, acute myeloid leukemia, and bronchial carcinoma. 
Because of confounding effects of other previous chemotherapy 
in these patients, the relationship to bendamustine could not be 
determined. 
8.1.12 
Drug Interactions 
8.1.12.1 
Bendamustine is a substrate for the cytochrome 
P450(CYP) 1A2 isoenzyme. 
8.1.12.1.1 
Bendamustine is metabolized to minimally 
active metabolites by CYP1A2. Concurrent 
administration of a CYP1A2 inhibitor such 
as atazanavir, cimetidine, ciprofloxacin, 
fluvoxamine, 
mexiletine, 
tacrine, 
thiabendazole, zileuton, norfloxacin, and/or 
ethinyl 
estradiol 
may 
increase 
bendamustine concentrations in plasma. 
Caution should be exercised, or alternative 
treatments 
considered, 
when 
coadministering 
bendamustine 
with 
a 
CYP1A2 inhibitor. 
8.1.12.1.2 
Bendamustine is metabolized to minimally 
active metabolites by CYP1A2. Concurrent 
administration of a CYP1A2 inducer such as 
barbiturates, 
carbamazepine, 
and/or 
rifampin 
may 
cause 
a 
decrease 
in 
bendamustine plasma concentrations and a 
potential decrease in cytotoxicity. The 
parent compounds are believed to be 
primarily responsible for the cytotoxicity of 
this agent. Caution should be exercised, or 
alternative treatments considered, when 
coadministering 
bendamustine 
with 
a 
CYP1A2 inducer. 


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8.1.12.1.3 
Bendamustine is metabolized to minimally 
active metabolites by CYP1A2. Smoking 
tobacco 
has 
been 
shown 
to 
induce 
CYP1A2, and may cause a decrease in 
bendamustine plasma concentrations and a 
potential decrease in cytotoxicity. The 
parent compound is believed to be primarily 
responsible for the cytotoxicity of this agent. 
Caution should be exercised, or smoking 
cessation considered, when coadministering 
bendamustine with a CYP1A2 inducer. 
8.1.13 
Nursing /Patient Implications 
1.  Monitor CBC, platelet count. Advise patients of increased risk of 
infection with absolute neutrophil count less than 500 cells/mm³ 
and increased risk of bleeding with platelet counts less than 
20,000 cells/ mm³. Advise patients to call the clinic if they develop 
a fever above 101ºF or notice any easy bruising, petechiae 
(pinpoint red spots on skin), or prolonged bleeding. 
2.  Advise patient of possible alopecia, although this is very 
uncommon with bendamustine therapy. 
3.  Assess hydration and fluid balance. Patients should be 
encouraged to have at least 1 liter of fluids per day for 72 hours 
after administration.  
4.  Consider premedication with with antiemetics. 
5.  Observe for possible phlebitis at injection site. 
6.  Administer antiemetics as indicated. 
8.1.14 
References 
Bertoni F, Zucca E. Bendamustine in lymphomas: More to combine? 
Leukemia & Lymphoma 2007;48(7):1264-6. 
Chow KU, Sommerlad WD, Boehrer S, Schneider B, Seipelt G, 
Rummel MJ, et al. Anti- CD20 antibody (IDEC-C2B8, rituximab) 
enhances efficacy of cytotoxic drugs on neoplastic lymphocytes in 
vitro: role of cytokines, complement, and caspases. Haematologica 
2002;87(1):33-43. 
Friedberg J, Cohen P, Chen L, Robinson K, Forero-Torres A, La 
Casce A, et al. Bendamustine in patients with rituximab-refractory 
indolent and transformed non- Hodgkin’s lymphoma: Results form a 
Phase II multicenter, single-agent study. J Clin Oncol 2008;26(2):204-
10. 
Robinson K, Williams M, Cohen P, Tulpule A, van der Jagt R, Herst J, 
et al. Phase II multicenter study of bendamustine plus rituximab in 
patients with relapsed indolent Bcell and mantle cell non-Hodgkin's 
lymphoma. J CLin Oncol [serial online] 2008;17.001v1:[Epub]. 
Rummel MJ, Al-Batran SE, Kim SZ, Welslau M, Hecker R, Kofahl-


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Krause D, et al. Bendamustine plus rituximab is effective and has a 
favorable toxicity profile in the treatment of mantle cell and low-grade 
non-Hodgkin's lymphoma. J Clin Oncol 2005;23(15):3383-9. 
8.2 
Rituximab  
8.2.1 
Other Names 
IDEC-C2B8, Chimeric anti-CD20 monoclonal antibody, Rituxan. 
8.2.2 
Classification 
Antibody. 
8.2.3 
Mode of Action 
Rituximab is a chimeric murine/human gamma 1 kappa monoclonal 
antibody (Chinese hamster ovary [CHO] transfectoma). It recognizes 
the CD20 antigen expressed on normal B cells and most malignant B-
cell lymphomas. It binds with high affinity to CD20-positive cells, 
performs human effector functions in vitro, and depletes B cells in 
vivo. The Fab domain of rituximab binds to the CD20 antigen on B-
lymphocytes and the Fc domain recruits immune effector functions to 
mediate Bcell lysis in vitro. The biological effect is manifested by B-
cell depletion in peripheral blood, lymph nodes, and bone marrow. 
8.2.4 
Storage And Stability 
Intact vials of rituximab are stored at refrigerated temperatures of 2 
degrees to 8 degrees Celsius (36 degrees to 46 degrees Fahrenheit). 
Protect vials from direct sunlight. Once diluted to a concentration of 1 
to 4 mg/mL in polyvinylchloride or polyolefin IV bags containing 
normal saline or 5% dextrose, the product is stable for up to 24 hours 
at 2 degrees to 8 degrees Celsius, and at room temperature for an 
additional 12 hours after refrigeration (for a maximum period of 36 
hours) if protected from light. 
8.2.5 
Dose Specifics 
Rituxumab will be administered at 375 mg/m² intravenously 
throughout each aspect of this trial (induction and continuation). 
8.2.6 
Preparation 
Withdraw the necessary amount of rituximab and dilute to a final 
concentration of 1 to 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. 
8.2.7 
Administration 
Rituximab is administered intravenously. An in-line filter is not 
required. The initial rate is 50 mg/hr for the first hour. If no toxicity is 
seen, the rate may be escalated gradually in 50 mg/hour increments 
at 30-minute intervals to a maximum of 300mg/hr. If the first dose is 
well tolerated, the initial rate for subsequent dose is 100mg/hr, 


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increased gradually in 100 mg/hr increments at 30-minute intervals, 
not to exceed 400 mg/hr. If the patient experiences fever and rigors, 
the antibody infusion is discontinued. The severity of the side effects 
should be evaluated. If the symptoms improve, the infusion is 
continued initially at one-half the previous rate. Following the antibody 
infusion, the intravenous line should be maintained for medications as 
needed. If there are no complications after one hour of observation, 
the intravenous line may be discontinued. Oral pre-medication (2 
tablets, 650 to 1000 mg, of acetaminophen and 25 to 50 mg 
diphenhydramine) will be administered 30 to 60 minutes prior to 
starting each infusion of rituximab. The patient should be treated 
according to the best available local practices and procedures. In 
patients with detectable circulating lymphoma cells, it is strongly 
advised that the initial infusion rate be reduced to 25 mg/hr; these 
patients may experience more frequent and severe transient fever 
and rigors, shortness of breath, and hypotension. 
NOTE:  In addition, alternative rituximab infusion rates (i.e., “rapid 
rituximab infusion”) can be used per institutional guidelines 
as long as the total number of milligrams of rituximab is the 
same and that “rapid infusion” is not administered with the 
patients first rituximab cycle. Further, a rituximab infusion 
time should never be given over less than 90 minutes 
(common infusion time for “rapid infusion” is 20% of the bag 
volume over 30 minutes, and then 80% of the remaining bag 
volume over 60 mintues). 
8.2.7.1 
Hypersensitivity and Infusion Reactions  
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. 
Rituximab should be administered intravenously through a 
dedicated line at an initial rate of 50 mg/hr.  If 
hypersensitivity or infusion-related events do not occur, 
escalate the infusion rate in 50 mg/hr increments every 30 
minutes, to a maximum of 300 mg/hr. If hypersensitivity or 
infusion-related events develop, the infusion should be 
temporarily slowed or interrupted.  The patient should be 
treated according to the appropriate standard of care. The 
infusion can be continued at one-half the previous rate 
when symptoms abate. Subsequent rituximab infusions 
can be administered at an initial rate of 100 mg/hr, and 
increased at 30-minute intervals by 100 mg/hr increments 
to a maximum of 400 mg/hr. 


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Rituximab Infusion Rate Adjustments 
Infusion  
Rate 
Fever 
 
 
Rigors 
 
 
Mucosal 
Congestion/ 
Edema 
 
 
Hypotension 
 
(or) 
 
(or) 
 
 
 
 
Decrease ½ >38.0ºC 
 
Mild 
 
Mild 
 
Mild 
Interrupt 
>39.0ºC 
 
Moderat
e 
 
Moderate 
 
Mild to Moderate 
During the rituximab infusion, the patient's vital signs 
(blood pressure, pulse, respiration, temperature) should be 
monitored at least every 15 minutes x 4 and then hourly 
until the infusion is discontinued.  Following the antibody 
infusion, the intravenous line should be maintained for 
medications as needed. If there are no complications after 
one hour of observation, the intravenous line may be 
discontinued. 
8.2.7.2 
Cardiovascular 
Infusions should be discontinued in the event of serious or 
life threatening cardiac arrhythmias. Patients who develop 
clinically significant arrhythmias should undergo cardiac 
monitoring during and after subsequent infusions of 
rituximab. Patients with preexisting cardiac conditions 
including arrhythmias and angina have had recurrences of 
these events during rituximab therapy and should be 
monitored throughout the infusion and immediate post-
infusion period. 
8.2.7.3 
Tumor Lysis Syndrome   
Rituximab rapidly decreases benign and malignant CD20 
positive cells.  Tumor lysis syndrome has been reported to 
occur within 12 to 24 hours after the first rituximab infusion 
in patients with high numbers of circulating malignant 
lymphocytes. Patients with high tumor burden (bulky 
lesions) may also be at risk.  Patients at risk of developing 
tumor lysis syndrome should be followed closely and 
appropriate laboratory monitoring performed. Appropriate 
medical therapy should be provided for patients who are at 
risk for, or who develop, tumor lysis syndrome. 
8.2.8 
Compatibility/Incompatibilities 
Do not mix or dilute rituximab with other drugs. No incompatibilities 
between rituximab and polyvinylchloride or polyethylene bags have 
been observed. 
8.2.9 
Availability 
Commercially available: Preservative-free injection 10mg/mL, in 10 
and 50 mL single-unit vials. 


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Please see Package Insert for further information. 
8.2.10 
Side Effects 
Please refer to the CAEPR in Section 5.3.3. 
8.2.11 
Nursing /Patient Implications 
1.  Monitor blood pressure, pulse, respiration, and temperature every 
15 minutes x 4 or until stable and then hourly until the infusion is 
discontinued. 
2.  Have epinephrine for subcutaneous injections, diphenhydramine 
for intravenous injection, and resuscitation equipment for 
emergency management of anaphylactoid reactions available. 
3.  Monitor and alter infusion rates in the presence of toxicities. 
4. 
Carriers of hepatitis B virus should be closely monitored for 
clinical and laboratory signs of active HBV infection and for signs 
of hepatitis throughout study participation. 
5. 
Due to the risks of bowel obstruction and bowel perforation, 
patients should be monitored for complaints of abdominal pain, 
especially early in the course of treatment. 
6. 
Patients with concurrent RA should be monitored throughout the 
infusion and rituximab ahould be discontinued in the event of a 
serious or life-threatening cardiac event. 
Rituximab shows no significant effect on bone marrow reserve and no 
apparent increased rate of infections in heavily pretreated, relapsed 
lymphoma patients. Prophylaxis for Tumor Lysis Syndrome (TLS) 
should be used in patients with bulky tumor masses (> 10cm). 
Patients should be provided IV hydration and administered allopurinol. 
Precautionary hospitalization should be made available for patients 
who experience severe infusional symptoms which do not resolve 
after discontinuation or completion of the infusion. Hospitalization is 
not mandated for these patients. This will be left to the discretion of 
the investigator. It is unlikely that TLS will be seen in this study of 
stages 1 and 2 diffuse large cell disease. 
8.2.12 
References 
Product Information: rituximab. IDEC Corporation, December, 1998. 
Reff ME et al. Depletion of B cell in vivo by a chimeric mouse human 
monoclonal antibody to CD20. Blood 1994; 83:435-45. 
Demidem A et al. Chimeric anti-CD20 antibody (IDEC-C2B8) is 
apoptic and sensitizes drug resistant human B cell lymphomas and 
AIDS related lymphomas to the cytotoxic effect of CDDP, VP-16, and 
toxins. FASEB 1995; J9:A206. 
Maloney DG et al. Phase I clinical trial using escalating single dose 
infusion of chimeric anti-CD20 monoclonal antibody (IDEC-C2D8) in 
patients with recurrent B-cell Lymphoma. Blood 1993; 82(Suppl 
1):445a. 


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Maloney DG et al. Initial report in a phase I/II multiple dose clinical 
trial of IDEC-C2B8 (chimeric anti-CD20) in relapsed B-cell lymphoma. 
Proc Am Soc Clin Oncol 1994; 13:993. 
8.3 
Bortezomib (NSC 681239) 
For complete information, please refer to the Investigator Brochure or the 
package insert. 
8.3.1 
Chemical Name or Amino Acid Sequence  
N-Pyrazinecarbonyl-L-phenylalanine-L-leucine boronic acid 
8.3.2 
Other Names  
MLN341, LDP-341, Velcade®, bortezomib, PS-341 
8.3.3 
Classification  
Proteasome Inhibitor 
8.3.4 
CAS Registry Number  
179324-69-7 
8.3.5 
Molecular Formula  
C19H25BN4O4 
8.3.6 
Mechanism of Action  
Inhibitors of the 26S proteasome act through multiple mechanisms to 
suppress tumor survival pathways, arrest tumor growth, tumor spread, 
and angiogenesis. By inhibiting the proteasome, bortezomib affects a 
combination of cellular regulatory mechanisms thereby providing a 
novel therapeutic approach to cancer treatment. This multiple 
mechanistic approach potentially represents a more effective 
anticancer strategy compared to the antitumor activity afforded by 
conventional chemotherapy. The mechanisms of anti-tumor activity 
that have been established for bortezomib involve many pathways 
thought to be integral to cancer treatment strategies. The following 
observations were made in in vitro and in vivo experiments:  
· 
Directly induces apoptosis of tumor cells. 
· 
Inhibits activation of NF-ΚB in cells and in tumor 
microenvironment. 
· 
Reduces adherence of myeloma cells to bone marrow stromal 
cells. 
· 
Blocks production and intracellular signaling of IL-6 in myeloma 
cells. 
Blocks production and expression of pro-angiogenic mediators. 
· 
Overcomes defects in apoptotic regulators, such as Bcl-2 
overexpression and alterations (i.e., mutations) in tumor 
suppressor p53 and loss of Apaf-1. 


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· 
In MM, bortezomib is directly cytotoxic to myeloma cells and also 
modulates the micro-environment via inhibition of NF-KB. 
8.3.7 
How Supplied 
Drug Orders: 
Drug is available in sterile, single use vials containing 3.5 mg of 
bortezomib. Please refer to Section 8.3.8 for instructions on preparing 
the drug for injection. 
Initial Orders: Following submission of the required documents and 
patient randomization to Arm B, a supply of Bortezomib may be 
ordered from UVI, Inc. Institutions must electronically submit the 
completed E2408 Bortezomib Drug Request Form (Appendix XII and 
available 
on 
the 
ECOG 
Web 
Site) 
to 
UVI, 
Inc 
at 
mdubois@uintavision.com. 
When ordering Bortezomib for Arm B, please see below for the 
recommended time table for drug requests. A total of 2 shipments are 
recommended for patients on Arm B. Recommended time points for 
drug requests are as follows: 
Shipment # 
Patient Treatment Time Point 
1 
Cycles 1-3 
2 
Cycles 4-6 
Please indicate the number of vials needed on the E2408 Bortezomib 
Drug Request Form (Appendix XII).  NOTE: A supply of individual 
vials of bortezomib is currently available for distribution through UVI, 
Inc. Once this supply is depleted, vials of bortezomib must be ordered 
in multiples of 4. 
Institutions should allow 3 business days for receipt of the Bortezomib 
from the date the drug request is received by UVI, Inc. Shipments will 
be made from UVI, Inc. Drug orders received by 2PM EST Monday 
through Thursday will be processed for shipment that day. Approved 
orders will be delivered onsite Tuesday through Friday.   
There will be no weekend or holiday delivery of drugs. 
Reorders: See table above for recommended time points for 
submitting drug requests for patients on Arm B. Institutions should 
keep in mind that shipments take 3 business days from the date the 
drug request is received by UVI, Inc. Reorders using the E2408 
Bortezomib Drug Request Form (Appendix XII) should be emailed to 
UVI, Inc, at mdubois@uintavision.com. NOTE: A supply of individual 
vials of bortezomib is currently available for distribution through UVI, 
Inc. Once this supply is depleted, vials of bortezomib must be ordered 
in multiples of 4. Once approved by UVI, Inc, the drug will be received 
on site within 3 business days. Shipments will be made from UVI, Inc. 
Drug orders received by 2PM EST Monday through Thursday will be 
processed for shipment that day. Approved orders will be delivered 
onsite Tuesday through Friday. 
Rev. 12/10 
Rev. 12/10 
Rev. 12/10 


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There will be no weekend or holiday delivery of drugs. 
Drug Inventory Records: 
Investigational Product Records at Investigational Site(s):It is the 
responsibility of the Investigator to ensure that a current record of 
investigational product disposition is maintained at each study site 
where investigational product is inventoried and disposed. Records or 
logs must comply with applicable regulations and guidelines. 
Drug Destruction and Return: 
All unused bortezomib must be returned to Millennium.  Sites are 
advised to fax a completed E2408 Clinical Trial Material Return 
Request Form (Appendix XII, page 2) to 1-866-422-4797. Millennium 
will provide a call tag for free pick up of the bortezomib to be returned, 
as well as instructions on preparing the package for pick up. 
Please maintain appropriate records of the return, including dates and 
quantities. 
8.3.8 
Preparation  
INTRAVENOUS 
AND 
SUBCUTANEOUS 
ROUTE 
OF 
ADMINISTRATION 
HAVE 
DIFFERENT 
RECONSTITUTED 
CONCENTRATIONS. CAUTION SHOULD BE USED WHEN 
CALCULATING THE VOLUME TO BE ADMINISTERED. 
INTRAVENOUS: Drug is available in sterile, single use vials 
containing 3.5 mg of bortezomib.  Each vial of bortezomib for Injection 
should be reconstituted under a laminar flow biological cabinet (hood) 
within eight hours before dosing with 3.5 mL of normal (0.9%) saline, 
Sodium Chloride Injection USP, so that the reconstituted solution 
contains bortezomib at a concentration of 1 mg/mL.  Prior to 
reconstitution the vials should remain in the cartons to protect them 
from light.  Dissolution is completed in approximately 10 seconds.  
The reconstituted solution is clear and colorless, with a final pH of 5 to 
6.  Reconstituted bortezomib should be administered promptly and in 
no case more than 8 hours after reconstitution.  All materials that have 
been used for preparation should be disposed of according to 
standard practices.  A log must be kept of all disposed materials. 
SUBCUTANEOUS: Drug is available in sterile, single use vials 
containing 3.5 mg of VELCADE.  Each vial of VELCADE for Injection 
should be reconstituted under a laminar flow biological cabinet (hood) 
within eight hours before dosing with 1.4 mL of normal (0.9%) saline, 
Sodium Chloride Injection USP, so that the reconstituted solution 
contains VELCADE at a concentration of 2.5 mg/mL for subcutaneous 
administration. 
8.3.9 
Storage  
Vials containing lyophilized bortezomib for Injection should be stored 
according to the label requirements.  For the United States, store at 
USP Controlled Room Temperature which is 25ºC (77ºF); excursions 
permitted from 15 to 30ºC (59 to 86ºF).  For Europe, do not store 
above 30ºC (86ºF).  To date, stability data indicate that the lyophilized 
Rev. 4/13 


ECOG-ACRIN 
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drug product is stable for at least 18 months when stored under the 
recommended conditions. Stability studies are ongoing, and 
Millennium Pharmaceuticals, Inc. will notify the investigator should this 
information be revised during the conduct of the study. 
Bortezomib is cytotoxic.  As with all cytotoxic drugs, caution is 
required when preparing and handling bortezomib solutions.  
Cytotoxic drugs should only be handled by staff specially trained in 
the safe handling of such preparations. The use of gloves and other 
appropriate protective clothing is recommended.  In case of skin 
contact, wash the affected area immediately and thoroughly with soap 
and water for at least 15 minutes.  If product contacts eye, 
immediately flush eye thoroughly with water for at least 15 minutes.  
Always contact a physician after any form of body contact. All 
materials that have been used for preparation should be disposed of 
according to standard practices. A log must be kept of all disposed 
materials. 
8.3.10 
Dose Specifics  
Bortezomib will be given at a dose of 1.3 mg/m² on days 1, 4, 8, and 
11 of each cycle for patients randomized to receive BVR induction.  
Dose escalation is not allowed in any patient, and there must be at 
least 72 hours between each dose of bortezomib.  
8.3.11 
Route of Administration  
Intravenous OR Subcutaneous 
8.3.12 
Method of Administration 
For intravenous administration: IV push over 3-5 seconds 
For subcutaneous administration: The drug quantity contained in one 
vial (3.5 mg) may exceed the usual dose required.  Caution should be 
used in calculating the dose to prevent overdose.  When administered 
subcutaneously, sites for each injection (thigh or abdomen) should be 
rotated as noted in the below diagram.   
New injections should be given at least one inch from an old site and 
never into areas where the site is tender, bruised, erythematous, or 
indurated. If local injection site reactions occur following VELCADE 
administration subcutaneously, a less concentrated VELCADE 
solution (1 mg/mL instead of 2.5 mg/mL) may be administered 
subcutaneously. Alternatively, the IV route of administration should be 
considered.  
In clinical trials of VELCADE IV, local skin irritation was reported in 
5% of patients, but extravasation of VELCADE was not associated 
with tissue damage. In a clinical trial of subcutaneous VELCADE, a 
local reaction was reported in 6% of patients as an adverse event, 
mostly redness. 
Rev. 4/13 
Rev. 4/13 


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7
SC injection site rotation
Within the same cycle
Injections at the same site 
should be avoided
Alternate between
– right and left abdomen
– upper and lower quadrant
or between
– right and left thigh
– proximal and distal sites
1
2
3
4
5
6
7
8
L
R
 
8.3.13 
Incompatibilities  
Bortezomib is metabolized by cytochrome P-450 CYP3A4 and 
CYP2D6 and may interact with other drugs which are either inducers 
or inhibitors of these isoenzymes. Examples of enzyme-inducing 
agents - phenytoin, carbamazepine, phenobarbital, rifampin and 
rifabutin - may decrease serum concentrations of bortezomib, thereby 
diminishing the therapeutic efficacy. Enzyme-inhibiting drugs such as 
erthromycin, clarithromycin, ketoconazole, itraconazole, voriconazole, 
fluconazole, diltiazem and cyclosporine may increase serum 
concentrations of bortezomib, thereby increasing the risk of toxicity. 
Specialized references should be consulted when attempting to 
predict drug interactions. To date, there are no clinical studies to 
address drug interactions with bortezomib. 
8.3.14 
Special Handling  
Shelf life surveillance of the intact vials is ongoing. The solution as 
reconstituted is stable for 43 hours at room temperature. 
CAUTION: The single-use lyophilized dosage form contains no 
antibacterial preservatives. Therefore, it is advised that the 
reconstituted product be discarded 8 hours after initial entry. 
8.3.15 
Side Effects  
Please refer to the CAEPR in Section 5.3.1. 
8.3.16 
Nursing/Patient Implications  
Patients and nurses should share side-effects with treating clinician so 
they can be treated if appropriate.  
1. 
Monitor for signs of myelosuppression such as infection, bleeding 
or shortness of breath. 
2.  Evaluate for gastrointestinal toxicity providing antiemetics as 
appropriate and monitor bowel habits. 


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3.  Counsel the patient regarding the risk of peripheral neuropathy 
and that it is likely to be dose-related. Patients who have received 
neurotoxic chemotherapy in the past (e.g. Vinca alkaloids, 
taxanes, etc.) may be at higher risk for this complication.  
4.  Have patient promptly report any vision changes. 
8.3.17 
References  
Bortezomib Investigator Drug Brochure. Millennium Pharmaceuticals. 
Version 13. 
Richardson P, Barlogie B, Berenson J, et al. A Phase II multicenter 
study of the proteasome inhibitor bortezomib (Velcade, formerly 
PS341) in multiple myeloma patients with relapsed/refractory disease. 
Proc Am Soc Hematology 2002 #385. 
Chris Fausel, Pharm.D. 317-278-3402 
8.4 
Lenalidomide (NSC 703813) 
For complete information, please refer to the Investigator Brochure or the 
package insert. 
8.4.1 
Other names 
IMiDTM compound CC-5013, Revlimid® (formerly RevimidTM ) 
8.4.2 
Classification 
Immunomodulatory drug  
8.4.3 
Mode of Action 
Lenalidomide, a Thalidomide analog is an immunomodulatory agent 
with a spectrum of activity that is not fully characterized.  In vitro, it 
inhibits secretion of the pro-inflammatory cytokines TNF-α, IL-1β, and 
IL-6 and increases secretion of the anti-inflammatory cytokine IL-10.  It 
also induces T-cell proliferation, IL-2 and IFN-γ production in vitro. 
8.4.4 
Storage and Stability 
How Supplied: Lenalidomide is supplied as 5 mg, 10 mg, or 15 mg 
hard gelatin capsules for oral administration in tamper evident, child-
resistant, opaque, high density polyethylene (HDPE) bottles with 
HDPE caps. Bottles will contain a sufficient number of capsules for 
one cycle of dosing.  
The capsules also contain anhydrous lactose, microcrystalline 
cellulose, croscarmellose sodium, and magnesium stearate.  
Storage: 
The capsules should be stored at room temperature (15-
30°C) away from moisture and direct sunlight, and 
protected from excessive heat and cold. 
Stability: Shelf life surveillance of the intact containers is on-going. 
The intact bottles of 5 mg, 10 mg, and 15 mg capsules are 
stable for at least 36 months when stored at controlled room 
temperature (15-30°C). 


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8.4.5 
Dose Specifics 
Patients will receive lenalidomide at 20mg orally on days 1 through 21 
on 28 day cycles (i.e., days 22 to 28 to stop/not take lenalidomide) 
during continuation therapy. Only enough Lenalidomide for 1 cycle of 
therapy may be provided to the patient each cycle.  Dose reductions 
(for adverse events) are discussed in Section 5.4.4.1 and Table 8). 
Patients with creatinine clearance of ≥ 30 mL/min but < 60 mL/min 
should be started at lenalidomide 10mg daily on Days 1-21 of each 
28-day cycle (these patients could be escalated once to 15mg daily 
on Days 1-21 of each 28-day cycle if they are tolerating lenalidomide 
well – the escalation should occur at the start of a cycle).  For these 
patients who start on 10mg daily, de-escalation will be allowed to 5mg 
(dose level -1), and then 5mg every other day (dose level -2).  Once a 
subject’s dose has been reduced, no dose re-escalation is permitted. 
8.4.6 
Patients with creatinine clearance of < 30 mL/min by Cockroft-Gault 
formula should be started at lenalidomide 5mg daily on Days 1-21 of 
each 28-day cycle (these patients could be escalated once to 10mg 
daily on Days 1-21 of each 28-day cycle if they are tolerating 
lenalidomide well – the escalation should occur at the start of a 
cycle).  For these patients who start on 5mg daily, de-escalation will 
be allowed to 5mg every other day (dose level -1).  Once a subject’s 
dose has been reduced, no dose re-escalation is permitted. 
8.4.7 
Route of Administration 
Oral.  Clinical studies have shown that lenalidomide administration 
coincident with food intake appears to delay absorption to some degree, 
although the extent of absorption is not altered.  Therefore, lenalidomide 
can be taken with or without food. 
8.4.8 
Potential Drug Interactions 
Periodic monitoring of digoxin levels is recommended during 
coadministration with lenalidomide.  Digoxin levels were slightly higher 
when digoxin was administered with lenalidomide in a clinical study.  
There was no effect on lenalidomide pharmacokinetics.  
Warfarin and lenalidomide may be co-administered without additional 
monitoring.  No pharmacokinetic or pharmacodynamic interactions were 
observed between lenalidomide and warfarin.  
Nonclinical in vitro metabolism studies suggest that lenalidomide is 
not likely to result in metabolic drug interactions in humans.  In vitro, 
lenalidomide did not significantly inhibit marker enzyme activities for 
CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4.  In 
rats, no induction of any CYP450 enzymes was observed. 
Administration of lenalidomide in monkeys showed no effects on the 
activities of CYP1A, CYP2B, CYP2C, CYP2E, CYP3A, or CYP4A.  


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8.4.9 
Availability 
Drug Orders: 
RevAssist® Program 
Lenalidomide will be provided to patients on Arm F 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 
RevAssist® program of Celgene Corporation.  Per standard 
RevAssist® requirements all physicians who prescribe lenalidomide 
for research subjects enrolled into this trial, and all research subjects 
randomized to Arm C who then proceed on to Arm F of this trial, must 
be registered in and comply with all requirements of the RevAssist® 
program.   
Scheduling Considerations: 
Lenalidomide cannot be shipped to patients until all of the steps 
outlined below have been completed.  Due to the multiple steps 
involved in ordering lenalidomide we ask that sites allow adequate 
time for order processing to ensure patient treatment is not delayed.   
For initial orders, steps 1 through 4 can be completed anytime after 
randomization to Arm C.  These steps register the patient and 
physician into the RevAssist program. Once it is determined the 
patient is eligible to proceed on to Arm F sites can complete the 
remaining steps.  Step 5 begins the prescription process and all 
subsequent steps must be completed within 7 days. 
Sites should educate patients that they must register in and comply 
with all requirements of the RevAssist® program including the patient 
survey and patient education in order for drug orders to be approved.  
Shipments will be made from Biologics, Inc. Monday through 
Thursday for delivery Tuesday through Friday.  Upon approval of drug 
orders, patients will receive lenalidomide via FedEx in 1-2 business 
days.  Please note that lenalidomide will be shipped directly to 
patients. 
There will be no weekend or holiday delivery of drugs. 
Prescriptions must be filled within 7 days and only enough 
lenalidomide for one cycle of therapy will be supplied to the patient 
each cycle.   
No Starter Supplies are available for this protocol.  
 


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Strengths Available and Order Recommendations: 
Lenalidomide is available as a 5mg, 10mg or 15 mg capsule for oral 
administration.  For this study, the maximum daily dose of 
lenalidomide is 20mg, given to patients on Arm F, on days 1 through 
21 of each cycle.  Only enough lenalidomide for one cycle of therapy 
will be supplied to the patient at a time.   
If the patient is dosed at 20 mg, you may order one of the following 
combinations per cycle: 
Capsule Strength 
Quantity needed for one cycle 
10mg 
42 pills 
                         OR 
5mg 
Plus 
15mg 
21 pills 
Plus 
21 pills 
                         OR     
5mg 
84 pills 
Initial Orders:   
Please note that lenalidomide cannot be shipped to patients until 
all of the following steps have been completed.  Steps 1 through 
4 can be completed at anytime after randomization to Arm C.  
These steps register the patient and physician into the RevAssist 
program. Once it is determined the patient is eligible to proceed 
on to Arm F sites can complete the remaining steps.  Step 5 
begins the prescription process and all subsequent steps must 
be completed within 7 days. 
1. Prescribing physician registers in the RevAssist® program by 
either 
calling 
1-888-423-5436 
or 
registering 
through 
www.REVLIMID.com.   
2. Patient must be randomized to Arm C and eligible to proceed on 
to Arm F. 
3. Prescribing physician assists patient to enroll in the RevAssist® 
program by obtaining and signing a Patient-Physician Agreement 
Form (PPAF) either through calling Celgene Customer Care at 1-
888-423-5436 or via www.REVLIMID.com 
4. Patient signs the appropriate PPAF and agrees to follow all the 
procedures of the commercial RevAssist® Program.  The 
prescribing physician will then fax the completed PPAF to Celgene 
at 1-888-432-9325 
5. Patient and prescriber complete the phone surveys as required by 
the RevAssist® Program by calling Celgene Customer Care at 1-
888-423-5436 or utilizing the RevAssist online® access.   
6. At the completion of the survey, the prescribing physician is given 
a RevAssist® authorization number.  They complete the 
RevAssist® for Study Participants Clinical Trial Prescription Form 
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(Appendix IX and available on the ECOG Web Site) and faxes it to 
Biologics, Inc. at 919-256-0794.   
7. Prescribing physician advises the patient that a representative 
from a RevAssist® contract pharmacy will contact them by phone 
within 24 hours. 
8. RevAssist® contract pharmacy calls patient to conduct patient 
education. 
9. RevAssist® contract pharmacy calls Celgene Customer Care for 
confirmation number. 
10. RevAssist® contract pharmacy approves the order and ships 
lenalidomide and FDA-approved Medication Guide directly to the 
patient.  Once the order is approved, patient will receive 
lenalidomide via FedEx in 1-2 business days. 
Reorders:   
Please note that lenalidomide cannot be shipped to patients until 
all of the following steps have been completed: 
1. Patient and prescriber complete the phone surveys as required by 
the RevAssist® Program by calling Celgene Customer Care at 1-
888-423-5436 or utilizing the RevAssist online® access.   
2. At the completion of the survey, the prescribing physician is given 
a RevAssist® authorization number.  They complete the 
RevAssist® for Study Participants Clinical Trial Prescription Form 
(Appendix IX and available on the ECOG Web Site) and faxes it to 
Biologics, Inc. at 919-256-0794.   
3. Prescribing physician advises the patient that a representative 
from a RevAssist® contract pharmacy will contact them by phone 
within 24 hours. 
4. RevAssist® contract pharmacy calls patient to conduct patient 
education. 
5. RevAssist® contract pharmacy calls Celgene Customer Care for 
confirmation number. 
6. RevAssist® contract pharmacy approves the order and ships 
lenalidomide and FDA-approved Medication Guide directly to the 
patient.  Once the order is approved, patient will receive 
lenalidomide via FedEx in 1-2 business days. 
Scheduling Considerations: 
Lenalidomide cannot be shipped to patients until all of the steps 
above have been completed.  Due to the multiple steps involved in 
ordering lenalidomide we ask that sites allow adequate time for order 
processing to ensure patient treatment is not delayed.   
Sites should educate patients that they must register in and comply 
with all requirements of the RevAssist® program including the patient 
survey and patient education in order for drug orders to be approved.  
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Shipments will be made from Biologics, Inc. Monday through 
Thursday for delivery Tuesday through Friday.  Upon approval of drug 
orders, patients will receive lenalidomide via FedEx in 1-2 business 
days.  Please note that lenalidomide will be shipped directly to 
patients. 
There will be no weekend or holiday delivery of drugs. 
Prescriptions must be filled within 7 days and only enough 
lenalidomide for one cycle of therapy will be supplied to the patient 
each cycle.   
Drug Destruction and Return: 
Sites are to instruct patients to return any unused lenalidomide to 
Celgene for destruction. Instructions for return of drug are included 
with each shipment of lenalidomide and instruct patients to call 
Celgene Customer Care at 1-888-423-5436 to begin the return 
process.  Once notified, Celgene will provide patients with a pre-paid 
UPS label to return unused lenalidomide to the company. 
8.4.10 
Side Effects 
Please refer to the CAEPR in Section 5.3.2. 
8.4.11 
Nursing/ Patient Implications 
1. Ensure women of childbearing potential are not pregnant and 
sexually active women and men are abstaining or are using an 
effective form of contraception while taking lenalidomide. This 
should be discussed prior to each course of treatment. 
2. Caution patient not to drive or use hazardous machinery until the 
potential sedative effects of the drug are known in the patient. 
3. Caution patient to report leg swelling or shortness of breath, 
because of the risk of thrombosis/embolism 
4. All subjects who receive lenalidomide are required to have deep 
vein thrombosis (DVT) prophylaxis during lenalidomide therapy. 
Subjects with a history of a thrombotic vascular event are required 
to have full anticoagulation, therapeutic doses of low molecular 
weight heparin or Coumadin to maintain an INR between 2.0–3.0, 
or any other accepted full anticoagulation regimen (e.g. direct 
thrombin inhibitors or Factor Xa inhibitors) with appropriate 
monitoring for that agent. All subjects without a history of a 
thromboembolic event are required to take a daily aspirin (81mg 
or 325 mg) for DVT prophylaxis. Subjects who are unable to 
tolerate aspirin should receive low molecular weight heparin 
therapy or Coumadin treatment  or another accepted full 
anticoagulation regimen. 
5. Counsel patient to report abnormal sensations in hands or feet, 
such as decreased sensation or dysesthesia.  Paresthesias are 
often noted early before neuropathy develops. 
6. Advise patient to immediately report rashes or fever. 
7. Advise patient to take dose at the same time each day. 
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8. 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. 
9. 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. 
8.4.12 
References 
Richardson PG, Schlossman RL, Weller E, et al. Immunomodulatory 
drug CC-5013 overcomes drug resistance and is well tolerated in 
patients with relapsed Multiple Myeloma. Blood 2002; 100:3063-7. 
Richardson P, Jagannath S, Schlossman R, et al. A Multi-center, 
Randomized, Phase 2 Study to Evaluate the Efficacy and Safety of 2 
CDC-5013 Dose Regimens When Used Alone or in Combination with 
Dexamethasone (Dex) for the Treatment of Relapsed or Refractory 
Multiple Myeloma (MM). Blood 2003; 102:235a. 
Zangari M, Tricot G, Zeldis J, Eddlemon P, Saghafifar F, Barlogie B. 
Results of Phase I Study of CC-5013 for the Treatment of Multiple 
Myeloma (MM) Patients Who Relapse after High Dose Chemotherapy 
(HDCT). Blood 2001:775a (A3226). 
Davies FE, Raje N, Hideshima T, et al. Thalidomide and 
immunomodulatory derivatives augment natural killer cell cytotoxicity 
in Multiple Myeloma. Blood 2001; 98:210-6. 
 


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9. 
Statistical Considerations 
9.1 
Primary Endpoints 
The study is a randomized three arm trial at 1:2:2 ratios to the control arm (Arm 
A: BR+R) and two experimental arms (Arm B: BVR+R and Arm C: BR+R/L). 
Patients will be randomized to the three arms stratified on patient follicular 
lymphoma international prognostic index (0-2 vs 3 vs 4-5 risk factors) and GELF 
tumor burden (low vs. high). With 250 patients accrued over 25 months (10 
patients per month) and a projected 5% ineligible rate, the study will have 236 
eligible patients with 48 on the control arm and 94 on each of the experimental 
arms.  
At the Fall 2013 DSMC meeting, 185 out of 250 patients have enrolled to the 
study. We observed a 9% ineligible or inevaluable rate, which is higher than the 
5% rate projected in the original design. In addition, 23% patients did not 
registered for step 2 continuation after step 1 treatment.  The non-enrollment rate 
was 17% after BR induction for arm A and C, and was 33% after BVR induction 
for  arm B.  
After discussion with NCI, the study team decided to increase the accrual to arms 
A and C in order to preserve the power for the second primary analysis of the 
lenalidomide question, while closing arm B once the original accrual goal is met. 
Assume a 9% ineligibility rate and 17% non-enrollment rate (percentage of 
patients that will not register for step 2 continuation) after BR induction,  24% (1-
0.91*0.83) of initial enrollment will not be available for the analysis of the 
secondary primary endpoint (1-year DFS after BR induction).  Therefore, the 
accrual goal is increased from 250 to 286. The additional 36 patients will be 
randomized at 1:2 ratios to the control arm (Arm A+D: BR+R) and the 
experimental arm Arm C+F: BR+R/L.  This increase in accrual will ensure around 
48 patients on the Arm A+D (BR+R) and 94 patients on arm C+F (BR+R/L) 
registered for step 2 and available for the analysis of the second primary 
endpoint. The calculation used an average drop-off rate from two BR induction 
arms (arm A and C), we consider that the impact on power of uneven drop-off 
rate between these two arms is small. 
9.1.1 
The first primary endpoint  
The first primary objective is to compare the complete remission (CR) 
rate after induction with BVR vs BR. The definition of complete 
remission (CR) is based upon the criteria from the Revised Response 
Criteria for Malignant Lymphoma (158). It is expected that the CR rate 
for the BR arm will be 50% based on a compilation of data in the 
literature. The study will target a 16% increase in CR rate to 66% for 
the BVR arm. With 142 patients on BR (Arms A +C) and 94 patients 
on BVR, the trial will have 90% power, at the one-sided 0.15 
significance level, to detect a difference in CR rate of 16% or more 
between the BVR and BR arms (Fisher’s exact test). The primary 
analysis will be performed using Cochran-Mantel-Haenszel (CMH) 
test, stratified on the FLIPI (scores of 3 vs 4,5) and GELF (low vs 
high) criteria. In case few FLIPI 0-2 patients enter the study; they will 
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be included into the group of FLIPI 3. 
9.1.2 
The second primary endpoint 
The second primary objective is to compare the 1-year post-induction 
disease-free survival (DFS) rate of rituximab/lenalidomide (R/L) with 
rituximab (R) alone continuation following BR induction. DFS rate is 
defined as the percentage of patients that are alive and in complete 
remission (CR). The proportion of patients achieving CR during 
induction or consolidation and maintaining CR at 1 year after induction 
completion will be determined. As above, the expected CR rate for BR 
is 50%. Assuming 95% of induction patients proceed to continuation 
(CR=50%, PR/SD=45%), we expect about 18% of PR/SD of patients, 
or about 8% of all continuation patients, to improve response to CR 
after 1-year of standard rituximab continuation. We also expected that 
about 8% of continuation patients will progress during this period of 
time (16% of induction CR patients). Therefore, the expected 1-year 
post-continuation DFS rate for the rituximab continuation following 
standard BR induction therapy is 50%.  With 48 patients on BR+R 
(Arm A) and 94 patients on BR+R/L (Arm C), the trial will have 87% 
power, at the one-sided 0.15 significance level (Fisher’s exact test), to 
detect a difference in DFS rate of 20% or more between the rituximab-
alone arm (Arm A) and the rituximab + lenalidomide arm (Arm C) 
following 
BR 
induction. 
This 
difference 
corresponds 
to 
an 
improvement in DFS rate from 50% in the rituximab-alone 
consolidation therapy to 70% in the combination of rituximab and 
lenalidomide arm (Arm C). A per-protocol analysis will be performed 
including all patients registered to step 2 continuation. Sensitivity 
analysis will also be conducted by treating patients that do not 
continue on treatment beyond induction (e.g., progressed on induction 
therapy) as not being in disease-free status 1 year after induction. 
9.2 
Secondary Endpoints 
The secondary endpoints include progression-free survival (PFS) and overall 
survival (OS). With 48 patients on BR+R and 94 patients on both BR+R/L and 
BVR+R, the trial will have 84% power to detect a 15% difference in 3-yr PFS rate 
from 75% on R-bendamustine+R to 90% on BR+R/L and BVR +R, and a 15% 
difference in 5-yr OS rate from 75% on BR+R to 90% on BR+R/L and BVR +R, at 
one-sided 0.15 significance level. 
As part of the in-depth analysis, we will assess the effect of continuation therapy 
(DFS, PFS and OS rate) in converting partial response (PR) or stable disease 
(SD) from induction into complete remission (CR). Descriptive statistics (mean 
and 95% confidence interval) will be used to summarize the conversion rate for 
each of the three arms. Potential prognostic factors will be correlated with 
conversion status by Fisher’s exact test or Chi-square test, logistic regression will 
be used to assess the effect on conversion from the combination of multiple 
factors. We will also evaluate the effect of continuation therapy in maintaining 
disease-free status for patients who achieve CR after induction, summary 
statistics will be used to report 1-yr DFS, 3-yr PFS and 5-yr OS rate for induction 
CRs for each of the three arms.  
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We will also examine the association of the original FLIPI score (FLIPI-1) and the 
recently reported FLIPI-2 score that was recently reported (132). We will also 
determine the relationship between FLIPI-2 score and outcome (CR, DFS, PFS, 
and OS). For binary outcomes, logistic regression will be used to assess this 
relationship; for time-to-event outcomes, the method of Kaplan and Meier and the 
logrank test, as well as Cox proportional hazards models, will be used to assess 
the relationship with FLIPI score. 
9.2.1 
Image and Tissue Bank 
To explore the potential of metabolic tumor burden to predict clinical 
outcome and enhance existing prognostic indices, we will centrally 
archive PET/CT scans at baseline and after 3 and 6 cycles of 
induction therapy. Patients who do not enter complete remission after 
the completion of induction (i.e. stable disease or partial remission), 
will have restaging PET scans continued during the continuation 
phase of treatment (see Table 10). This inventory can be used to 
support exploratory analyses of new methods for quantitative imaging 
such as measurement of metabolic tumor burden (MTB). MTB can be 
correlated with clinical outcomes in the E2408 study (CR rate, DFS 
rate, PFS, OS), conventional prognostic indices (FLIPI, GELF), and 
host and tumor biomarkers in future studies.  
Another measure of tumor burden with high potential to better predict 
clinical outcome is the quantitative assessment of t(14;18)-containing 
cells. To allow future exploration of this biomarker in the context of 
E2408, we will obtain blood samples at baseline; after 1, 3 and 6 
cycles of induction; and after 12 and 24 months continuation. Bone 
marrow samples will be obtained at baseline and upon restaging after 
12 and 24 months continuation. Collection of these samples will allow 
correlations of this biomarker with MTB and FLIPI score, and absolute 
values and changes in quantitative t(14;18) PCR can be correlated 
the clinical endpoints of the E2408 study. As the combination of MTB 
(above) and quantitative t(1418) assessment may emerge as a better 
predicter of treatment efficacy, banking of both image and 
biospecimens will afford studies of all E2408 participants and 
analyses within each treatment arm. PET scans will be obtained at 
baseline and after 3 and 6 cycles of induction therapy. All subsequent 
scheduled restaging scans will be CTs only, unless a patient has not 
entered complete remission as discussed above. In addition, bone 
marrow aspirates will be performed only at baseline and prior to 
continuation. 
In 2009, both the follicular lymphoma tumor and the tumor 
microenvironment in the host appear to play major roles in prognoses. 
Establishing a tumor bank of paraffin-embedded tissues and host 
DNA positions us to study the best available markers at the 
conclusion of E2408. In this endeavor, we will be led by funded, 
ongoing correlative research including gene expression profiling, 
microarray analyses, and single nucleotide polymorphism studies in 
ECOG’s completed E1496 and E4402 studies. The resources of 
E2408 can be used to validate findings from these prior studies as 


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123 
well as providing specimens for discovery particular to the treatment 
arms of E2408. Among these are measures of T and NK cell 
activation markers potentially related to the immunomodulatory 
activities of lenalidomide and changes in TNF-alpha and proteasome 
levels related to bortezomib.  
We anticipate approximately 2/3 of patients will have a measurement 
of metabolic tumor burden (MTB) by PET/CT scan and a 
measurement of molecular tumor burden by quantitative assessment 
of t(14;18)-containing cells, at baseline and at one or more time points 
through the treatment. We propose to pool patients from all three 
arms based on the hypothesis that MTB combined with quantitative 
t(14;18) measurement at varied time points may better predict 
treatment efficacy regardless of actual treatment received. (There are 
data in Ladetto et al. Blood 2008 that support the similar predictive 
ability of t(14;18)+ cells despite highly significant differences in 
treatment efficacy) (45). For both the absolute value and log rate of 
change with respect to baseline at each follow-up time point, two-
sample Wilcoxon rank test will be used to correlate MTB and 
molecular tumor burden measurement with dichotomized clinical 
outcomes, such as with or without CR at the end of induction, FLIPI 1-
3 versus 4-5 and DFS status 1-year post induction; Spearman 
correlation metric will be used to correlate the two measurements at 
each time point. We propose to use regression analysis to evaluate 
the potentially prognostic value of MTB and/or measurement in 
addition to standard clinical assessments (e.g. FLIPI, GELF score). 
The methods include logistic regression model for dichotomized 
outcomes (disease-free or not) and Cox proportional hazard model for 
time to event outcomes (DFS, PFS). In addition, the classification and 
regression trees (CART) method can be used to select important 
prognostic factors to classify patient disease or progression status at 
the landmark time points. As knowledge is moving quickly in 
biomarker field, the actual analysis plan to correlate MTB and 
molecular 
tumor 
burden 
measurement 
with 
host 
tumor 
microenvironment characterized by series markers will be determined 
based on the state-of-the-art biomarker knowledge at the conclusion 
of patient accrual. 
9.2.2 
Quality of Life (QOL) 
Patient-reported outcomes measures will be administered to assess 
overall HRQL, disease-related symptoms, distress (anxiety and 
depression) 
and 
treatment-related 
symptoms. 
Overall 
HRQL 
(physical, functional, emotional and social well-being) will be 
prospectively measured using the 42-item FACT-Lymphoma subscale 
(FACT-Lym) throughout trial participation and at follow-up. This will 
also capture disease-related symptoms and concerns. Treatment-
related symptoms, specifically fatigue and neurotoxicity, will be 
measured using the 13-item FACT-Fatigue scale and the 11-item 
FACT/GOG-Neurotoxicity scale. The patient self-report assessment 
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This assessment will be administered at six time points:  
1. Baseline (pre-treatment) 
2. Mid-way through induction (after cycle 3)  
3. End of induction (before continuation).  
4. At 6 months of continuation (s/p 6 cycles of lenalidomide) 
5. End of 1st year of continuation. 
6. End of 2nd year of continuation. 
The timing of these assessments will allow us to examine symptom 
palliation within a several weeks of treatment initiation (2nd time point) 
and throughout induction treatment where bortezomib will be added to 
BR therapy. Since bortezomib is known to cause neurotoxicity, the 
FACT/GOG-neurotoxicity scale will be collected prior to each 
induction cycle for patients randomized to BVR therapy.  Time points 
were also selected to assess treatment-related symptoms following 
maximum exposure to treatment agents (3rd and 5th time points). 
Assessment at the end of continuation (6th time point) will provide us 
with important data on patients’ well-being and functional status as 
they transition from active treatment to survivorship. 
Scores from assessment instruments will be examined at each time 
point for differences between treatment arms (induction or 
continuation) on overall HRQL, disease-related symptoms, distress, 
and treatment-related symptoms.  Data will also be examined to 
identify 
differences 
between 
treatment 
arms 
(induction 
or 
continuation) on change scores over time. The impact of disease-
related symptoms and treatment-related symptoms on overall HRQL 
will be examined to establish the extent to which symptom palliation 
and treatment-induced symptoms impact functioning and well-being. 
The standard deviation of the physical and functional well-being 
domains are approximately 6 and the standard deviation of the FACT-
G is approximately 16. Differences which can be detected with 80% 
power between two arms in the change of scores from baseline (pre-
treatment) are computed 1) allow for slightly less and more variability 
for the scales without data (standard deviation of 4,6,8,16,20), 2) 
assuming correlation between repeated scores of 0.4, 0.6, 0.8, 3) 
assuming equal percentage of patients completed assessment in the 
two arms at any time point, 4) using a two-sided t-test with a 0.05 
significance level.  Assuming that 90%, 80%, 60% or 40% of patients 
have completed assessment at both time points (lower completion 
rate at later time point), Table 12 shows the difference between that 
can be detected with 80% power. Power calculations are base on the 
number of complete cases, and therefore are conservative.  
Table 12. Difference that can be detected in the change in 
domain score at each time point from baseline between two arms 
using two-sided t-test at significance level of 0.05 for various 


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125 
standard deviations of the scores, correlation between repeated 
measures and number of patients with complete assessments.  
Standard 
deviation 
Correlation 
Standard 
Deviation of 
change 
Difference detected with 80% power 
Induction  
Continuation  
90% 
(N=128, 
85) 
80% 
(N=114, 
75) 
60% 
(N=85,    
56) 
80% 
(N=75, 
38) 
60% 
(N=56, 
29) 
40% 
(N=38
, 19) 
4 
0.4 
4.38 
1.73 
1.83 
2.13 
2.47 
2.84 
3.51 
0.6 
3.58 
1.41 
1.50 
1.73 
2.02 
2.32 
2.87 
0.8 
2.53 
1.00 
1.06 
1.23 
1.42 
1.64 
2.03 
6 
0.4 
6.57 
2.59  
2.75 
3.19 
3.70 
4.26 
5.26 
0.6 
5.37 
2.12  
2.25 
2.61 
3.02 
3.48 
4.30 
0.8 
3.79 
1.49  
1.59 
1.84 
2.13 
2.46 
3.04 
8 
0.4 
8.76 
3.45  
3.67 
4.26 
4.93 
5.68 
7.02 
0.6 
7.16 
2.82  
3.00 
3.48 
4.03 
4.64 
5.74 
0.8 
5.06 
1.99  
2.12 
2.46 
2.85 
3.28 
4.05 
16 
0.4 
17.5 
6.90   
7.33   
8.50   
9.85 
11.34 
14.02 
0.6 
14.3 
5.63   
5.99   
6.95   
8.05   
9.27 
11.45 
0.8 
10.1 
3.98  
4.23 
4.91 
5.69 
6.54 
8.09 
20 
0.4 
21.9 
8.63   
9.18 
10.64 
12.33 
14.19 
17.54 
0.6 
17.9 
7.05   
7.50   
8.70 
10.08 
11.60 
14.34 
0.8 
12.6 
4.96   
5.28   
6.12   
7.09   
8.16 
10.09 
For induction question (BR vs. BVR), patients from BR+R and 
BR+R/L will be combined together (total 142 patients) to compare with 
that from BVR +R arm (94 patients). And for continuation questions 
comparing the effect of R/L and R-alone, only patients under 
treatment of BR+R (48 patients) and BR+R/L (94 patients) will be 
included. It is nature to anticipate higher percentage of complete 
cases in early phase of the study and the proportion decreases as 
study pursue, therefore we anticipate as much as 90% complete 
cases in the induction phase and 80% complete case in continuation 
phase. For example, assuming the standard deviation of the FACT-G 
is 16, there is at least 80% power to detect a difference in the change 
of the total FACT-G score of 5.63-6.95 between the two induction 
treatments, or 8.05-11.45 between two continuation treatments after 
BR induction, if the correlation is 0.6 and 3.98-4.91 or 5.69-8.09  if the 
correlation is 0.8.  
The additional patients enrolled will be included in the analysis of 
quality of life. However, it should not affect power for step 2 analysis 
due to the non-enrollment rate. It will increase power for step 1 
analysis, but the effect is anticipated to be small. 
Besides comparing QOL scores between arms at each time point, 
repeated measures analysis techniques will also be utilized to 
examine the treatment effect, time effect and potential interaction on 
QOL score through time.  Patient variation will be treated as random 
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effect in modeling the longitudinal data (QOL score) with linear mixed 
models. Data with and without missing data imputation will be 
analyzed and results will be compared. Imputations will be done by 
fitting informative censoring model using EM algorithm (38, 101). 
These methods consider informative missing by jointly modeling 
longitudinal response (QOL score) and the time to dropout. 
Frequency, descriptive statistics will be utilized to summarize and 
understand the quality of life data for this population.  
9.2.3 
Co-Morbidity 
We will collect the number of co-morbidities for each patient at 
baseline and at the end of therapy (i.e., at the end of 2 years of 
continuation therapy) utilizing the Cumulative Illness Rating Scale and 
assess the relationship between CIRS score and outcome (CR, DFS, 
PFS). Van Sprousen and colleagues reported that the prevalence of a 
serious co-morbidity of non-Hodgkin lymphoma patients aged 60-69 
years and >70 years was 43% and 61%, respectively (133). The most 
common co-morbid conditions were patients 60–69 years and ≥ 70 
years were cardiovascular disease (15% and 22%, respectively), 
hypertension (14% and 14%, respectively), diabetes mellitus (8 and 
10%, respectively), and COPD (6% and 10% respectively).  Van de 
Schans and colleagues recently validated the original FLIPI score 
(i.e., FLIPI-1) in a cohort of 353 FL patients (134).  Furthermore, they 
examined the impact of co-morbidity with survival in these same 
patients. Interestingly, they found that a survival model that included 
age in three categories (≤60, 61–70 and >70 years) and presence of 
cardiovascular disease resulted in a better prognostic index than the 
standard FLIPI-1.  Examining cardiovascular disease (CVD) alone, 
presence of CVD predicted for significantly inferior 5-year and 10-year 
overall survival (48% and 24%, respectively) vs patients without 
history of CVD (71% and 56%, respectively; p<0.0001). 
The comprehensive geriatric assessment (CGA) has been developed 
as a procedure to assess the objective health status of elderly 
persons (135-139). The CGA is considered to be more effective than 
standard medical evaluation for the care of the elderly.  Initially, use of 
a CGA was based on its ability to predict morbidity and mortality in the 
general geriatric population, although accumulating data show the 
benefits of using the CGA specifically in patients with cancer 
(135,138,139).  Comorbidity is an essential part of the CGA.  Several 
comorbidity scales have been used in research, although the 
Cumulative Illness Rating Scale (CIRS) is one of the more prominent 
tools utilized in geriatrics (135,140).  The CIRS measures chronic 
medical illness burden while taking into account the severity of chronic 
diseases. The CIRS has been revised to reflect common problems of 
elderly people and was renamed the Cumulative Illness Rating Scale 
for Geriatrics (CIRS-G) (141); this version has subsequently been 
validated (142). Furthermore, several recent cancer related studies 
have validated the relevance of the CIRS to define comorbidities 
among oncology patient populations, some of which correlated with 
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For binary outcomes such as CR, logistic regression will be used to 
assess the relationship with CIRS score; for time-to-event outcomes, 
the method of Kaplan and Meier and the logrank test, as well as Cox 
proportional hazards models, will be used to assess the association 
with co-morbidity. 
9.2.4 
Peripheral Neuropathy 
As of amendment #5, the study allows subcutaneous administration of 
bortezomib for patients that are randomized to Arm B (BVR arm).  In a 
report by Moreau et al (2011) in multiple myeloma patients, peripheral 
neuropathy of any grade was observed in 38% vs 53%, respectively, 
of grade 3 or worse was observed in 6% vs 16% patients, 
respectively,with subcutaneous vs intravenous bortezomib 
administration. We will report percent patients that experience 
peripheral neuropathy of any grade and of grade 3 or higher, with 
90% confidence interval. Based on current accrual and the expected 
activation time for amendment #5, we anticipate that 65% of patients, 
respectively, will received intravenous bortezomib and 35% will 
receive subcutaneous bortezomib.  
Out of 94 eligible patients, the estimate leads to 61 and 33 patients 
with intravenous and subcutaneous bortezomib, respectively. Thus, 
the width of 90% confidence interval will be no wider than 22% and 
30% for intravenous and subcutaneous bortezomib, respectively. 
9.3 
Gender and Ethnicity  
Based on previous data from E1496 the anticipated accrual in subgroups defined 
by gender and race is: 
Follicular Patients (Accrual goal = 286) 
Table 13. 
Ethnic Category 
Gender 
Females 
Males 
Total 
Hispanic or Latino 
5 
12 
17 
Not Hispanic or Latino 
121 
148 
269 
Ethnic Category: Total of all subjects 
126 
160 
286 
Racial Category 
 
American Indian or Alaskan Native 
0 
1 
1 
Asian 
0 
1 
1 
Black or African American 
2 
10 
12 
Native Hawaiian or other Pacific Islander 
0 
0 
0 
White 
124 
148 
272 
Racial Category: Total of all subjects 
126 
160 
286 
 
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10. 
Pathology Review 
NOTE:  
ECOG-ACRIN requires that all biological samples submitted be entered and 
tracked via the online ECOG-ACRIN Sample Tracking System (STS).  An STS 
shipping manifest form must be generated and shipped with the sample 
submissions.  See Section 10.4. 
NOTE: 
An informed consent must be signed prior to the submission of any samples 
including mandatory diagnostic reviews, laboratory studies and/or banking. 
Samples for laboratory studies and/or banking should be submitted only from 
patients who have given written consent for the use of their samples for these 
purposes. 
10.1 
Submitting Diagnostic Material 
Diagnostic material from the original diagnostic tumor biopsy must be submitted 
for review and classification and laboratory studies. Diagnostic materials from 
additional biopsies performed while on study should be submitted for use in the 
laboratory studies and/or banking.  
The clinical investigator and the submitting pathologist have the responsibility for 
submitting representative diagnostic material for review and classification. Refer 
to Appendix II (Pathology Submission Guidelines). 
10.2 
Materials Required For This Protocol 
10.2.1 
Forms (Submit with every pathology submission) 
· 
ECOG-ACRIN Generic Specimen Submission Form (#2981). 
Please identify the clinical status of the submitted material (i.e., 
pretreatment as opposed to remission and relapse). 
· 
A copy of the surgical pathology report 
· 
Immunologic studies, if available 
· 
Sample Tracking System Shipping Manifest Form 
In addition to the surgical pathology report, if immunologic studies 
have been performed at the home institution, it is necessary that 
these be forwarded as well.  
10.2.2 
Biological Sample Submissions: 
NOTE: If unable to submit blocks contact the ECOG-ACRIN CBPF 
for alternatives at 844-744-2420 or 
eacbpf@mdanderson.org. 
10.2.2.1 
MANDATORY 
· 
Tumor block from the original diagnostic biopsy 
sample. 
NOTE:  Submission of pathology materials for diagnostic review is 
mandatory in order for the patient to be considered 
evaluable. Failure to submit pathology materials may render 
the case unevaluable. 
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NOTE: The original tumor biopsy will also be used for the optional 
laboratory studies outlined in Section 11 for those patients 
who have consented to participate. 
10.2.2.2 
From patients who answer “Yes” to participation in the 
laboratory research studies or to “I agree to provide 
additional specimens for research.” 
· 
Tissue 
blocks 
from 
any 
diagnostic 
biopsies 
performed while on study. 
10.3 
Shipping Procedures  
Access to the shipping account for shipments to the ECOG-ACRIN CBPF at MD 
Anderson Cancer Center can now be obtained by logging onto fedex.com with an 
account issued by the ECOG-ACRIN CBPF. For security reasons, the account 
number will no longer be given out in protocols, over the phone, or via email. If 
your site needs to have an account created, please contact the ECOG-ACRIN 
CBPF by email at eacbpf@mdanderson.org. 
Ship at ambient temperature, using a cool pack during warm months. 
Submission Schedule  
 
The required initial pathology materials must be submitted within one 
month of patient randomization.   
 
Additional tumor biopsies should be submitted within one month of 
collection.  
Shipping Address 
ECOG-ACRIN Central Biorepository and Pathology Facility 
MD Anderson Cancer Center 
Department of Pathology, Unit 085 
Tissue Qualification Laboratory for ECOG-ACRIN, Room G1.3586 
1515 Holcombe Blvd 
Houston, TX 77030 
Phone: Toll Free 844-744-2420 (713-745-4440 Local or International Sites) 
Fax: 713-563-6506 
Email: eacbpf@mdanderson.org 
Log the samples into the ECOG-ACRIN Sample Tracking System (STS) prior to 
shipping. An STS shipping manifest form must be generated and shipped with all sample 
submissions. If STS is unavailable, follow the instructions in Section 10.4 regarding 
alternative form requirements. 
10.4 
ECOG-ACRIN Sample Tracking System 
It is required that all samples submitted on this trial be entered and tracked 
using the ECOG-ACRIN Sample Tracking System (STS).  The software will allow 
the use of either 1) an ECOG-ACRIN user-name and password previously 
assigned (for those already using STS), or 2) a CTSU username and password.   
When you are ready to log the collection and/or shipment of the samples 
required for this study, please access the Sample Tracking System software by 
clicking https://webapps.ecog.org/Tst  
Rev. 10/11 
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Rev. 4/13 
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Important: Please note that the STS software creates pop-up windows, so you 
will need to enable pop-ups within your web browser while using the 
software. A user manual and interactive demo are available by 
clicking this link: http://www.ecog.org/general/stsinfo.html Please 
take a moment to familiarize yourself with the software prior to using 
the system. 
A shipping manifest must be generated and shipped with all sample 
submissions. 
Please direct your questions or comments pertaining to the STS to ecog-
acrin.tst@jimmy.harvard.edu. 
10.4.1 
Study Specific Notes 
An Generic Specimen Submission Form (#2981) will be required only 
if STS is unavailable at time of sample submission or if baseline 
samples are submitted prior to randomization to the treatment trial 
(patient must sign consent prior to collection). Indicate the 
appropriate Lab on the submission form: 
· 
ECOG-ACRIN Central Biorepository and Pathology Facility 
· 
Mayo Clinic Lymphoma Laboratory 
· 
QARC 
Retroactively enter all collection and shipping information when STS 
is available. 
10.5 
Central Biorepository and Pathology Facility: Sample Processing and Routing 
· 
Slides will be cut from the original diagnostic blocks and initial materials 
will be forwarded to Randy Gascoyne, M.D. for review. 
· 
Shavings from all submitted blocks will be forwarded to Randy Gascoyne, 
M.D. for use in the optional laboratory studies outlined in Section 11. 
· 
Blocks from patients who consented to banking of residuals for future 
studies: Four 3 mm cores will be taken from each block and placed into 
tissue microarrays (TMA). The regions of interest will be designated by 
Randy Gascoyne, M.D. 
10.6 
Banking 
TMAs and residual material from the blocks/slides submitted will be retained at 
the ECOG-ACRIN Central Repository for possible use in future ECOG-ACRIN 
approved studies.  Any residual blocks will be available for purposes of individual 
patient management on specific written request.  If future use is denied or 
withdrawn by the patient, the samples will be removed from consideration for use 
in any future study. 
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11. 
Correlative Studies 
Creation of an image and tissue bank for correlative studies is an important aspect of 
modern clinical research. We plan to develop such a resource from the E2408 study in 
order to pursue the most promising state-of-the-art investigations at the study’s 
conclusion. At this time, we have organized our ideas regarding correlative studies in 
two areas: 1) improved assessment of tumor burden with imaging and molecular 
biomarkers, and 2) evaluation of the heterogeneity in tumor characteristics and the host 
immune system.  
What 
follows 
(Section 
11.2) 
is 
an 
outline 
of 
our 
current 
thinking 
and 
background/rationale for funding applications. However, we acknowledge that the pace 
of current scientific developments may necessitate following alternative or new avenues 
when the E2408 study is fully accrued. In fact, foremost among emerging study data, are 
the funded correlative assessment of E1496 samples for gene expression, SNP 
analyses, and immunohistochemical markers and the SNP and TMA assays of E4402, 
both prior ECOG-led follicular lymphoma studies. 
11.1 
Submission of Scans and Biological Materials 
ECOG-ACRIN requires that all scans and biological samples submitted be 
entered and tracked via the online ECOG-ACRIN Sample Tracking System.  An 
STS shipping manifest form must be generated and shipped with the 
submissions.  See Section 10.4.  
Submission of PET/CT and CT scans are outlined in Section 11.1.1. Submission 
of blood and bone marrow are outlined in Section 11.1.2. 
11.1.1 
Centralized Review of FDG-PET/CT and CT Scans (MANDATORY) 
An important secondary objective of this study is to create an image 
and tissue bank including serial PET/CT scans.  Separate CT’s of the 
neck/chest/abdomen/pelvis will be required in addition to the PET/CT 
if the PET/CT is performed without intravenous and oral contrast (see 
Appendix VI: FDG-PET/CT and CT IMAGING). 
The imaging archived in this bank will be centrally read by the E2408 
Nuclear Medicine physician on the Study Committee.   
NOTE:  
For purposes of treatment decision, the local reading will be 
used. The central review is for the establishment of the 
image bank and will not be returned to the site. 
11.1.1.1 
Required Scan Submissions 
Combined clinical PET/CT scans and clinical CTs 
performed to determine patient eligibility and monitoring of 
disease must be submitted from the following time points: 
· 
Pretreatment  
· 
Restaging after cycle three (3) of induction 
· 
Restaging after completion of induction prior to start 
of continuation (after 6 cycles) 
· 
Restaging after following completion of continuation*  
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· 
At relapse* 
NOTE: Combined PET/CT scan will be sufficient if the 
PET/CT is performed with intravenous and oral 
contrast; 
if 
PET/CT 
is 
without 
oral 
and 
intravenous contrast, then separate/dedicated 
CTs of neck/chest/abdomen/pelvis (in addition to 
the PET/CT) must be obtained and submitted at 
the same time points as above. 
NOTE: For patients who do not enter complete remission 
at the completion of induction, restaging FDG-
PET/CT scans are done during the continuation 
phase (see Table 10 in Section 7.1)  
11.1.1.2 
FDG-PET/CT and CT with Infusion Scan Submissions 
To ensure the highest standards and consistency between 
different centers, all FDG-PET scans must be submitted to 
the Quality Assurance Review Center (QARC) in Lincoln, 
RI, for centralized review (see Appendix VI: FDG-PET/CT 
and CT IMAGING).  All FDG-PET/CT and CT scans with 
intravenous contrast should be submitted to QARC.  
QARC will transmit the scans to the ECOG-ACRIN 
central 
reviewer, 
Dr. 
Andrew 
Quon 
(Stanford 
University). 
Borderline metabolism in a lesion will be considered 
negative as determined by the international harmonization 
conference. Details of submission of FDG-PET/CT scans 
to QARC for centralized review and on the performance 
and recommended scoring/interpretation of FDG-PET/CT 
scans are outlined in Appendix VI: FDG-PET/CT and CT 
IMAGING. 
For questions please contact ECOG-ACRIN Study 
Manager at QARC at the ph: (401) 753-7600 or by e-mail:  
ECOG@QARC.org. 
11.1.1.3 
Shipping Guidelines 
Scans must be sent in DICOM format via CD via overnight 
delivery, or submitted electronically via SFTP to the Quality 
Assurance Review Center (QARC).   
NOTE:  
Instructions on how to obtain an SFTP can be 
found on the QARC website: www.QARC.org 
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CD’s should be submitted to the address below.  Multiple 
studies for the same patient may be submitted on one CD, 
however, please submit only one patient per CD. 
Quality Assurance Review Center (QARC) 
640 George Washington Highway 
Suite 201 
Lincoln, RI 02865 
Phone: 401-753-7600 
Fax: 401-753-7601 
Log the scans into the ECOG-ACRIN Sample Tracking 
System (STS) prior to shipping. An STS shipping manifest 
form must be generated and shipped with all sample 
submissions. If the STS is unavailable, follow the 
instructions in Section 10.4 regarding alternative form 
submission. 
For each patient, study data acquisition information and 
patient information must be recorded on the PET 
acquisition form (Appendix VI) and forwarded to QARC.  
Image data must be transferred to QARC at the same 
time as the completed FDG-PET/CT acquisition form. 
11.1.2 
Submission of Blood and Bone Marrow 
Samples are to be submitted from patients who answer “Yes” to “I 
agree to participate in the laboratory research studies that are being 
done as part of this clinical trial.” 
11.1.2.1 
Sample Submission Schedule 
Samples should be shipped on the day they are drawn at 
room temperature. If you have any questions concerning 
sample collection and shipment, please contact Kim 
Henderson at (507) 284-3805 or 
Henderson.Kimberly@Mayo.edu at the Mayo Clinic 
Lymphoma Laboratory. 
Please contact Kim Henderson prior to the collection of 
the samples for the air bills in order ship the samples. 
A. 
Bone marrow aspirate (3-5 mL requested) to be 
submitted at the following time points: 
· 
Baseline (if submitted prior to randomization or 
if the biopsy was performed previously and 
another will not be done, contact the receiving 
laboratory) 
· 
Restaging 
after 
completion 
of 
induction 
therapy (prior to start of continuation) 
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NOTE: Samples may be submitted from patients 
who answer “Yes” to “I agree to provide 
additional specimens for research.” 
B. 
Peripheral blood to be collected at the five (5) 
following time points: 
· 
Baseline 
(after 
randomization, 
prior 
to 
treatment) 
· 
Prior to the administration of any cycle two (2) 
treatment 
· 
Prior to the start of continuation therapy* (prior 
to administration of first rituximab (Arms A and 
B) or Lenalidamide (Arm C) treatment) 
· 
At twelve (12) months of continuation* 
· 
At twenty-four (24) months of continuation* 
(end of continuation) 
* May be collected at time of restaging assessments. 
If collected on a day of treatment, collect prior to 
administration of any study drugs. 
11.1.2.2 
Sample Preparation Guidelines 
The following CBC information must be entered into STS 
with each time point: WBC and lymphocyte count.  
Samples should be shipped the day they are drawn.  
Samples from multiple patients can be shipped together, 
but must be placed in separately labeled tubes and bags. 
Please 
contact 
Kim 
Henderson 
(507-284-3805 
or 
Henderson.Kimberly@Mayo.edu)  prior to the collection of 
the samples for the air bills in order ship the samples. 
Sample tubes must be clearly labeled with the ECOG-
ACRIN protocol number (E2408), the patient’s ECOG-
ACRIN sequence number (if available), the patient’s initials 
(last name, first name), the date and time the sample was 
collected, and the sample type (PB, BM). 
· 
Peripheral blood, no anticoagulant, red top tubes: 
Draw approximately 10mL of whole blood into the 
red top tubes at each time point. 
· 
Peripheral blood, EDTA purple top tubes: 
o BASELINE: draw approximately 30mL of 
whole blood into three (3) 10mL EDTA 
purple top tubes  
o All other time points: draw approximately 
20mL of whole blood into two (2) 10mL 
EDTA purple top tubes  
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· 
EDTA (purple top tube) bone marrow aspirate 
(while 3-5mL is recommended, any amount is 
acceptable). 
NOTE: For patients with an inaspirable bone 
marrow (“dry tap”), or if bone marrow 
has been done previously and the patient 
refuses to have another aspiration done, 
call 
Kim 
Henderson 
(Mayo 
Clinic 
Lymphoma Laboratory) at (507) 284-3805 
to discuss the case and the possibility for 
submitting peripheral blood only.  Be 
prepared to report the WBC count and the 
blast count in the peripheral blood at the 
time of the call. 
11.1.2.3 
Shipping Procedures 
Please 
contact 
Kim 
Henderson 
(507-284-3805 
or 
Henderson.Kimberly@Mayo.edu)  prior to the collection of 
the samples for the air bills in order ship the samples. 
Samples should be mailed the day they are obtained and 
shipped overnight to arrive during normal working hours. 
The laboratory is open to receive shipments Monday 
through Friday. If samples are sent late in the week and 
will arrive on the weekend, please note "Saturday Delivery" 
on the Federal Express form.  
FRIDAY AND PRE-HOLIDAY SHIPMENTS SHOULD BE 
AVOIDED 
· 
Place samples in individual plastic bags and place 
them in the Styrofoam container and close the lid.  
· 
Place the Styrofoam container and the Sample 
Tracking System Shipping Manifest Form within the 
cardboard mailing sleeve. 
· 
Prepare the package for shipping, applying packing 
tape as needed.  Complete the sender portion of 
the return FedEx Air Bill and adhere to the exterior 
lid of the box.  Ship samples priority overnight 
delivery the same day collected. 
· 
Notify Federal Express for pick-up and/or leave 
package at the designated FedEx drop-off location. 
If your shipment was not logged into the ECOG-
ACRIN STS please call Kim Henderson at (507) 
284-3805 
or 
e-mail 
Henderson.Kimberly@mayo.edu 
to 
notify 
the 
laboratory when samples are being shipped.   
Indicate the ECOG-ACRIN protocol number and 
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the name of the contact person and phone number. 
The samples should be shipped to the following: 
Ship to:  
Kim Henderson 
Mayo Clinic Lymphoma Laboratory 
613 Stabile 
200 First Street Southwest 
Rochester, MN  55905 
Log the samples into the ECOG-ACRIN Sample Tracking 
System (STS) prior to shipping. An STS shipping manifest 
form must be generated and shipped with all sample 
submissions. If STS is unavailable or if baseline samples 
are being submitted prior to randomization to the treatment 
trial, follow the instructions in Section 10.4 regarding 
alternative form requirements. 
11.2 
Identification of Relevant Biomarkers for Comparison of Treatment Effects  
11.2.1 
Assessment of tumor burden with imaging and molecular biomarkers 
Tumor burden at diagnosis is prognostic in follicular lymphoma, 
forming the basis of the GELF tumor burden score (high or low).[33, 
34] Likewise, in our prior E1496 study, GELF tumor burden was 
prognostic in both standard and maintenance rituximab arms.[7] FLIPI 
risk score has also been associated with PFS in the modern 
immunochemotherapy era.[9] However, these systems of tumor 
burden and disease risk are categorical rather than quantitative and 
also fail to incorporate the diversity of disease presentations. We 
hypothesize that the integration of quantitative imaging data and a 
molecular 
indicator 
of 
tumor 
burden 
with 
standard 
clinical 
assessments at presentation and post-treatment will better predict 
disease risk and clinical outcome.  
Positron emission tomography (PET) scans will be centrally reviewed 
at baseline and indicated timepoints and the imaging features of each 
lesion (semantic type, location, axial dimensions/area/volume, and 
standard uptake value [SUV]) will be recorded with a calculation of 
overall volume and metabolic tumor burden, using an open source 
software framework built on caBIG technologies (Dr. Rubin). 
Quantitative imaging results at baseline will be evaluated to determine 
value added to standard clinical criteria. Accuracy of standard clinical 
prognostic criteria (number of nodal sites, number of nodal sites >3 
cm, and masses >7 cm) will be assessed. Metabolic tumor burden at 
presentation will be correlated with DFS and PFS endpoints and value 
added to FLIPI and GELF will be determined. Quantitative metabolic 
tumor burden during and after therapy will also be compared to 
International Harmonization Criteria in the assessment of response to 
treatment and correlated with DFS and PFS. Quantitative imaging 
may serve as a biomarker of response to newer therapeutics (ie RB- 
bendamustine) with the potential to shorten or adapt clinical trials. 
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Molecular assessment of t(14;18)-positive cells in the blood and 
marrow compartments has been studied over the past two decades in 
FL, sometimes with mixed results. In the chemotherapy era, half or 
fewer follicular lymphoma patients achieved quantitative t(14;18) after 
a full course of treatment. With more than 10 years of follow-up, 
autologous transplantation results in follicular lymphoma continue to 
demonstrate the prognostic significance of achieving quantitative 
t(14;18) in both the patient and the transplanted cells assessed ex 
vivo.[114,115] Although some early data suggested that quantitative 
t(14;18) assessment in the rituximab era was less predictive, the 
results of three randomized clinical trials demonstrated the prognostic 
significance of achieving quantitative t(14;18) and the higher rate of 
quantitative 
t(14;18) 
achieved 
with 
chemotherapy 
plus 
rituximab.[45,116,130] Notably, the Italian trial reported that 
achievement of quantitative t(14;18) neutralized the marked PFS 
difference in the treatment arms. Because ~75-85% of patients 
treated with a full course of modern therapy such as R- bendamustine 
clear the marrow and circulating compartment of t(14-18)+ cells as 
assessed by real-time quantitative PCR, the log clearance or rate of 
reduction may be more predictive of DFS and PFS.[116] Varied 
methods in the study of t(14;18)+ cells have contributed to lack of 
reproducibility across a range of international laboratories.[117] 
Recent technologic advances include an international effort to 
standardize quantitative t(14;18) assessment in European lymphoma 
clinical trials (C. Pott personal communication) and the enhancement 
of detection of t(14;18) with probes covering additional Bcl-2 
breakpoint 
regions.[118] 
Coordination 
with 
the 
international 
community and use of probes expanded to cover additional Bcl-2 
breakpoint regions is important for current clinical trials. It will be key, 
in addition, to view quantitative t(14;18) results in context and with 
appreciation for the diversity of anatomic presentations of FL. Thus, 
we hypothesize that quantitative t(14;18) analyses will significantly 
add to standard determinants of tumor burden and clinical response, 
and that quantitative t(14;18) combined with quantitative imaging may 
better predict treatment efficacy as determined by DFS and PFS. In 
the context of this study, we will correlate baseline quantitatative 
t(14;18) (blood, marrow) with quantitative metabolic tumor burden and 
FLIPI score, and DFS and PFS endpoints. Quantitative t(14;18) will be 
measured after cycle 1 (blood, marrow), cycle 6 (blood, marrow) and 
months 1, 12, and 24 (blood) of continuation. The association of log 
change in quantitative t(14;18) and absolute values with DFS and 
PFS will be determined. 
11.2.2 
Tumor and host characteristics and treatment arm 
We hypothesize that variation in response to treatment is attributable 
to heterogeneity in tumor characteristics and the host immune system 
and that these attributes contribute to response of specific therapeutic 
interventions. Molecular profiling of follicular lymphoma demonstrated 
the significance of the tumor microenvironment and engendered 


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interest in the interaction between the malignant B-cells and 
bystander cells (T cells, dendritic cells, fibroblasts, and macrophages) 
in lymph node or bone marrow infiltrates. Two immune response 
signatures, one with favorable and one with unfavorable prognostic 
significance, in the chemotherapy era have been proposed. [105] 
Although the more favorable expression signature IR1 is enriched for 
genes expressed in various T-cell subsets, whereas the unfavorable 
IR2 signature harbors genes expressed in macrophages and dendritic 
cells, the biological conclusions are not straightforward. These 
signatures appear to capture a picture of intricate interactions 
between the neoplastic B cells with their microenvironment rather than 
the presence of particular cell types in the lymphoma infiltrate. This 
may explain the somewhat contradictory studies correlating the 
number or distribution of various cells of the microenvironment, such 
as macrophages (CD68) or T-cell subsets (CD4, CD8, and Treg) with 
the clinical course of follicular lymphoma.[106,107,108,110] In 
addition, the therapeutic intervention must also be considered in the 
context of its impact on the FL cells and their microenvironment. 
Three recent papers published data on the prognostic impact of 
macrophages, FoxP3 positive T-cell and mast cells in FL patients 
treated with CHOP chemotherapy with or without the addition of 
rituximab.[107,119,131] Remarkably, the prognostic impact of these 
cell populations was lost or reversed in patients treated with rituximab, 
supporting the notion that specific therapeutics influence the impact of 
the microenvironment in FL. For instance, fludarabine has a rather 
specific effect on FoxP3-positve regulatory T-cells in B-CLL patients, 
impacting inhibitory function as well as cell numbers.[120] Very low-
dose radiotherapy (2 Gray x 2) provides another example of effect on 
the microenvironment through the induction of activation of cytotoxic 
T-cells and macrophages.[129] Lenalidomide has emerged as a 
interesting promising new agent in FL based on efficacy in clinical 
trials 
and 
the 
potential 
immunomodulatory 
effects 
on 
the 
microenvironment. Contact between FL B-cells and T-cells results in 
an immunologic defect, including creation of T-regulatory cells. 
[121]Lenalidomide abolished or markedly inhibited the suppressive 
function of T regulatory cells in pre-clinical studies, downregulating 
FoxP3 expression.[122,123] In a recent elegant study, Gribben and 
colleagues showed that lenalidomide repairs suppressed T-cell 
immunological synapse formation in FL.[124] The Gribben lab was 
able to show that lenalidomide repaired in part the suppressed 
recruitment of integrin LFA-1, Lck, Itk, Rab27A and filamin-A to the 
synapse in subsequent T cell:APC interactions. Further, they 
validated the expression of Itk, Rab27A and filamin-A in FL tissue 
microarrays (TMA) and reported that elevated expression of 
intrafollicular Rab27A (mediator of targeted secretion of CD8 T cell 
cytolytic granules) was a favorable prognostic marker. Together, 
these data suggest that lenalidomide offers the exciting prospect of 
repairing T-cell suppression in FL and that the observed variability in 
the microenvironment by immunohistochemical analysis of TMA may 


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correlate with clinical outcomes and impact of lenalidomide. We 
therefore plan to build a TMA of all E2408 cases and evaluate the 
staining patterns of the microenvironment in the context of clinical 
outcomes and treatment. 
In the current study, lenalidomide will be combined with rituximab, a 
circumstance in which its additional immunomodulatory activities 
should prove beneficial. In particular, the ability of lenalidomide to 
enhance natural killer (NK) cell and monocyte-mediated antibody 
dependent cellular cytotoxicity (ADCC). In vitro, lenalidomide-
enhanced rituximab efficacy was associated with increased granzyme 
B and Fas ligand expression and could be inhibited by a granzyme B 
inhibitor.[125] We plan to measure T and NK subsets and determine 
expression of CD107a (LAMP-1), a marker for degranulation of NK 
and activated CD8+ T cells.[126] Recent data in children treated with 
lenalidomide demonstrate the feasibility of this approach; NK numbers 
and activation status were statistically increased upon treatment.[127]  
The host immune system may also play an important role upon 
combination of rituximab and bortezomib, as rituximab efficacy has 
already been linked to the Fc receptor status of host immune 
cells.[112,113] In addition, a recent analysis of mantle cell patients 
treated with bortezomib suggests that plasma biomarkers may relate 
to efficacy,[62] while an analysis in multiple myeloma showed that 
peripheral blood proteasome levels predicted response to bortezomib 
therapy.[128] Accordingly, we plan to collect tissue and serum 
specimens to measure TNF-alpha and proteasome levels at baseline 
and after the first cycle of chemotherapy. Results will be correlated 
with the quality of response and also with the change in measured 
t(14;18) circulating cells determined at the same time points. A variety 
of markers including CTAG1B, EEF2, CFLAR and GAS5 are being 
tested in ongoing bortezomib trials. We will have the opportunity to 
test those of interest at a later date on the TMA generated from the 
E2408 study. 
A major area of interest relates to the potential toxicity issues as well 
as efficacy in the investigational arms of our study. We plan to bank 
germline DNA from the peripheral blood for potential future studies of 
interest related to single nucleotide polymorphisms. This effort will 
afford the opportunity to evaluate the interventions in the current study 
and, theoretically, can be combined with ~500 samples collected in 
the preceding E4402 study with regard to immune response 
polymorphisms that may predict survival in FL.[109]   
In summary, the essential nature of our correlative studies is 
acquisition of baseline tumor and peripheral blood at strategic time 
points in order to study the characteristics of the FL and host 
response that best describe clinical outcomes for standard and 
investigational therapeutics in the E2408 trial. We recognize that 
knowledge is moving quickly and that it is likely that some studies 
proposed at this time will be outdated while new studies will emerge 
as important at the conclusion of this trial. Therefore, it is essential to 


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collect the relevant biospecimens in preparation for state-of-the-art 
biomarker studies at the conclusion of patient accrual. 
11.3 
Banking 
Upon completion of the analysis, the residuals and/or derivatives of the bone 
marrow and blood collected for the laboratory studies will be retained in an 
ECOG-ACRIN designated repository for possible use in ECOG-ACRIN approved 
future studies. If future use is denied or withdrawn by the patient, the samples will 
be removed from consideration for use in any future study. 
11.4 
Sample Inventory Submission Guidelines 
Inventories of all samples collected, aliquoted, and used on the above mentioned 
laboratory studies and/or banking will be submitted electronically by secure web 
application to the ECOG-ACRIN Operations Office - Boston on a monthly basis 
or upon request by any laboratory holding and/or using any specimens 
associated with this study.  
11.5 
Lab Data Transfer Guidelines 
The data collected or generated on the above mentioned laboratory studies will 
be submitted electronically by secure web application to the ECOG-ACRIN 
Operations Office - Boston on a quarterly basis. The quarterly cut-off dates are 
March 31, June 30, September 30, and December 31.  
 
Rev. 10/11 


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12. 
Records to Be Kept 
Please refer to the E2408 Forms Packet for the forms submission schedule and copies 
of all forms. The E2408 Forms Packet may be downloaded by accessing the ECOG 
World Wide Web Home Page (http://www.ecog.org). Forms must be submitted to the 
ECOG-ACRIN Operations Office - Boston, FSTRF, 900 Commonwealth Avenue, 
Boston, MA 02215 (ATTN: DATA). 
This study will be monitored by the CTEP Data Update System (CDUS) version 3.0. 
Cumulative CDUS data will be submitted quarterly from the ECOG-ACRIN Operations 
Office - Boston to CTEP by electronic means. 
12.1 
Records Retention  
This study is being conducted under an IND exemption and is not intended to 
support any FDA-related filings. However, ECOG-ACRIN requires clinical 
investigators to retain all trial-related documentation, including source 
documents, for at least one year from the posting of the final technical report of 
the outcome of this trial to support any publication of the data.  
Please contact the ECOG-ACRIN Operations Office - Boston prior to destroying 
any source documents. 
 
13. 
Patient Consent and Peer Judgment 
Current FDA, NCI, state, federal and institutional regulations concerning informed 
consent will be followed. 


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inhibit the proliferation and function of T regulatory cells. Cancer Immunol 
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Oncology Group Phase I Consortium Report. ASH Annual Meeting Abstracts, 
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Bruce D. Cheson 
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Refractory Follicular Lymphoma: Encouraging Activity in the Phase 2 VERTICAL 
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Bendamustine in patients with rituximab-refractory indolent and transformed non- 


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Hodgkin’s lymphoma: Results form a Phase II multicenter, single-agent study. J 
Clin Oncol 2008; 26:204-10. 
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Phase II multicenter study of bendamustine plus rituximab in patients with 
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2008; 26(27):4473-9. 
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Rummel MJ, Al-Batran SE, Kim SZ, Welslau M, Hecker R, Kofahl-Krause D, et 
al. Bendamustine plus rituximab is effective and has a favorable toxicity profile in 
the treatment of mantle cell and low-grade non-Hodgkin's lymphoma. J Clin 
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Rummel M, von Grunhagen U, Niederle N, Rothmann F, Ballo H, Weidmann E, 
et al. Bendamustine plus rituximab versus CHOP plus rituximab in the first-line 
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Lymphomas, Germany). ASH Annual Meeting Abstracts 2007; 110:385. 
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Rummel M, Niederle N, Maschmeyer G, et al.  Bendamustine Plus Rituximab Is 
Superior in Respect of Progression Free Survival and CR Rate When Compared 
to CHOP Plus Rituximab as First-Line Treatment of Patients with Advanced 
Follicular, Indolent, and Mantle Cell Lymphomas: Final Results of a Randomized 
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RT, Dreyling M, Tobiani K, Vose JM, Connors JM, Federico M, Diehl V. Revised 
response criteria for malignant lymphoma. International Harmonization Project on 
Lymphoma. J Clin Oncol. 2007 Feb 10; 25(5): 579-86. 
 
 
 


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A 3-Arm Randomized Phase II Trial of Bendamustine-Rituximab (BR) Followed by 
Rituximab vs Bortezomib-BR (BVR) Followed by Rituximab vs BR Followed by 
Lenalidomide/Rituximab in High Risk Follicular Lymphoma 
 
Appendix I 
 
Informed Consent Template for Cancer Treatment Trials (English Language) 
[Deleted in Addendum #5] 
INFORMED CONSENT INTENTIONALLY REMOVED FROM 
PROTOCOL DOCUMENT 
Appendix I was removed from the protocol document in Addendum #5  and is posted as 
a separate document on the ECOG website. This was removed from the protocol to 
comply with NCI formatting guidelines. 
 
 


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A 3-Arm Randomized Phase II Trial of Bendamustine-Rituximab (BR) Followed by 
Rituximab vs Bortezomib-BR (BVR) Followed by Rituximab vs BR Followed by 
Lenalidomide/Rituximab in High Risk Follicular Lymphoma 
 
Appendix II 
 
Pathology Submission Guidelines 
1. Guidelines for Submission of Pathology Materials  
(instructional sheet for Clinical Research Associates [CRAs]) 
2. Instructional memo to submitting pathologists 
3. List of Required Materials for E2408. 
4. ECOG-ACRIN Generic Specimen Submission Form (#2981) 
 
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Guidelines for Submission of Pathology Materials 
The following items should always be included when submitting pathology materials 
to the ECOG-ACRIN Central Biorepository and Pathology Facility: 
· 
Institutional Surgical Pathology Report 
· 
Pathology materials (see attached List of Required Material) 
· 
ECOG-ACRIN Generic Specimen Submission Form (#2981) 
Instructions: 
1. Provide the following information to the pathologist. “*” indicate information to be provided 
with the submitted materials 
* Patient's name (last, first) 
* Protocol number 
* Protocol case number (the patient's ECOG-ACRIN sequence number 
Patient's hospital number 
* Institution and  
Affiliate (if appropriate) 
* The submitted materials must be labeled with the institution’s specimen specific 
assession number 
2. Complete blank areas of the pathologist's instructional memo and forward it, along with the 
List of Required Material to the appropriate pathologist. 
3. The pathologist should return the required pathology samples and surgical pathology 
reports, along with the completed ECOG-ACRIN Generic Specimen Submission Form 
(#2981); if used. If any other reports are required, they should be obtained from the 
appropriate department at this time. 
4. Keep a copy of the ECOG-ACRIN Generic Specimen Submission Form (#2981) or STS-
shipping manifest for your records. 
5. Double-check that ALL required forms, reports and pathology samples are included in the 
package to the Central Biorepository and Pathology Facility. (See appropriate List of 
Required Material.) 
Pathology specimens submitted WILL NOT be processed by the Central 
Biorepository and Pathology Facility until all necessary items are received. 
6. Mail pathology materials to: 
ECOG-ACRIN Central Biorepository and Pathology Facility 
MD Anderson Cancer Center 
Department of Pathology, Unit 085 
Tissue Qualification Laboratory for ECOG-ACRIN, Room G1.3586 
1515 Holcombe Blvd 
Houston, TX 77030 
If you have any questions concerning the above instructions or if you anticipate any problems in 
meeting the pathology material submission deadline of one month, contact the Pathology 
Coordinator at the ECOG-ACRIN Central Biorepository and Pathology Facility by telephone 
844-744-2420 or by email: eacbpf@mdanderson.org. 
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List of Required Material 
E2408     A 3-Arm Randomized Phase II Trial of Bendamustine-Rituximab (BR) Followed by 
Rituximab vs Bortezomib-BR (BVR) Followed by Rituximab vs BR Followed by 
Lenalidomide/Rituximab in High Risk Follicular Lymphoma 
Baseline (submit within one month of patient randomization) 
1. ECOG-ACRIN Generic Specimen Submission Form (#2981). 
2. Institutional pathology report (must be included with EVERY pathology submission). 
3. Required Pathology Materials: 
· 
Tumor block from the original diagnostic biopsy sample.   
NOTE: Submission of pathology materials for diagnostic review is mandatory in order 
for the patient to be considered evaluable. Failure to submit pathology 
materials may render the case unevaluable. 
 
During Treatment (submit within one month of collection) 
1. ECOG-ACRIN Generic Specimen Submission Form (#2981). 
2. Institutional pathology report (must be included with EVERY pathology submission). 
3. Pathology Materials: 
· 
Tissue blocks from any diagnostic biopsies performed while on study. 
 
NOTE 
If unable to submit blocks contact the ECOG-ACRIN CBPF for alternatives at 844-
744-2420 or eacbpf@mdanderson.org. 
NOTE: Since blocks are being used for laboratory studies, in some cases the material may 
be depleted and, therefore, the block may not be returned. 
 
 
Rev. 1/15 


 
158 
MEMORANDUM 
TO:  
 
 
(Submitting Pathologist) 
FROM: 
Stanley Hamilton, M.D., Chair 
 
ECOG-ACRIN Laboratory Science and Pathology Committee 
DATE:  
 
SUBJECT: 
Submission of Pathology Materials for A 3-Arm Randomized Phase II 
Trial of Bendamustine-Rituximab (BR) Followed by Rituximab vs 
Bortezomib-BR (BVR) Followed by Rituximab vs BR Followed by 
Lenalidomide/Rituximab in High Risk Follicular Lymphoma 
 
The patient named on the attached request has been entered onto an ECOG-ACRIN 
protocol by ______________________________ (ECOG-ACRIN Investigator).  This 
protocol requires the submission of pathology materials for pathology review and 
laboratory studies and banking. 
Keep a copy of the submission for your records. Forward the surgical pathology 
report(s), the slides and/or blocks and any other required material (see List of Required 
Material) to the Clinical Research Associate (CRA).  The CRA will forward all required 
pathology material to the ECOG-ACRIN Central Biorepository and Pathology Facility. 
Blocks and/or slides submitted for this study will be retained at the ECOG-ACRIN 
Central Repository for future studies.  Blocks will be returned for purposes of patient 
management upon request. 
Please note: Since blocks are being used for laboratory studies, in some cases the 
material may be depleted, and, therefore, the block may not be returned. 
If you have any questions regarding this request, please contact the Central 
Biorepository and Pathology Facility at 844-744-2420 or eacbpf@mdanderson.org. 
 
Rev. 9/14 
Rev.1/15 


ECOG-ACRIN Generic Specimen Submission Form     Form No. 2981v3 
Page 1 of 1 
159 
Institution Instructions: This form is to be completed and submitted with all specimens ONLY if the Sample Tracking System (STS) is not available. Use one form per patient, per time- 
point. All specimens shipped to the laboratory must be listed on this form. Enter all dates as MM/DD/YY. Keep a copy for your files. Retroactively log all specimens into STS once the system 
is available. Contact the receiving lab to inform them of shipments that will be sent with this form. 
Protocol Number    
 
Patient ID     
 
Patient Initials   Last  
 First     
 
Date Shipped    
 
Courier     
 
Courier 
Tracking Number    
 
Shipped To (Laboratory Name)   
 
Date CRA will log into STS    
 
FORMS AND REPORTS: Include all forms and reports as directed per protocol, e.g., pathology, cytogenetics, flow cytometry, patient consult, etc. 
 
Required fields for all samples 
Additional fields for tissue submissions 
Completed by  
Receiving Lab 
Protocol Specified Timepoint: 
Sample Type  
(fluid or fresh tissue, 
 include collection tube type) 
Quantity 
Collection  
Date and Time 24 HR 
Surgical or 
Sample ID 
Anatomic 
Site 
Disease Status  
(e.g., primary, mets, 
normal) 
Stain or 
Fixative 
Lab ID 
 
Fields to be completed if requested per protocol. Refer to the protocol-specific sample submissions for additional fields that may be required. 
Leukemia/Myeloma Studies: 
Diagnosis 
Intended Treatment Trial 
Peripheral WBC Count (x1000) 
Peripheral Blasts % Lymphocytes % 
 
 
 
 
Study Drug Information: 
Therapy Drug Name 
Date Drug Administered 
Start Time 24 HR 
Stop Time 24HR 
 
 
 
 
Caloric Intake: 
Date of Last Caloric Intake 
Time of Last Caloric Intake 24HR 
 
CRA Name   
 
CRA Phone   
 
CRA Email   
 
Comments 
 
9/12/14 


ECOG-ACRIN 
E2408 
Cancer Research Group 
Version Date: June 15, 2016 
 
NCI Update Date: January 23, 2015 
160 
A 3-Arm Randomized Phase II Trial of Bendamustine-Rituximab (BR) Followed by 
Rituximab vs Bortezomib-BR (BVR) Followed by Rituximab vs BR Followed by  
Lenalidomide/Rituximab in High Risk Follicular Lymphoma 
 
Appendix III 
 
Patient Thank You Letter 
We ask that the physician use the template contained in this appendix to prepare a letter 
thanking the patient  for enrolling in this trial. The template is intended as a guide and 
can be downloaded from the ECOG web site at http://www.ecog.org. As this is a 
personal letter, physicians may elect to further tailor the text to their situation. 
This small gesture is a part of a broader program being undertaken by ECOG-ACRIN 
and the NCI to increase awareness of the importance of clinical trials and improve 
accrual and follow-through. We appreciate your help in this effort. 
 ______________________________________________________________________  
 
[PATIENT NAME] 
[DATE] 
[PATIENT ADDRESS] 
 
 
Dear [PATIENT SALUTATION], 
 
Thank you for agreeing to take part in this important research study.  Many questions 
remain unanswered in cancer.  With the participation of people like you in clinical trials, 
we will improve treatment and quality of life for those with your type of cancer. 
We believe you will receive high quality, complete care.  I and my research staff will 
maintain very close contact with you.  This will allow me to provide you with the best 
care while learning as much as possible to help you and other patients. 
On behalf of [INSTITUTION] and the ECOG-ACRIN Cancer Research Group, we thank 
you again and look forward to helping you. 
 
 
Sincerely, 
 
 
 
 
[PHYSICIAN NAME] 
 
 
Rev. 9/14 


ECOG-ACRIN 
E2408 
Cancer Research Group 
Version Date: June 15, 2016 
 
NCI Update Date: January 23, 2015 
161 
A 3-Arm Randomized Phase II Trial of Bendamustine-Rituximab (BR) Followed by 
Rituximab vs Bortezomib-BR (BVR) Followed by Rituximab vs BR Followed by  
Lenalidomide/Rituximab in High Risk Follicular Lymphoma 
 
Appendix IV 
 
Follicular Lymphoma International Prognostic Index (FLIPI) 
FLIPI 1 
Each patient should be assessed for the presence or absence of the following 5 adverse 
prognostic factors (adverse factor in italics): FLIPI 1 
1) Age (> 60 years vs. ≤ 60 years) 
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 (> 4 vs 4 or less; see figure below 
please) 
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) 
                      Figure.  Nodal map according to FLIPI model. (Bilateral involvement = 2) 
 
high risk (3 or more adverse factors) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Solal-Celigny P, et al. Blood 2004; 104:1258-1265; and Buske C, et al. Blood. 2006;108:1504-1508. 
 
Rev. 4/13 
Rev. 2/14 


ECOG-ACRIN 
E2408 
Cancer Research Group 
Version Date: June 15, 2016 
 
NCI Update Date: January 23, 2015 
162 
 
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 treated in E2408 should be further 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; 27:1-9. 


ECOG-ACRIN 
E2408 
Cancer Research Group 
Version Date: June 15, 2016 
 
NCI Update Date: January 23, 2015 
163 
A 3-Arm Randomized Phase II Trial of Bendamustine-Rituximab (BR) Followed by 
Rituximab vs Bortezomib-BR (BVR) Followed by Rituximab vs BR Followed by  
Lenalidomide/Rituximab in High Risk Follicular Lymphoma 
Appendix V 
 
Patient Pill Diary for Lenalidomide 
Patient Name______________________________________________________ 
Dates: __________________________ through __________________________ 
Lenalidomide 20 mg PO (by mouth) Days 1 to 21, every 28 days (If dose other than 
20mg: ________) 
DAY 
Date 
 
Number of 
capsules taken 
Aspirin (or other 
anticoagulant) 
Comments 
Day 1 
 
 
 
 
Day 2 
 
 
 
 
Day 3 
 
 
 
 
Day 4 
 
 
 
 
Day 5 
 
 
 
 
Day 6 
 
 
 
 
Day 7 
 
 
 
 
Day 8 
 
 
 
 
Day 9 
 
 
 
 
Day 10 
 
 
 
 
Day 11 
 
 
 
 
Day 12 
 
 
 
 
Day 13 
 
 
 
 
Day 14 
 
 
 
 
Day 15 
 
 
 
 
Day 16 
 
 
 
 
Day 17 
 
 
 
 
Day 18 
 
 
 
 
Day 19 
 
 
 
 
Day 20 
 
 
 
 
Day 21 
 
 
 
 
Day 22 
 
 
 
 
Day 23 
 
 
 
 
Day 24 
 
 
 
 
Day 25 
 
 
 
 
Day 26 
 
 
 
 
Day 27 
 
 
 
 
Day 28 
 
 
 
 


ECOG-ACRIN 
E2408 
Cancer Research Group 
Version Date: June 15, 2016 
 
NCI Update Date: January 23, 2015 
164 
Additional Instructions for Patients 
· 
Bring the diary to every appointment 
· 
Record doses as you take them and do not batch entries at a later time 
· 
Correct errors if they occur by crossing them out and writing in the correct information 
· 
Do not open, crush or chew lenalidomide capsules 
· 
If you miss a dose, take it as soon as you remember on the same day. If you miss taking 
your dose for the entire day, take your regular dose the next scheduled day. Do NOT 
double your regular dose to make up for the missed dose. 
· 
If you take more than the prescribed dose of lenalidomide you should seek emergency 
medical care if needed and contact study staff immediately.


ECOG-ACRIN 
E2408 
Cancer Research Group 
Version Date: June 15, 2016 
 
NCI Update Date: January 23, 2015 
165 
A 3-Arm Randomized Phase II Trial of Bendamustine-Rituximab (BR) Followed by 
Rituximab vs Bortezomib-BR (BVR) Followed by Rituximab vs BR Followed by 
Lenalidomide/Rituximab in High Risk Follicular Lymphoma 
 
Appendix VI 
 
FDG-PET IMAGING 
FDG-PET/CT scans with 18Fluorine- fluorodeoxyglucose (FDG) will be performed at baseline, 
after three (3) cycles of induction chemotherapy, at completion of induction chemotherapy (i.e., 
after six (6) cycles of induction chemotherapy) and at relapse.  FDG-PET/CT will then be 
repeated until a patient achieves CR status, then only CTs will be obtained.  
NOTE: 
Scan data must be submitted to QARC at each time point, i.e. after baseline, interim 
response, final response, continuation, and relapse. 
Baseline FDG-PET/CT scan: 
All patients should have a pre-treatment FDG-PET/CT scan as a baseline to compare with 
subsequent scans to assess response.  This should be performed no more than six (6) weeks 
before starting chemotherapy.  
Interim Response FDG-PET/CT scan: 
To assess the response to the first thee (3) cycles of chemotherapy, an interim PET/CT scan 
will be performed after cycle three (3) of induction chemotherapy.  Scan data must be submitted 
to QARC.   
Final Response Assessment FDG-PET/CT scan: 
To assess the final response after completion of all therapy, patients should have repeat whole 
body PET/CT scans and diagnostic quality, contrast-enhanced CT scans of the chest, 
abdomen, and pelvis (and neck, if done at baseline), 30 days after completion of the last dose of 
induction chemotherapy. 
Continuation:   
Re-staging will be repeated after 7, 13, 18, and 24 months of continuation. Once a patient 
achieves CR status, then FDG-PET/CT will not be performed (i.e., only CT with contrast). 
Patients not in CR at start of continuation should have both contrast CT and FDG-PET/CT 
performed- until CR is achieved. 
Scans should also be submitted at relapse. 
Scanning Facilities 
•  
Only full-ring integrated FDG-PET/CT scanners are acceptable (coincidence cameras are 
not acceptable). The CT of the FDG-PET/CT is used for attenuation correction of PET data 
and anatomic localization. CT settings should follow institutional guidelines.  
•  
Scans must be sent in DICOM format via CD via overnight delivery or electronically via 
SFTP to the Quality Assurance Review Center (QARC).  See central review section below 
for further requirements. 
· Instructions to obtain an sFTP are found on the QARC website:  www.QARC.org 
Rev. 4/13 
Rev. 2/14 


ECOG-ACRIN 
E2408 
Cancer Research Group 
Version Date: June 15, 2016 
 
NCI Update Date: January 23, 2015 
166 
· CD’s should be submitted to the address below.  Multiple studies for the same patient 
may be submitted on one CD; however, please submit only one patient per CD. 
Quality Assurance Review Center (QARC) 
640 George Washington Highway 
Suite 201 
Lincoln, RI 02865 
Phone: 401-753-7600 
Fax: 401-753-7601 
· For questions please contact ECOG-ACRIN Study Manager at QARC at the phone 
number above or by e-mail:  ECOG@QARC.org 
Scanning Protocol   
Patient preparation 
Non-diabetic patients should fast for at least 8 hours prior to the scan.  Plain (unflavored water) 
should be taken during the period of fasting and the uptake period to ensure good hydration. 
Diabetic patients should ideally be given a morning appointment. They should take their usual 
antidiabetic medication (oral or insulin) and eat a light meal (lighter than they normally would) on 
that morning. The time interval between that morning meal and PET/CT scan should be 
approximately 3-4 hours. 
Oral diazepam or beta blockers may be given if desired to reduce brown fat uptake one hour 
prior to tracer injection.   
Oral diluted contrast (e.g., Gastografin or 2% barium sulfate) may be administered, according to 
institutional guidelines. Intravenous contrast may also be administered, provided this is done in 
a technique that avoids deterioration of the CT images by streak artifacts from high-
concentration intravenous contrast bolus.    
Detailed scanning protocol 
1. 
Administer 260 - 555 MBq (7-15mCi) 18F- FDG 
2. 
Emission part of the scan should start no earlier than 60 and no later than 90 minutes after 
injection. 
3. 
The exact same period of uptake must be used for staging and response scans – within 15 
minutes.  
4. 
Perform attenuation corrected PET-CT scan to cover the area from the base of the skull to 
mid-thigh. This should be done with the arms above the head.  
5. 
Perform a separate head and neck scan, with arms down, ONLY IF this is the only site of 
disease. 
6. 
Attenuation correction of PET emission data will be based on the low dose CT from the 
FDG-PET/CT. 
Acquisition should be performed using the institution’s standard protocol, i.e. with regard to time 
per bed position, 2D or 3D, CTAC parameters, reconstruction parameters etc. Images should be 
reconstructed using OSEM or a similar iterative reconstruction algorithm. Both attenuation-
corrected and non attenuation-corrected images should be reconstructed. The proposed data 
acquisition/reconstruction protocol (including details of all the parameters above) must be 
agreed with the core lab prior to the start of the study. 
Image data transfer 
Image data must be transferred to QARC at the same time as the completed FDG-PET/CT 
acquisition form.  


ECOG-ACRIN 
E2408 
Cancer Research Group 
Version Date: June 15, 2016 
 
NCI Update Date: January 23, 2015 
167 
The following DICOM files are required (save screens, post-processed movies, static 
DICOM re-renderings of images or similar files are NOT adequate for interpretation): 
· Attenuation corrected images (skull base to mid thigh) 
· Non-attenuation corrected half body images 
· CT scan (skull base to mid thigh) 
· Attenuation corrected view of head and neck (if performed) 
· Non-attenuation corrected view of head and neck (if performed) 
· Head and neck CT scan (if performed) 
Projection images (MIPs) are not required. 
NOTE: 
For PET/CT imaging, the transferred imaging data should include uncorrected and 
attenuation-corrected PET projection data, as well as the reconstructed PET or 
PET/CT images used by the institution to achieve a response assessment. The 
imaging data submitted for central review must allow the study to be reconstructed 
and displayed in transaxial, sagittal and coronal formats using standard 
reconstruction techniques. Reconstructed MPEG clips and similar types of 
reconstructions will not be accepted.  
Central Review. 
Response determinations and treatment decisions will NOT be based on the centralized review.  
The central review is for the establishment of an image bank. 
Reporting. 
Visual interpretation will be used. The PET response scans will be scored with reference to sites 
of presumed lymphomatous involvement on the PET staging scan. 
Negative 
1 
no uptake  
2 
uptake ≤ mediastinum 
3 
uptake > mediastinum but ≤ liver 
Positive 
4 
uptake > liver in some sites even if uptake ≤ liver or mediastinum at other sites 
5 
uptake > liver in over 90% of sites or development of new uptake consistent with 
progressive disease 
For the purpose of this study, scores 1, 2, 3 with uptake in sites abnormal on the staging scan 
equal or less than liver uptake will be regarded as ‘negative’ for disease and scores 4, 5 with 
uptake greater than liver will be regarded as ‘positive’ for disease. A separate analysis will be 
performed on patients with a score of 3 whose scan findings are analogous to the concept of 
‘minimal residual disease’ (MRU) referred to in earlier published data on the use of PET in 
lymphoma.  However for the purposes of treatment, patients with a score of 3 on the interim 
PET scan will be regarded as negative for disease. 
Absolute and relative standard uptake values (SUVs) will be recorded for research 
purposes but SHOULD NOT be used to determine scan positivity (because of inter-
institution variations in scan performance and the acknowledged lack of standardization 
for SUV values).   


ECOG-ACRIN 
E2408 
Cancer Research Group 
Version Date: June 15, 2016 
 
NCI Update Date: January 23, 2015 
168 
Standard uptake values (SUVs) will be used to quantify tracer uptake, and response to therapy 
will be determined by the change in SUV for scans acquired before and after therapy. The 
change in SUV will be correlated with actual prognosis to test the possibility of defining 
"quantitative response categories" which may have prognostic value. SUV numbers will be used 
in a post hoc analysis and the most appropriate measure to be used will be determined. The 
use of SUVmax and variations of SUVmax will be used in this analysis. 
SUVs will be measured either by using a volumetric region of interest (ROI) that clearly 
encompasses a given lesion (carefully avoiding areas of higher normal activity in the vicinity, 
such as kidneys or bladder), or with a circular ROI. If a circular ROI is used, this needs to be 
done in several slices to assure that the recorded SUV is indeed the highest SUV within a given 
lesion. SUV max will be reported, normalized to body weight. A total of 6 lesions will be 
measured in this protocol. 
Radiation Dosimetry 
The whole body dose for FDG is about 0.10 rad/mCi, and the effective dose equivalent about 
0.10 rem/mCi (0.03mSv/MBq). For the suggested activity range of 7-15mCi, the effective dose 
equivalent will be 0.7-1.5 rem (7.8 – 16.6mSv) (ARSAC Notes for Guidance 2006). The target 
organ is the urinary bladder wall, which will receive 0.22rad/mCi with a realistic one hour voiding 
interval (ICRP Publication 53). The dose from a low dose (140kV, 80mA) CT as part of a 
PET/CT is about 0.9 rad (rem) or 9mSv (Wu et al. Eur J Nucl Med Mol Imaging 31:38-43, 2004).   
 


ECOG-ACRIN 
E2408 
Cancer Research Group 
Version Date: June 15, 2016 
 
NCI Update Date: January 23, 2015 
169 
 
E2408 ACQUISITION DATA FOR FDG-PET/CT SCAN 
(To be completed by PET scanning facility. Please submit the scans along with 
the corresponding radiology reports for the scans to QARC) 
 
 
PET-CT Scan acquired at    
__________________________ 
Patient’s initials: 
 
 
__________________________ 
Patient’s ECOG-ACRIN  
sequence number: 
__________________________ 
Referring Consultant:  
 
__________________________ 
Consultant telephone number: 
__________________________ 
Consultant fax number: 
 
__________________________ 
Hospital name and address:  
__________________________ 
 
 
 
 
 
__________________________ 
 
 
 
 
 
__________________________ 
Date of PET scan: 
 
 
__________________________ 
Time of administration of activity (hour:min) ____________________ 
Site of tracer administration and state left or right 
______________ 
Patient height (cm) 
 
 
__________________________ 
Patient weight (kg) 
 
 
__________________________ 
 
 
 
 
 
START TIME 
NO OF BED 
POSITIONS 
DURATION PER 
BED POSITION 
TOTAL SCAN 
DURATION 
Skull Base-Thighs 
 
 
 
 
HEAD & NECK 
SCAN (if acquired) 
 
 
 
 
 
 
 
 
 
 
 
 


ECOG-ACRIN 
E2408 
Cancer Research Group 
Version Date: June 15, 2016 
 
NCI Update Date: January 23, 2015 
170 
 
RESULT OF INTERIM PET-CT SCANS (AFTER CYCLE 3 AND AFTER CYCLE 
6 OF INDUCTION CHEMOTHERAPY AND DURING CONTINUATION IF CR IS 
NOT ACHIEVED AND AT RELAPSE) according to 5 point scale:  
1 :   no uptake 
2 :   uptake ≤ mediastinum 
3 :   uptake > mediastinum but ≤ liver 
4 :   uptake > liver at some sites even if uptake ≤ liver or mediastinum at other      
       sites 
5 :   uptake > liver in > 90% of initial sites or development of new sites consistent  
       with progressive disease 
 
 
 
Local Report 
 
Score  
1 
2 
3 
4 
5                                (please circle) 
 
List sites of residual uptake (score 4 and 5): 
 
                                          
   . 
 
Comments e.g. positive sites elsewhere in the body: 
 
Name:                        Date: 
 
Signature: 
 
 
 
 


ECOG-ACRIN 
E2408 
Cancer Research Group 
Version Date: June 15, 2016 
 
NCI Update Date: January 23, 2015 
171 
WHEN COMPLETED, SEND BOTH SHEETS WITH IMAGE DATA FILES (SEE PROTOCOL) 
TO QARC AND RETAIN FIRST COPY FOR FDG-PET/CT CENTER RECORDS 
 
SUV ANALYSIS 
 
The study will rely on visual interpretation only.  However data will be collected for post hoc 
analysis to determine whether visual interpretation can be refined and semi-quantitative 
measures used to subgroup patients further into ‘tighter’ quantitative response categories which 
may have prognostic value. A scheme for analysis of semi-quantitative data is suggested below. 
 
The ‘hottest’ lesions at staging will be chosen for SUV analysis but if subsequently the response 
scan shows residual activity at sites different from the ‘hottest’ lesions at staging, these sites will 
be used as the index lesions instead. Uptake in up to 6 lesions will be documented. The 
maximum SUV within the lesion will be calculated using decay corrected administered dose and 
body weight. The maximum SUV will be selected using a region of interest placed on the axial 
PET slice with the highest uptake. The maximum CT diameter of the mass will be recorded on 
the axial slice with the greatest CT diameter. Note the PET and CT axial slices may not match 
as the maximum SUV may occur within the lesion in a different axial plane to the maximum size 
on CT. If this occurs and the entire lesion shows at least some degree of FDG uptake, the 
maximum CT diameter in transaxial dimension should be recorded. However, if only a section of 
a large residual mass shows residual FDG uptake on the interim scan, then the CT diameter 
should be measured on the slice where that residual FDG uptake occurs.  
 
Initial staging CT scan (with intravenous contrast) 
 
Index 
lesion 
Site 
e.g. left supraclavicular 
SUV max 
PET axial 
slice 
CT max  
transverse 
diameter (mm) 
CT axial slice 
1 
 
 
 
 
 
2 
 
 
 
 
 
3 
 
 
 
 
 
4 
 
 
 
 
 
5 
 
 
 
 
 
6 
 
 
 
 
 
 
Response CT scans (with intravenous contrast) after primary chemotherapy 
Correlate with staging scan index lesions and note any additional lesions with higher uptake  
 
Index 
lesion 
Site 
e.g. left supraclavicular 
SUV max 
PET axial 
slice 
CT max  
transverse 
diameter (mm) 
CT axial slice 
1 
 
 
 
 
 
2 
 
 
 
 
 
3 
 
 
 
 
 
4 
 
 
 
 
 
5 
 
 
 
 
 
6 
 
 
 
 
 
 
FORM COMPLETED BY: 
Rev. 10/11 


ECOG-ACRIN 
E2408 
Cancer Research Group 
Version Date: June 15, 2016 
 
NCI Update Date: January 23, 2015 
172 
A 3-Arm Randomized Phase II Trial of Bendamustine-Rituximab (BR) Followed by 
Rituximab vs Bortezomib-BR (BVR) Followed by Rituximab vs BR Followed by  
Lenalidomide/Rituximab in High Risk Follicular Lymphoma 
 
Appendix VII 
 
Bendamustine Reconciliation 
Certificate of Destruction of Clinical Trial Drugs  
 
Instructions: 
Complete this form when patient’s treatment is completed at your institution. All 
unused drugs, partially used, or empty containers must be destroyed according 
to institutional policy for drug destruction. A copy of this form should emailed to 
Teva Oncology at carolyn.paugh@tevapharm.com or faxed to 610-756-2030.  A 
copy should be maintained with the drug accountability records for this protocol. 
 
Sponsor: 
Teva Oncology/ECOG-ACRIN 
ECOG-ACRIN Study No. 
E2408 
DPM: 
Carolyn Paugh 
 
Investigator Name: 
 
Investigator Number: 
 
Investigator Address: 
 
 
 
Drug Name 
Lot Number 
Expiry Date 
Amount 
Used 
Amount 
Unused 
Number of Bottles 
destroyed at site 
Bendamustine 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Reason for destruction: _______________________________________________________ 
 
Method & Location of destruction: ______________________________________________ 
 
Date of Destruction: __________________________________________________________ 
 
I confirm the above material has been destroyed in a safe and appropriate manner. 
Name and Title: ______________________________________________________________ 
Date: ____________________________________ 
Signature: ________________________________ 
PI Signature: _____________________________ 
Rev. 4/13 
Rev. 9/14 


ECOG-ACRIN 
E2408 
Cancer Research Group 
Version Date: June 15, 2016 
 
NCI Update Date: January 23, 2015 
173 
A 3-Arm Randomized Phase II Trial of Bendamustine-Rituximab (BR) Followed by 
Rituximab vs Bortezomib-BR (BVR) Followed by Rituximab vs BR Followed by  
Lenalidomide/Rituximab in High Risk Follicular Lymphoma 
 
Appendix VIII 
 
Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable Birth Control 
Methods 
Risks Associated with Pregnancy 
The use of lenalidomide in pregnant females and nursing mothers has not been studied 
nor has the effect of the lenalidomide on human eggs and sperm. The risks to a fetus 
are not known.  However, because lenalidomide is related to thalidomide, and 
thalidomide is known to cause severe birth defects, the following requirements must be 
observed. 
All study participants must be registered into the mandatory RevAssist® program, and 
be willing and able to comply with the requirements of RevAssist®. 
Females of childbearing potential (FCBP)† must agree to use two reliable forms of 
contraception simultaneously or to practice complete abstinence from heterosexual 
intercourse during the following time periods related to this study: 1) for at least 28 days 
before starting lenalidomide; 2) while participating in the study; and 3) for at least 28 
days after discontinuation from the study. The two methods of reliable contraception 
must include one highly effective method (i.e. intrauterine device (IUD), hormonal [birth 
control pills, injections, or implants], tubal ligation, partner’s vasectomy) and one 
additional effective (barrier) method (i.e. latex condom, diaphragm, cervical cap).  FCBP 
must be referred to a qualified provider of contraceptive methods if needed.  
· 
Because of the increased risk of venous thromboembolism in patients with multiple 
myeloma taking lenalidomide and dexamethasone, combined oral contraceptive pills 
are not recommended. If a patient is currently using combined oral contraception the 
patient should switch to one of the effective method listed above. The risk of venous 
thromboembolism continues for 4−6 weeks after discontinuing combined oral 
contraception. The efficacy of contraceptive steroids may be reduced during co-
treatment with dexamethasone. 
· 
Implants and levonorgestrel-releasing intrauterine systems are associated with an 
increased risk of infection at the time of insertion and irregular vaginal bleeding. 
Prophylactic antibiotics should be considered particularly in patients with 
neutropenia. 
Before starting lenalidomide: 
Female Subjects:   
· 
FCBP must have two negative pregnancy tests (sensitivity of at least 25 mIU/mL) 
prior to prescribing lenalidomide. The first pregnancy test must be performed within 
10-14 days prior to prescribing lenalidomide and the second pregnancy test must be 
performed within 24 hours prior to prescribing lenalidomide (prescriptions must be 
filled within 7 days).  The subject may not receive lenalidomide until the Investigator 
has verified that the results of these pregnancy tests are negative. 
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† A female of childbearing potential is a sexually mature woman who: 1) has not undergone a hysterectomy 
or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months 
(i.e., has had menses at any time in the preceding 24 consecutive months). 
Male Subjects:   
· 
Must agree to use a latex condom during sexual contact with females of childbearing 
potential while participating in the study and for at least 28 days following 
discontinuation from the study even if he has undergone a successful vasectomy.  
During study participation and for 28 days following discontinuation from the study: 
All Subjects: 
· 
If pregnancy or a positive pregnancy test does occur in a study subject or the partner 
of a male study subject during study participation, lenalidomide must be immediately 
discontinued. 
Female Subjects:   
· 
FCBP with regular or no menstrual 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 
FCBP that she is continuing to use two reliable methods of birth control at each visit.   
· 
Pregnancy testing and counseling must be performed if a subject misses her period 
or if her pregnancy test or her menstrual bleeding is abnormal.  Lenalidomide 
treatment must be discontinued during this evaluation. 
Male Subjects: 
· 
Must agree to use a latex condom during sexual contact with females of childbearing 
potential while participating in the study and for at least 28 days following 
discontinuation from the study even if he has undergone a successful vasectomy. 


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A 3-Arm Randomized Phase II Trial of Bendamustine-Rituximab (BR) Followed by 
Rituximab vs Bortezomib-BR (BVR) Followed by Rituximab vs BR Followed by  
Lenalidomide/Rituximab in High Risk Follicular Lymphoma 
 
Appendix IX 
 
RevAssist for Study Participants 
 
RV-E2408 
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A 3-Arm Randomized Phase II Trial of Bendamustine-Rituximab (BR) Followed by 
Rituximab vs Bortezomib-BR (BVR) Followed by Rituximab vs BR Followed by  
Lenalidomide/Rituximab in High Risk Follicular Lymphoma 
Appendix X 
 
Modified Cumulative Illness Rating Scale (CIRS) 
 
The Modified Cumulative Illness Rating Scale (CIRS). 
 
 
Body system 
Score 
1. 
Cardiac (heart only) 
0 
1 
2 
3 4 
2. 
Hypertension (rating is based on severity; organ damage is rated separately) 
0 
1 
2 
3 4 
3. 
Vascular (blood, blood vessels and cells, bone marrow, spleen, lymphatics) 
0 
1 
2 
3 4 
4. 
Respiratory (lungs, bronchi, trachea below the larynx) 
0 
1 
2 
3 4 
5. 
EENT (eye, ear, nose, throat, larynx) 
0 
1 
2 
3 4 
6. 
Upper GI (esophagus, stomach, and duodenum; pancreas; do not include 
diabetes) 
0 
1 
2 
3 4 
7. 
Lower GI (intestines, hernias) 
0 
1 
2 
3 4 
8. 
Hepatic (liver and biliary tree) 
0 
1 
2 
3 4 
9. 
Renal (kidneys only) 
0 
1 
2 
3 4 
10. Other GU (ureters, bladder, urethra, prostate, genitals) 
0 
1 
2 
3 4 
11. Muscolo-skeletal-integumentary (muscle, bone, skin) 
0 
1 
2 
3 4 
12. Neurological (brain, spinal cord, nerves, do not include dementia) 
0 
1 
2 
3 4 
13. Endocrine-Metabolic (includes diabetes, thyroid; breast; systemic infections; 
toxicity) 
0 
1 
2 
3 4 
14. Psychiatric/Behavioral 
(includes 
dementia, 
depression, 
anxiety, 
agitation/delirium, psychosis) 
0 
1 
2 
3 4 
PHILOSOPHY AND DEVELOPMENT OF THE SCALE 
Compiling and quantifying medical problems in the elderly population will allow meaningful 
comparison of medical burden and treatment outcomes in elderly patients with variable and 
complex medical problems. 
The Cumulative Illness Rating Scale (CIRS) was initially developed by Linn et al. and published 
in JAGS 1968 (1); it appeared immediately a user friendly but comprehensive review of medical 
problems by organ systems, based on a 0 thru 4 rating, yielding a cumulative score.  This scale 
was successively revised by Miller et al. to reflect common problems of the elderly with an 
emphasis on morbidity using specific examples and was renamed CIRS for Geriatrics (CIRS-G) 
(2); moreover, Miller and Towers provided also a manual of guidelines for scoring their version 
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Then, in 1995, Parmelee et al. validated a Modified CIRS version, based on a 1 thru 5 rating 
and with some differences in categories, in a geriatric residential population (4). Finally, Mistry 
et al. used this latter Modified CIRS version with a 0 thru 4 rating to measure medical burden in 
psychogeriatric participants of the UPBEAT program, showing that inclusion of acute medical 
conditions did not undermine the usefulness of the CIRS (5). Based on the version of Miller and 
Towers, current guidelines were adapted to the Modified CIRS version and updated. 
RATING SUGGESTIONS (GENERAL PRINCIPLES) 
Every single disease must be classified in the appropriate system. If there are several problems 
in the same system, only the most severe is rated. Example: for a patient suffering from mild 
diet-controlled diabetes (Grade 1) and hyperthyroidism in pharmacologic treatment (Grade 2), 
only the higher rated condition would be scored in the Endocrine system (e.g. rating is 2). 
The spread of a cancer may lead to rate the condition in more than one category. For example, 
lymphoma with bone involvement treated with nonsteroidal anti-inflammatory drugs (NSAID) is 
Rated 4 in Respiratory and 2 in Musculoskeletal. 
General rules for severity rating: 
0 -  No problem affecting that system or past problem without clinical relevance. 
1 -  Current mild problem or past significant problem. 
2 -  Moderate disability or morbidity and/or requires first line therapy. 
3 -  Severe problem and/or constant and significant disability and/or hard to control chronic 
problems (complex therapeutic regimen). 
4 -  Extremely severe problem and/or immediate treatment required and/or organ failure and/or 
severe functional impairment. 
LEVEL 0 
No problem or healed minor injuries; past childhood illnesses (chickenpox); minor surgery 
(carpal tunnel completely healed, caesarean); uncomplicated healed fractures; other past 
problems healed without sequel, residual or complication (pneumonia). 
LEVEL 1 
Any current medical problem that causes mild discomfort or disability, or has occasional 
exacerbations, having only minor impact on morbidity (asthma controlled with PRN 
bronchodilators, occasional heartburn relieved with PRN antiacids). Medical problems that are 
not currently active but were significant problems in the past (passage of a kidney stone) or 
required major surgery (hysterectomy, cholecystectomy, appendectomy). 
LEVEL 2 
Medical conditions that require daily treatment or first line therapy (asthma controlled with 
inhaled steroids, gastro-esophageal reflux treated with daily medication, osteoarthritis requiring 
daily NSAID, etc.) and/or have moderate disability or morbidity. 
LEVEL 3 
Chronic conditions that are not controlled with first line therapy (asthma needing continuous 
corticosteroid therapy, symptomatic angina despite medical regimes, heart failure with 
symptoms or uncontrolled hypertension despite complex therapeutic regimen) and/or constant 
significant disability, but not severe disability. 
LEVEL 4 
Any acute condition that requires immediate treatment or hospitalization (unstable angina, acute 
myocardial infarction, stroke, but also bladder outlet obstruction) and/or extremely severe 


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problems; organ failure (end-stage renal disease needing dialysis, oxygen-dependent chronic 
obstructive pulmonary disease, terminal heart failure); severe sensory impairment (almost 
complete blindness or deafness, being wheelchair bound) and/or severely affected quality of 
life, severe impairment in function; delirium by medical (organic) conditions. 
ORGAN SPECIFIC CATEGORIES 
The following organ specific categories will attempt to provide guidelines for consistent rating of 
comparable severity. Common conditions will be stressed with the focus on the “judgement 
strategy” that can be applied to other problems not listed.  
If there are several problems in the same system, only the most severe is rated. 
HEART 
In this category only heart and coronary disease have to be considered (not vascular): coronary 
arteries disease, heart failure, valvular heart diseases, heart disease secondary to hypertension, 
endocardities, miocardities, pericardities, arrhythmias (extrasystoles, bundle-branch blocks, 
atrial fibrillation, PMK placement), heart malignancies. Functional impact must be considered 
too, e.g. NYHA II heart failure has different value between dependent and independent persons. 
0. No problems 
1. Remote MI (>5 years ago); occasional [exertion] angina; asymptomatic valvular disease 
2. CHF compensated with meds (NYHA I-II); daily anti-angina meds; left ventricular 
hypertrophy; atrial fibrillation, bundle branch block, daily anti-arrhythmic drugs (even for 
prophylaxis); PMK placement for asymptomatic bradycardia (relieved by Holter EKG 
monitoring); valvular disease requiring medical treatment 
3. Previous MI (<5 years ago); abnormal stress test; status post (previous) percutaneous 
coronary angioplasty, coronary artery bypass graft surgery or other cardiac surgery (valve 
replacement); moderate CHF (NYHA II-III) or complex medical treatment; bifascicular block; 
PMK placement for cardiogenic syncope; pericardial effusion or pericarditis 
4. Acute coronary syndrome, unstable angina or acute MI; intractable CHF (NYHA III-IV acute 
or chronic); marked restriction to the normal activity of daily living secondary to cardiac status 
HYPERTENSION 
Consider only hypertension severity; organ damage (complications) should be considered into 
the respective categories. 
0. Normotension 
1. Borderline hypertension; hypertension compensated with salt restriction and weight loss, 
drug free (when drug therapy is indicated, but the patient does not take meds, the score is at 
least 2) 
2. Daily antihypertensive meds: hypertension controlled by 1 pill therapy (even fixed doses 
combinations) 
3. Hypertension requiring two or more pills for control 
4. Malignant hypertension, or hypertension non controlled by complex therapeutic regimen 
VASCULAR-HEMATOPOIETIC 
Artery disease: carotid atherosclerosis, peripheral arteries disease (PAD), aneurysms (every 
site); 
Venous disease: venous insufficiency, varices, deep venous thrombosis (DVT), pulmonary 
embolism, primary pulmonary hypertension; 
Hematopoietic disease: anemia, leucopenia, thrombocytopenia, hematological malignancy; 
Lymphopoietic disease: chronic lymphatic edema, lymphoma, spleen and thymus disease; 


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Immunologic disease: systemic lupus erythematosus, systemic sclerosis (scleroderma), 
sarcoidosis, hypersensitivity 
0. No problem 
1. Venous insufficiency, varices, lymphedema; carotid stenosis < 70%; hemoglobin 10-12 g/dl 
(in females), 12-14 g/dl (in males); anemia of chronic “inflammatory” disease 
2. Previous DVT; one symptom of atherosclerosis disease (claudication, bruit, amaurosis fugax, 
absent pedal pulses) or daily meds (e.g. anti-platelets drugs); PAD IIa-IIb by Fontaine; 
carotid stenosis > 70%; aortic aneurysm < 4 cm; hemoglobin 8-10 g/dl (in females), 10-12 
g/dl (in males); anemia secondary to iron, B12 vitamin or folate deficiency, or to chronic renal 
failure; total white blood cell (WBC) 2000-4000/mmc; mild thrombocytopenia (50000-
150000/mmc) 
3. DVT or recent DVT (< 6 months ago); two or more symptoms of atherosclerosis (see above); 
PAD Fontaine III or recent/previous angioplasty (with or without stenting); hemoglobin <8g/dl 
(in females), < 10 g/dl (in males); dyserythropoietic anemia; WBC < 2000/mmc; severe 
thrombocytopenia (< 50000/mmc) 
Pulmonary embolism (acute or recent/previous); atherosclerosis requiring surgical intervention 
(e.g. aortic aneurysm > 4 cm, symptomatic carotid stenosis >70%, PAD Fontaine IV or 
amputation for vascular causes, etc.); recent/previous vascular surgery; any hematological or 
vascular malignancy (including multiple myeloma) 
In case of immunological disease, score should be assigned by considering blood 
abnormalities, stadium of organ damage and/or functional disability (2: symptoms controlled by 
daily meds; 3: symptoms not well controlled; 4: symptoms impossible to be controlled or short 
time poor prognosis). 
RESPIRATORY 
In this category we consider COPD, asthma, emphysema, restrictive pulmonary interstitial lung 
diseases, malignancies of lung and pleura, pneumonia, and smoking status too. 
0. No problem 
1. Recurrent episodes of acute bronchitis; currently treated asthma with prn inhalers when 
required; cigarette smoker > 10 but < 20 pack years 
2. Instrumental diagnosis of COPD or pulmonary interstitial disease (x-ray, TC, spirometry); 
daily prn inhalers (≤ 2 pharmacological classes); two or more episodes of pneumonia in the 
last 5 years; cigarette smoker > 20 but < 40 pack years 
3. exertion dyspnea secondary to limited respiratory capacity, not well controlled by daily meds; 
required oral steroids for lung disease; daily prn inhalers (3 pharmacological classes); acute 
pneumonia treated as an outpatient 
4. Chronic supplementation of oxygen; respiratory failure requiring assisted ventilation, or 
previous (at least one episode); any lung or pleural neoplasm; acute pneumonia requiring 
hospitalization 
Smoking is an important respiratory and cardiovascular risk, so it is considered as a disease, 
and it is rated according to lifetime pack years:  
Number of cigarette packs smoked per day X Number of years smoked in their lifetime 
e.g. 
1 pack year = 20 cigarettes/die (1 pack) X 1 year 
Ex-smokers should be rated too, but those who have been smoke free for the most recent 20 
years would merit a lower rating than currently smoking 
Examples: 
A. Patient smoking 20 cig/die (1 pack) for 25 years = 25 pack years - CIRS score: 2 
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B. Patient smoking 40 cig/die (2 packs) for 25 years = 50 pack years – CIRS score: 3 
C. Ex-smoker of 20 cig/die (1 pack) for 25 years, he stopped 5 years ago – CIRS score: 2 
D. Ex smoker of 20 cig/die (1 pack) for 25 years, he stopped 20 years ago – CIRS score: 1 
Classification of COPD could be more specific when instrumental data (objective evidence) are 
available: blood gases, forced expiratory volume in 1 second (FEV1), etc. 
EYES, EARS, NOSE & THROAT, and LARYNX 
To simplify the potential complexity of this category it was decided to score according to the 
severity of the disability created by sensory diseases (degree of limited autonomy and 
communication), and avoid rating each type of pathology. Sensory impairments should be rated 
after instrumental correction (corrective lenses, hearing aid, etc.). 
Eyes: glaucoma, cataracts, macular degeneration (diabetic/hypertensive retinopathy), any other 
pathology 
Ears: otitis, dizziness, any cause of hearing impairment 
Nose & Throat: rhinitis, pharyngitis, nasal polyps, sinusitis, malignancies 
Larynx: dysphonia, acute and chronic laryngitis, malignancies 
0. No problems 
1. Corrected vision with glasses; mild hearing loss; chronic sinusitis 
2. Difficulty in reading newspaper or drive although glasses; required hearing aid; chronic 
sinonasal complaints requiring medication; vertigo/dizziness requiring daily meds 
3. Severe low vision, partially blind (required an escort to venture out, unable to read 
newspaper); severe ear impairment (conversational heading still impaired with hearing aid); 
laryngeal dysphonia (not neurological dysarthria) 
4. Functional blindness/deafness: unable to read, recognize a familiar face, unable to 
conversational heading, even if “organically” he is not completely blind or deaf; laryngectomy 
(every cause, especially malignancies); required surgical intervention for vertigo; aphonia 
secondary to laryngeal impairment. 
UPPER GASTROINTESTINAL SYSTEM 
This category is comprehensive of the intestinal tract from esophagus to duodenum, and 
pancreatic trees: dysphagia, GERD, hiatal hernia, esophageal diverticula, any type of gastritis 
(consider also H. Pylori eradication or not), gastric/duodenal ulcer, acute or chronic pancreatitis, 
malignancies (comprehensive of gastric lymphoma). 
Pay attention that type 1 diabetes is rated under “metabolic”. 
 
0. No problem 
1. Hiatal hernia, GERD or gastritis requiring prn meds; previous ulcer (>5 years ago); previous 
H. Pylori eradication therapy (> 5 years ago) 
2. Daily proton pump inhibitor/anti-acid meds; documented gastric or duodenal ulcer or H.P. 
eradication therapy within 5 years 
3. Active gastric or duodenal ulcer; positive fecal occult blood test; any swallowing disorder or 
dysphagia; chronic pancreatitis requiring supplemental pancreatic enzymes for digestion; 
previous episode of acute pancreatitis 
4. Any type of malignancies (see “Rating Malignancies”); previous gastric surgery because of 
cancer; history of perforated ulcer (gastric surgery not because of cancer, ulcorrhaphy); 
melena/heavy bleeding from upper GI source; acute pancreatitis 


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LOWER GASTROINTESTINAL SYSTEM 
Comprehensive of the rest of the G.I. system, from small bowel to anus: Whipple’s disease, 
diverticulosis, irritable bowel, malignancies. Constipation is rated, too, by type and frequency of 
laxatives required, or by history of impaction. 
 
0. No problems, previous appendectomy, previous hernia repair (without complications) 
1. Constipation managed with prn meds; active hemorrhoids; intestinal hernia requiring surgery; 
previous hernia repair with complications (intestinal adherences, laparocele, etc.); irritable 
bowel syndrome (few symptoms) 
2. Constipation requiring daily bulk laxatives (psyllium, policarbophil, sterculia, guar gum, etc.), 
or stool softeners; diverticulosis (previous diverticulitis); inflammatory bowel disease in 
remission with meds (> 5 years ago) 
3. Bowel impaction/diverticulitis within the last year; daily use of stimulant (irritant) or osmotic 
laxatives (bysacodil, senna, glycerol, sodium docusate; lactulose, polyethylene glycol) or 
enemas; chronic bowel inflammation in remission with meds (< 5 years ago) 
4. Diverticulitis flare up; active inflammatory disease; current impaction; hematochezia/active 
bleeding from lower GI source; bowel carcinoma 
 
LIVER AND BILIARY TREES 
Comprehensive of liver, gallbladder, biliary trees, portal system: acute and chronic hepatitis 
(viral, alcoholic, toxic, autoimmune, idiopathic), cirrhosis, portal hypertension, hemochromatosis, 
primary biliary cirrhosis, cholelithiasis, cholangitis, primary malignancies. As the hepato-biliary 
system is difficult to assess through the physical examination, therefore, laboratory results must 
be used. 
 
0. No problem 
1. History of hepatitis (actually normal values of transaminases); cholecystectomy 
2. Cholelithiasis; chronic hepatitis or previous hepatitis (< 5 years ago) or any other liver 
disease (hemochromatosis, primary biliary cirrhosis) with mildly elevated transaminases 
(within 3-times normal values); heavy alcohol use within 5 years (to rate in “psychiatric”, too) 
3. Chronic hepatitis or any other liver disease with marked elevation of transaminases (> 3-
times normal values); elevated bilirubin 
4. Acute cholecystitis; any biliary obstruction; active hepatitis/liver cirrhosis; any liver or biliary 
tree carcinoma 
 
RENAL 
This category is exclusive of kidney: kidney stones, acute/chronic renal failure, 
glomerulonephritis; nephrosic/nephritic syndrome; active/chronic pyelonephritis, diabetic or 
hypertensive nephropathy (albuminuria/proteinuria), renal carcinoma. 
Bence-Jones proteinuria in multiple myeloma should not be considered. 
 
0. No problem 
1. Asymptomatic kidney stone; kidney stone passage within the last ten years; pyelonephritis 
within 5 years; kidney cysts without hematuria 
2. Serum creatinine > 1.5 but < 3 mg/dl without diuretic or antihypertensive medication 
(particularly ACE-inhibitors or SRAA blockers); kidney calculi requiring daily meds 
3. Serum creatinine > 3 mg/dl or > 1.5 mg/dl in conjunction with diuretics, antihypertensive, or 
bicarbonate therapy; active pyelonephritis; nephrosic syndrome; colic symptoms treated as 
an outpatient 
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GENITOURINARY 
Ureters, bladder, urethra. 
Genitals, prostate, testicles, penis, seminal vesicles. 
Uterus, ovaries. Mammary gland is rated under “metabolic”. 
This category is comprehensive of all GU tract impairments: ureteral or bladder stones, benign 
prostate hypertrophy (BPH), urinary tract infections (UTI’s), prolapses, etc. Urinary incontinence 
and indwelling catheter should also be considered. 
 
0. No problem 
1. Stress incontinence; BPH without urinary symptoms; hysterectomy or ovariectomy (uterine 
fibroma, benign neoplasm) 
2. Pathological pap smear (or 2 consecutives abnormal); frequent UTI’s (3 or more in the past 
year) in female or current UTI’s; urinary incontinence (not stress) in females; BPH with 
urinary symptoms (frequency, urgency, hesitancy); status post TURP; any urinary diversion 
procedure; indwelling catheter; bladder calculi 
3. Prostatic cancer in situ (e.g. incidentally found during TURP); vaginal bleeding; cervical 
carcinoma in situ; hematuria (any cause); urinary incontinence (not stress) in males; bladder 
polyps 
4. Acute urinary retention; current urosepsis; any GU malignancies except as above 
 
MUSCULOSKELETAL/INTEGUMENT 
This is a very wide category, including: osteoarthritis, osteoporosis, any bone fracture; primary 
neoplasm (bone, muscle, connective tissue, skin), distinguishing melanoma from other localized 
skin cancers; rheumatoid arthritis and polymyalgia rheumatica; muscular injuries (rotator cuff, 
long head of the biceps); pressure sores; any dermatological disease. 
The scores of this category are strictly correlated to the disability they cause; for the evaluation 
of the level of disability, refer to BADL and IADL. 
 
NOTICE: score the severity of each illness according to the level of disability caused by the 
same illness in this category, without considering the disability caused by other diseases. For 
example: a patient affected both by osteoarthritis and hemiplegia from a previous stroke has a 
high level of disability, but you have to score 2 for disability by osteoarthritis (in this category) 
and 4 for disability by stroke (in the neurological category); for a patient with both a deforming 
rheumatoid arthritis and a previous stroke without remaining outcomes you have to score 4 for 
disability from arthritis (in this category) and 2 for disability from stroke (in the neurological 
category). 
0. No problem 
1. Requires PRN meds for osteoarthritis (NSAID) or has mildly limited IADL from joint 
pathology; excised skin cancers (except melanoma); skin infections requiring antibiotics 
within a year 
2. Daily anti-osteoarthritis meds (NSAID) or use of assisitive devices or little limitation in ADL 
(previous arthroprosthesis or treated fracture with a low level of remaining disability); 
osteoporosis without vertebral fractures; daily meds for chronic skin diseases (even local, as 
psoriasis or pressure sores); non metastatic melanoma; daily meds for rheumatoid arthritis 
(except steroids) with a low level of  disability 
3. Osteoarthritis with a moderate level of disability in ADL; requires chronic treatment with 
steroids for arthritic conditions or joints’ deformities or severely impaired; osteoporosis with 
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4. Wheelchair bound for osteomuscular disease; severe joint deformities or severely impaired 
usage; osteomyelitis; any bone or muscle or connective tissue neoplasm (see “Rating 
Malignancies”); metastatic melanoma. 
 
Fractures and/or arthroprosthesis (both recent and old) have to be scored according to the level 
of disability they cause (considering outcomes too), in order to avoid confusion about possible 
classifications of different fractures or joints. The same for muscular diseases. 
 
CENTRAL AND PERIPHERAL NERVOUS SYSTEM 
This category includes the “somatic” pathologies of the central and peripheral nervous system: 
any kind of stroke, neurodegenerative diseases (Parkinson’s disease and parkinsonism, 
multiple sclerosis, amyotrophic lateral sclerosis, etc.), myelopathies, traumas with neurological 
outcomes, primary or secondary epilepsy, neuropathies (diabetic, alcoholic, any other etiology), 
primary tumors, chronic headaches (migraine), insomnia, etc. It must carefully estimate the 
severity and prognosis of the illness but also the functional impairment that the illness causes. 
 
0. No problem (or fewer convulsions in childhood) 
1. Frequent headaches requiring PRN meds without impairment in Advanced ADL; previous 
TIA (one event); previous epilepsy, actually not treated, without crisis since more than 10 
years ago. 
2. Chronic headache requiring daily meds (even for prophylaxis) or with regularly functional 
impairment in Advanced ADL (bed rest, job withdrawal, etc.); actual TIA or more than one 
previous TIA; previous stroke without significant residual; mild severity neurodegenerative 
diseases (see above), treated and well controlled; epilepsy controlled with drugs. 
3. Previous stroke with mild residual dysfunction (hemiparesis, dysarthria); any neurosurgical 
procedure; moderate severity neurodegenerative diseases (see above), not well controlled 
by meds; epilepsy in treatment but with periodic crisis. 
4. Acute stroke or previous stroke with severe residual dysfunction (hemiplegia, aphasia, 
severe vascular dementia) or more than one previous stroke (multi-infarct encephalopathy); 
severe neurodegenerative diseases (see above) causing disability in ADL; neurological 
coma. 
 
Alzheimer’s disease and dementia should not be rated into this category (Psychiatric and 
behavioral diseases): Alzheimer’s disease should be listed only under psychiatric disorders; if 
dementia stems from vascular and/or mixed dementia and/or other neurological condition (e.g. 
Parkinson’s Disease), both “neurologic” and “psychiatric” categories should be endorsed at the 
appropriate level for severity, considering in this category the stroke and the multi-infarct 
encephalopathy responsible for the cognitive impairment (score 3 for stroke with remaining 
outcomes, score 4 for multi-infarct encephalopathy). 
 
ENDOCRINE-METABOLIC SYSTEM AND BREAST (systemic infections and poisonings 
too) 
Type 1 and type 2 diabetes (organ damage should be considered into the respective categories, 
like for hypertension), obesity and dyslipidemia (hypercholesterolemia) represent the core of this 
category; it includes also hypo- and hyper-thyroidism, hypo- and hyper-parathyroidism, adrenal 
pathologies (Cushing’ or Addison’ disease), hypogonadism, hypopituitarism, etc. Malignancies 
of these glands, both benignant (like thyroid nodules) and malignant (like thyroid or adrenal 
cancer, vipoma, etc.) are included too. 


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Even if it is an exocrine gland, breast was included in this category because the authors didn’t 
find a more appropriate one; so it includes the breast cancer too. 
Moreover, it includes: electrolyte disorders, sepsis, systemic infections (like tuberculosis, 
syphilis, AIDS) scored according to their severity and the functional impairment they cause (see 
general indications) and poisonings (chronic by metals or acute by pesticides or carbon 
monoxide). 
0. No problem 
1. Diabetes and/or dyslipidemia compensated with diet; mild obesity (BMI 30-35 kg/m2); 
hypothyroidism in replacement therapy (L-thyroxin); hyperthyroidism caused by Plummer’ 
adenoma surgically treated. 
2. Diabetes compensated with oral hypoglycemic drugs or insulin (hemoglobin A1c <7%); 
dyslipidemia well controlled by daily meds (c-LDL lower than the recommended target 
according to the individual global cardiovascular risk); moderate obesity (BMI 35-45 kg/m2); 
hyperthyroidism (Basedow, Plummer) in pharmacologic treatment; asymptomatic or 
surgically treated hyperparathyroidism; fibrocystic breast disease. 
3. Diabetes not well compensated by therapy (hemoglobin A1c 7-8.5%, presence of 
complications); dyslipidemia not well controlled (c-LDL higher than the recommended target 
according to the individual global cardiovascular risk; for instance, c-LDL>100 mg/dl in 
patients with previous myocardial infarction or stroke); severe obesity (BMI >45 kg/m2); 
symptomatic hyperparathyroidism (for instance, hypercalcaemia); replacement therapy for 
adrenal failure; any electrolytes disorder requiring hospitalization. 
4. Uncontrolled diabetes (hemoglobin A1c >8.5%) or one diabetic ketoacidosis or nonketotic 
hyperosmolar coma during the past year; genetic uncontrolled dyslipidemia; acute adrenal 
failure during hormonal replacement therapy; any neoplasm of thyroid, breast, adrenal gland 
(see “Rating Malignancies”). 
NOTICE: 
when the patient is not treated with drug therapy for diabetes or dyslipidemia but 
he should be for the optimal control of the pathology (for instance, hemoglobin A1c 
> 7%, total cholesterol > 250 mg/dl), score the pathology according to the 
laboratory values, which really define its severity. 
PSYCHIATRIC AND BEHAVIORAL DISEASES 
This category includes both dementia and related behavioral disorders (psychosis, anxiety, 
depression, agitation) and all the pre-existing and/or not related to dementia psychiatric 
disorders. Since this is the only item analyzing patient’s mental status (all the others refer to 
physical status), it is very important to evaluate it considering carefully further information 
derived from the Comprehensive Geriatric Assessment (MMSE; Geriatric Depression Scale, 
Neuro-Psychiatric Inventory if available) (8, 9). 
0. No psychiatric problem or history thereof 
1. Minor psychiatric condition or history thereof: previous (occasional) psychiatric treatment 
without hospitalization; major depressive event and/or use of antidepressants more than 10 
years ago without hospitalization; occasional use of minor tranquilizers (e.g. BDZ; even if as 
hypnotherapy for insomnia); mild cognitive impairment (MMSE 25-28). 
2. A history of major depression (according to DSM-IV criteria) within the last 10 years (treated 
or untreated); mild dementia (MMSE 20-25); previous admission to Psychiatric Department 
for any reason; history of substance abuse (more than ten years ago, including alcoholism). 
3. Current major depression (according to DSM-IV criteria) or more than two previous major 
depression episodes in the past 10 years; moderate dementia (MMSE 15-20); current and 
usual usage of daily anti-anxiety meds (even as hypnotherapy for insomnia); current or within 


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the past ten years substance abuse or dependence (according to DSM-IV criteria); requires 
daily antipsychotic medication; previous attempt at suicide. 
4. Current mental illness requiring psychiatric hospitalization, institutionalization, or intensive 
outpatient management (psychiatric emergency, as attempt at suicide or severe depression 
with suicide purpose, acute psychosis or acute decompensation of chronic psychosis, severe 
substance abuse; severe agitation from dementia); severe dementia (MMSE <15); delirium 
(acute confusion or altered mental status for medical (organic) reasons: in this case you have 
to codify also the medical cause in its own category with the appropriate level of severity). 
 
It could be requested psychiatric consult for this category; dementia and depression, the most 
frequent diseases in the elderly, can be scored in details using the MMSE and GDS. The 
severity of any mental disorder (dementia, depression, anxiety, psychosis, substance abuse and 
all the others) has to be scored according to the level of functional impairment or disability they 
cause. 
 
DRUG LIST 
Medical history 
1. Drugs list (fundamental), including laxatives and tranquilizers (drug doses not needed- but 
list of each medication here):   
___________________________________________ 
___________________________________________ 
___________________________________________ 
___________________________________________ 
___________________________________________ 
___________________________________________ 
___________________________________________ 
___________________________________________ 
___________________________________________ 
___________________________________________ 
___________________________________________ 
___________________________________________ 
___________________________________________ 
___________________________________________ 
___________________________________________ 
___________________________________________ 
___________________________________________ 
___________________________________________ 
 
REFERENCES 
1. Linn BS, Linn MW, Gurel L. Cumulative Illness Rating Scale. J Am Geriatr Soc 1968; 
16:622-6 
2. Miller MD, Paradis CF, Houck PR, Mazumdar S, Stack JA, Rifai H, Mulsant B, Reynolds CF 
III. Rating chronic medical illness burden in geropsychiatric practice and research: 
application of the Cumulative Illness Rating Scale. Psychiatry Res 1992; 41:237-48 
3. Miller MD, Towers A. A manual guidelines for scoring the Cumulative Illness Rating Scale 
for Geriatrics (CIRS-G). Pittsburg, PA: University of Pittsburgh; 1991 


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4. Parmelee PA, Thuras PD, Katz IR, Lawton MP. Validation of the Cumulative Illness Rating 
Scale in a geriatric residential population. J Am Geriatr Soc 1995; 43:130-7 
5. Mistry R, Gokhman I, Bastani R, Gould R, Jimenez E, Maxwell A, McDermott C, Rosansky 
J, Van Stone W, Jarvik L; UPBEAT Collaborative Group. Measuring medical burden using 
CIRS in older veterans enrolled in UPBEAT, a psychogeriatric treatment program: a pilot 
study. J Gerontol A Biol Sci Med Sci 2004; 59:1068-75 
6. Folstein MF, Folstein SE, McHugh PR. “Mini Mental State”: a pratical method for grading the 
cognitive state of patients for the clinician. J Psichiatr Res 1975; 12:189-98 
7. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders: 
DSM-IV. 4th ed. Washington: Amer. Psychiatric Assn., 1994 
8. Yesavage JA, Brink TL, Rose TL, et al. Development and validation of a geriatric depression 
screening scale: a preliminary report. J Psichiatr Res 1983; 17:37-49 
9. Cummings JL, Mega M, Gray K, Rosenberg-Thompson S, Carusi DA, Gornbein J. The 
Neuropsychiatric Inventory: comprehensive assessment of psychopathology in dementia. 
Neurology 1994; 44:2308-14 
 
 


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A 3-Arm Randomized Phase II Trial of Bendamustine-Rituximab (BR) Followed by 
Rituximab vs Bortezomib-BR (BVR) Followed by Rituximab vs BR Followed by  
Lenalidomide/Rituximab in High Risk Follicular Lymphoma 
Appendix XI 
 
Modified Ann Arbor Staging System 
Stage I  
Involvement of a single lymph node region. 
 
Stage II  
Involvement of 2 or more lymph node regions on the same side of the 
diaphragm. 
 
Stage III   
Involvement of lymph node regions on both sides of the diaphragm. 
 
Stage IV  
Diffuse or disseminated involvement of one or more extra lymphatic 
organs or tissues, with or without associated lymph node involvement. 
 
 
The subscript E (e.g., IIE or IIIE) is used to denote involvement of an extra lymphatic site 
primarily or by direct extension, rather than hematogenous spread, as in the case of a 
mediastinal mass 
extending to involve the lung. 
 
The presence of (B) or absence of (A) fever, night sweats, and/or unexplained loss of 
10% or more body weight in the 6 months prior to admission are denoted by the 
corresponding suffix letters B and A. 


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A 3-Arm Randomized Phase II Trial of Bendamustine-Rituximab (BR) Followed by 
Rituximab vs Bortezomib-BR (BVR) Followed by Rituximab vs BR Followed by  
Lenalidomide/Rituximab in High Risk Follicular Lymphoma 
Appendix XII 
 
Bortezomib Drug Ordering Form 
Rev
. 
12/1
0 
Section I (To be completed by Site)  
All shaded areas must be completed before forwarding the drug request to UVI, 
Inc. 
 ECOG-ACRIN Protocol Number:  E2408 
Millennium Protocol Number: X05341 
Delivery Address 
Institution Name: 
CTEP ID: 
Attention To: 
Street Address: 
 
City, State, Zip Code: 
 
Shipment Must Reach Destination By: 
 (MM/DD/YY) - Deliveries are not made on 
Mondays, weekends or holidays) 
Pharmacy Contact Name:   
Pharmacy Contact Phone:      
Pharmacy Contact Fax: 
Pharmacy Contact E Mail:     
Principal Investigator Name:    
Principal Investigator Address:                         
 
 
 
PATIENT SEQUENCE NUMBER: 
 
ARM RANDOMIZED TO: 
STUDY DRUG: 
BORTEZOMIB 
BORTEZOMIB QUANTITY: 
 
SHIPMENT #  
See below or Section 8.3.7 for Shipment Time 
Points 
(Place check mark below) 
SHIPMEN
T TIME 
POINT 
 
 
#1, Cycles 
1-3 
 
 
#2, Cycles 
4-6 
Drug is being provided at no charge.  Site may not submit any claims or receive any reimbursement for 
any source (whether public or private) for Drug and may not be returned to Millennium (or its 
distributor) for a refund or credit.  Drug must be used solely pursuant to the Protocol.  All other uses are 
strictly prohibited.   
 
By:  ______________________________________________ 
              (Signature//Title) 
 
Name (Print): _______________________________________ 
 
PLEASE EMAIL THIS DRUG REQUEST AS AN ATTACHMENT TO mdubois@uintavision.com 
Section II  (To be completed by UVI, Inc) 


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UVI, Inc. Approval:  
Confirm Patient on Arm B: 
UVI Personnel Name:  
 
 
          Signature: 
          
 
             Date:  
 
E2408 CLINICAL TRIAL MATERIAL RETURN REQUEST FORM 
 
Section I (To be completed by Site) 
 
Instruction – How to Return Commercial  Velcade (bortezomib) for Investigational Use Only : 
1. Complete form below and fax to # 1-866-422-4797 for Millennium approval 
2. Once form is received, you will receive a Return Authorization number and call tag for free pick up 
of the VELCADE to be returned, as well as instructions on preparing your package for pick up.  
3. Upon pick up of your package, please notify Barbara Franklin that the Return Request has been 
completed.  
NOTE: Please ensure that the VELCADE vials are adequately protected when packaging to prevent 
breakage. 
If you have any questions, please contact Barbara Franklin at phone #: 617-551-8985 or 
barbara.franklin@takeda.com 
 
RETURN PICK UP ADDRESS 
(Address the VELCADE will be picked up from): 
 
TOTAL Amount of VELCADE Vials to 
Be Returned: 
 
__________________________vials 
  
Contact Name:   
 
 
LOT NUMBER(s):  
Phone:      
Fax: 
Email Address: 
 
Reason for Return: 
Principal Investigator Name:                                             
Sub-Investigator Name (if applicable):    
 
Millennium Protocol Number: 
 
Section II  (To be completed by Millennium) 
Rev. 1/15 


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Millennium Approval (Commercial Operations):  
 
__________________________________________________________________________________
_____ 
Printed name  
 
 
Signature 
          
 
Date      
 
 
 
 


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A 3-Arm Randomized Phase II Trial of Bendamustine-Rituximab (BR) Followed by 
Rituximab vs Bortezomib-BR (BVR) Followed by Rituximab vs BR Followed by 
Lenalidomide/Rituximab in High Risk Follicular Lymphoma 
Appendix XIII 
 
Bendamustine Drug Ordering Form 
                                
 
 
ECOG 2408 (C18083/6248) 
REQUEST FOR DRUG SHIPMENT 
 
COMPLETE AND EMAIL TO: 
Carolyn.Paugh@tevapharm.com or 
Fax completed form to +1-610-756-2030 
 
 
Instructions for completion: Please allow for at least 3 days for delivery. Clearly type or print 
information in all sections below. For any questions related to drug shipment or completion of 
this form please contact Carolyn Paugh at Carolyn.Paugh@tevapharm.com or (610-727-
6360). 
___________________________________________________________________________ 
Product name: Treanda (Bendamustine HCL) 100 mg vials 
Number of vials needed (vials are shipped in multiples of 10): ___ vials 
Patient Number:______________ 
Initial order or resupply? : ___________ 
Date shipment needed:  _________________ 
___________________________________________________________________________ 
DRUG SHIPMENT ADDRESS AND CONTACT INFORMATION 
Institution name:   
Street address:   
City/state/zip:   
Attn to:   
Pharmacy phone number:   
Requester name:  
Requester phone number: 
Requestor fax number:  
Investigator name:   
 
Rev. 9/14 


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A 3-Arm Randomized Phase II Trial of Bendamustine-Rituximab (BR) Followed by 
Rituximab vs Bortezomib-BR (BVR) Followed by Rituximab vs BR Followed by 
Lenalidomide/Rituximab in High Risk Follicular Lymphoma 
 
Appendix XIV 
 
Lenalidomide Information Sheet 
 
FOR PATIENTS ENROLLED IN CLINICAL RESEARCH STUDIES 
Please read this Lenalidomide Information Sheet before you start taking lenalidomide and each 
time you get a new supply, since there may be new information. This Lenalidomide Information 
Sheet does not take the place of an informed consent to participate in clinical research or talking 
to your study doctor or healthcare provider about your medical condition or your treatment.   
What is the most important information I should know about lenalidomide? 
1. Lenalidomide may cause birth defects (deformed babies) or death of an unborn baby. 
Lenalidomide is similar to the medicine thalidomide. It is known thalidomide causes life-
threatening birth defects. Lenalidomide has not been tested in pregnant women but may 
also cause birth defects. 
If you are a female who is able to become pregnant: 
· 
Do not take lenalidomide if you are pregnant or plan to become pregnant 
· 
for 28 days before starting lenalidomide 
· 
while taking lenalidomide  
· 
during dose interruptions of lenalidomide  
· 
for 28 days after stopping lenalidomide  
· 
Stop taking lenalidomide if you become pregnant during lenalidomide 
treatment 
· 
Do not breastfeed while taking lenalidomide 
· 
You must have pregnancy testing done at the following times: 
· 
within 10 – 14 days and again 24 hours prior to the first dose 
of lenalidomide  
· 
weekly for the first 28 days 
· 
every 28 days after the first month or every 14 days if you 
have irregular menstrual periods 
· 
if you miss your period or have unusual menstrual bleeding 
· 
28 days after the last dose of lenalidomide (14 and 28 days 
after the last dose if menstrual periods are irregular) 
· 
You must practice complete abstinence or use two reliable, separate 
forms of effective birth control at the same time:  


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· 
for 28 days before starting lenalidomide 
· 
while taking lenalidomide 
· 
during dose interruptions of lenalidomide  
· 
and for 28 days after stopping Lenalidomide 
· 
Study doctors and healthcare providers are instructed to report 
all cases of pregnancy as outlined in Section 5.2.6 of the 
protocol. 
If you are a male: 
It is not known if lenalidomide passes into semen.  
· Male patients, including those who have had a vasectomy, must use a 
latex condom during sexual intercourse with a pregnant female or a 
female that can become pregnant: 
· 
While you are taking lenalidomide   
· 
for 28 days after you stop taking lenalidomide  
· 
Male patients should not donate sperm or semen while taking 
lenalidomide and for 28 days after stopping lenalidomide.  
2.   Lenalidomide may cause a reduction in the number of white blood cells and 
platelets.  This can lead to increased risk of infection and bleeding. You may 
need a blood transfusion or certain medicines if your blood counts drop too low.  
You will have blood tests done as part of the clinical research trial in which you 
are participating.  This is discussed in the informed consent document. 
3.   Lenalidomide may cause an increased chance for blood clots in the veins and in 
the lungs. Call your study doctor or get emergency medical care right away if 
you get the following signs or symptoms: 
· shortness of breath 
· chest pain 
· arm or leg swelling 
4. Lenalidomide restrictions in sharing lenalidomide and donating blood: 
· Do not share lenalidomide with other people 
· Do not give blood while you take lenalidomide and for 28 days after 
stopping lenalidomide  
· You will get no more than a 28-day supply of lenalidomide at one time 
Additional information is provided in the informed consent form and you can ask 
your study doctor for more information 


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E2408 A 3-Arm Randomized Phase II Trial of Bendamustine-Rituximab (BR) Followed by 
Rituximab vs Bortezomib-BR (BVR) Followed by Rituximab vs BR Followed by 
Lenalidomide/Rituximab in High Risk Follicular Lymphoma 
 
Appendix XV 
 
Investigator Statement 
 
In order to ship bendamustine, E2408 has a protocol-specific requirement to collect a site 
pharmacy license.  For sites who do not utilize a pharmacy, a signed statement by the 
investigator is required as follows:   
 
 
1.  
I have read and understand the storage and dispensing requirements related to the 
investigational inventory of bendamustine being supplied for use in this clinical trial. I 
acknowledge that this research site has appropriate facilities to provide adequate and 
secure storage of this agent. As Principal Investigator for this trial, it is my responsibility to 
ensure that a current record of investigational product receipt, storage and disposition is 
maintained and all records of drug accountability comply with applicable regulations. 
 
 
 
 
ACKNOWLEDGED AND AGREED 
 
Signature: 
 
Investigator’s Name 
(printed): 
 
Address: 
     
Telephone: 
(      )  
Date: 
 
 


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E2408 A 3-Arm Randomized Phase II Trial of Bendamustine-Rituximab (BR) Followed by 
Rituximab vs Bortezomib-BR (BVR) Followed by Rituximab vs BR Followed by 
Lenalidomide/Rituximab in High Risk Follicular Lymphoma 
 
Appendix XVI 
 
Instructions for Reporting Pregnancies on a Clinical Trial 
What needs to be reported? 
All pregnancies and suspected pregnancies (including a positive or inconclusive pregnancy test 
regardless of age or disease state) of a female patient while she is on protocol treatment, or 
within 28 days of the patient’s last dose of protocol treatment must be reported in an expeditious 
manner.  The outcome of the pregnancy and neonatal status must also be reported. 
How should the pregnancy be reported? 
The pregnancy, suspected pregnancy, or positive/inconclusive pregnancy test must be reported 
via CTEP’s Adverse Event Reporting System (CTEP-AERS)   
(http://ctep.cancer.gov/) 
When does a pregnancy, suspected pregnancy or positive/inconclusive pregnancy test 
need to be reported? 
An initial report must be done within 24 hours of the Investigator’s learning of the event, followed 
by a complete expedited CTEP-AERS report within 5 calendar days of the initial 24-hour report. 
What other information do I need in order to complete the CTEP-AERS report for a 
pregnancy? 
· 
The pregnancy (fetal exposure) must be reported as a Grade 3 “Pregnancy, puerperium and 
perinatal conditions – Other (pregnancy)” under the System Organ Class (SOC) “Pregnancy, 
puerperium and perinatal conditions” 
· 
The pregnancy must be reported within the timeframe specified in the Adverse Event 
Reporting section of the protocol for a grade 3 event.   
· 
The start date of the pregnancy should be reported as the calculated date of conception.   
· 
The potential risk of exposure of the fetus to the investigational agent(s) or chemotherapy 
agent(s) should be documented in the “Description of Event” section of the CTEP-AERS 
report.  
What else do I need to know when a pregnancy occurs to a patient? 
· 
The Investigator must follow the female patient until completion of the pregnancy and must 
report the outcome of the pregnancy and neonatal status via CTEP-AERS.  
· 
The decision on whether an individual female patient can continue protocol treatment will be 
made by the site physician in collaboration with the study chair and ECOG-ACRIN 
Operations Office - Boston.  Please contact the ECOG-ACRIN Operations Office - Boston to 
ask for a conference call to be set up with the appropriate individuals.  
· 
It is recommended the female subject be referred to an obstetrician-gynecologist, preferably 
one experienced in reproductive toxicity for further evaluation and counseling.  
Rev. 2/14, 
9/14 


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How should the outcome of a pregnancy be reported? 
The outcome of a pregnancy should be reported as an amendment to the initial CTEP-AERS 
report if the outcome occurs on the same cycle of treatment as the pregnancy itself.  However, if 
the outcome of the pregnancy occurred on a subsequent cycle, a new CTEP-AERS report 
should be initiated reporting the outcome of the pregnancy. 
What constitutes an abnormal outcome? 
An abnormal outcome is defined as any pregnancy that results in the birth of a child with 
persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions (formerly referred to as disabilities), congenital anomalies, or birth defects.  For 
assistance in recording the grade or category of these events, please contact the CTEP AEMD 
Help Desk at 301-897-7497 or aemd@tech-res.com, for it will need to be discussed on a case 
by case basis. 
Reporting a Fetal Death 
A fetal death is defined in CTCAE as “A disorder characterized by death in utero; failure of the 
product of conception to show evidence of respiration, heartbeat, or definite movement of a 
voluntary muscle after expulsion from the uterus, without possibility of resuscitation.” 
It must be reported via CTEP-AERS as Grade 4 “Pregnancy, puerperium and perinatal 
conditions - Other (pregnancy loss)” under the System Organ Class (SOC) “Pregnancy, 
puerperium and perinatal conditions”. 
A fetal death should NOT be reported as a Grade 5 event as currently CTEP-AERS recognizes 
this event as a patient’s death. 
Reporting a Neonatal Death 
A neonatal death is defined in CTCAE as “A disorder characterized by cessation of life occurring 
during the first 28 days of life” that is felt by the investigator to be at least possibly due to the 
investigational agent/intervention.  However, for this protocol, any neonatal death that occurs 
within 28 days of birth, without regard to causality, must be reported via CTEP-AERS AND any 
infant death after 28 days that is suspected of being related to the in utero exposure to protocol 
treatment must also be reported via CTEP-AERS.   
It must be reported via CTEP-AERS as Grade 4 “General disorders and administration - Other 
(neonatal loss)”under the System Organ Class (SOC) “General disorder and administration”.  
A neonatal death should NOT be reported as a Grade 5 event as currently CTEP-AERS 
recognizes this event as a patient’s death. 
Additional Required Forms: 
When submitting CTEP-AERS reports for pregnancy, pregnancy loss, or neonatal loss, the 
CTEP 'Pregnancy Information Form' must be completed and faxed along with any additional 
medical information to CTEP (301-230-0159). This form is available on CTEP's website 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/PregnancyReportFor
m.pdf)