A Randomized Phase II Trial of Ofatumumab and Bendamustine vs. Ofatumumab, Bortezomib (NSC # 681239) and Bendamustine in Patients With Untreated Follicular Lymphoma
Phase: PHASE2
Conditions: Ann Arbor Stage III Grade 1 Follicular Lymphoma, Ann Arbor Stage III Grade 2 Follicular Lymphoma, Ann Arbor Stage III Grade 3 Follicular Lymphoma, Ann Arbor Stage IV Grade 1 Follicular Lymphoma, Ann Arbor Stage IV Grade 2 Follicular Lymphoma, Ann Arbor Stage IV Grade 3 Follicular Lymphoma, Grade 3a Follicular Lymphoma
Sponsor: National Cancer Institute (NCI)

Update #09 
XX/XX/2017 
 
ALLIANCE FOR CLINICAL TRIALS IN ONCOLOGY 
_________________________________________ 
PROTOCOL UPDATE TO CALGB 50904 
_________________________________________ 
 
A RANDOMIZED PHASE II TRIAL OF OFATUMUMAB AND BENDAMUSTINE VS. OFATUMUMAB, 
BORTEZOMIB (NSC #681239, IND #58443) AND BENDAMUSTINE IN PATIENTS WITH UNTREATED 
FOLLICULAR LYMPHOMA 
Bortezomib (NSC #681239, IND #58443) will be supplied by NCI/PMB. 
Ofatumumab will be supplied by GlaxoSmithKline. 
Bendamustine will be supplied by Cephalon. 
 
X Update: 
 
 
Status Change: 
 
 
 
 
 
 
Eligibility changes 
 
 
Activation 
 
 
 
 
 
 
Therapy / Dose Modifications / Study Calendar changes 
 
 
Closure 
 
 
 
 
 
X Informed Consent changes 
 
 
Suspension / temporary closure 
 
 
 
 
 
 
 
Scientific / Statistical Considerations changes 
 
 
Reactivation 
 
 
 
 
 
 
 
Data Submission / Forms changes 
 
 
 
 
 
 
 
 
 
Editorial / Administrative changes 
 
 
 
 
 
 
 
 
X Other: Bortezomib CAEPR update 
 
 
 
 
 
 
 
The changes included in this update to CALGB 50904 have been made in response to the NCI Action 
Letter from Dr. John J. Wright, dated XX/XX2017. This Action Letter is posted on the CALGB 50904 
study page on the Alliance web site. A revised CAEPR for bortezomib with new risk information has 
been added to the protocol. Therefore, the model consent form has been revised to incorporate these 
new risks, consistent with the NCI Model Consent Template instructions. There are no changes to the 
risk/benefit ratio. 
 
IRB approval (or disapproval) is required within 90 days. Expedited review is allowed. 
Please follow your IRB of record guidelines.  
 
1 

UPDATES TO THE PROTOCOL: 
Section 17.3 (CAEPR for Bortezomib [Velcade, NSC 681239]) 
This section has been revised to include the updated bortezomib CAEPR (Version 2.6, May 25, 2017) 
provided by CTEP. Changes from Version 2.5 to Version 2.6 include the following: 
• 
The SPEER grades have been updated. 
• 
Increase in Risk Attribution: 
- 
Changed to Rare but Serious from Also Reported on Bortezomib Trials But With Insufficient 
Evidence for Attribution: Alanine aminotransferase increased; Alkaline phosphatase increased; 
Aspartate aminotransferase increased; Blood bilirubin increased; GGT increased; INR increased; 
Investigations - Other (albumin); Hepatic failure; Hepatobiliary disorders - Other (hepatitis); 
Tumor lysis syndrome 
• 
Provided Further Clarification: 
- 
A new footnote #4 has been added: “Cases of acute liver failure have been reported in patients 
receiving multiple concomitant medications and with serious underlying medical conditions. Other 
reported hepatic reactions include hepatitis, increases in liver enzymes, and hyperbilirubinemia.” 
- 
Footnote #4 has been added to: Alanine aminotransferase increased; Alkaline phosphatase 
increased; Aspartate aminotransferase increased; Blood bilirubin increased; GGT increased; INR 
increased; Investigations - Other (albumin); Hepatic failure; Hepatobiliary disorders - Other 
(hepatitis). 
• 
Additional Changes: 
In previous versions of the protocol, the footnotes were inadvertently left out of the CAEPR. Therefore, 
in addition to the new footnote #4 described above, the following footnotes have been added back to 
the protocol CAEPR with this update: 
- 
Footnote #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.” 
- 
Footnote #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.”  
- 
Footnote #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.” 
- 
Footnote #5: “Infection includes all 75 sites of infection under the INFECTIONS AND 
INFESTATIONS SOC.” 
_____________________________________________________________________________________ 
 
 
2 

UPDATES TO THE MODEL CONSENT: 
What side effects or risks can I expect from being in the study? 
Based on the updated bortezomib CAEPR described above, the following changes have been made to the 
NCI condensed risk profile for bortezomib (found under “Risks and side effects related to GROUP B 
treatment”): 
• 
Increase in Risk Attribution: 
- 
Changed to Rare from Also Reported on Bortezomib Trials But With Insufficient Evidence for 
Attribution (i.e., added to the Risk Profile): “Liver damage which may cause yellowing of eyes and 
skin, swelling” 
• 
Provided Further Clarification: 
- 
“Kidney damage which may cause swelling, may require dialysis” (under Rare) is now reported as 
“Kidney damage which may require dialysis” (under Rare). 
- 
“Damage to organs which may cause shortness of breath, or changes in thinking” (under Rare) is now 
reported as “Damage to organs (brain, lungs, blood vessel in lungs, others) which may cause changes 
in thinking, or shortness of breath” (under Rare). 
 
 
 
 
Replacement protocol and model consent documents have been issued. 
This study remains closed to new patient accrual. 
____________________________________________________________ 
 
ATTACH TO THE FRONT OF EVERY COPY OF THIS PROTOCOL 
____________________________________________________________ 
 
3 

ALLIANCE FOR CLINICAL TRIALS IN ONCOLOGY 
 
CALGB 50904 
 
A RANDOMIZED PHASE II TRIAL OF OFATUMUMAB AND BENDAMUSTINE VS. OFATUMUMAB, 
BORTEZOMIB (NSC #681239, IND #58443) AND BENDAMUSTINE IN PATIENTS WITH UNTREATED 
FOLLICULAR LYMPHOMA 
 
Clinicaltrials.gov Identifier: NCT01286272 
 
Bortezomib (NSC #681239, IND #58443) will be supplied by NCI/PMB. 
Ofatumumab will be supplied by GlaxoSmithKline. 
Bendamustine will be supplied by Cephalon. 
 
Study Chair 
Kristie A. Blum, MD 
Associate Professor of Internal Medicine 
The Arthur G. James Comprehensive Cancer Center 
Division of Hematology-Oncology 
A441 Starling Loving Hall 
320 West 10th Ave 
Columbus, OH 43210 
Tel: 614-293-8858 Fax: 614-293-7484 
kristie.blum@osumc.edu 
 
Lymphoma Committee Chair 
John P. Leonard, MD 
Tel: 646-962-2068  Fax: 646-962-1605 
Community Oncology Co-Chair 
Alvaro Alencar, MD 
Tel: 954-265-6363  Fax: 954-981-3872 
jpleonar@med.cornell.edu 
aalencar@mhs.net 
 
 
Imaging Committee Chair 
Imaging Committee Co-Chair 
Lawrence Schwartz, MD 
Lale Kostakoglu, MD 
Tel: 212-305-8994  Fax: 212-305-4835 
Tel: 212-241-6319  Fax: 212-831-2851 
lschwartz@columbia.edu 
lale.kostakoglu@msnyuhealth.org 
 
Laboratory Co-Chair 
Pathology Co-Chair 
John Byrd, MD 
Eric Hsi, MD 
Tel: 614-293-9321  Fax: 614-293-7526 
Tel: 614-444-5230  Fax: 216-444-4414 
john.byrd@osumc.edu 
hsie@ccf.org 
 
Faculty Statistician 
Staff Statistician 
Sin-Ho Jung, PhD 
Brandy Pitcher, MS 
Tel: 919-668-8658  Fax: 919-688-7122 
Tel: 919-681-6887  Fax: 919-681-8028 
sinho.jung@duke.edu 
brandy.pitcher@duke.edu 
 
Data Coordinator 
Protocol Coordinator 
Andrew Johnson 
Destin Carlisle 
Tel: 507-538-4372 Fax: 507-824-1902 
Tel: 773-702-8824  Fax: 312-345-0117 
johnson.andrew2@mayo.edu 
dcarlisle@uchicago.edu 
 
Participating Organizations: ALLIANCE/Alliance for Clinical Trials in Oncology
Version Date: 08/23/2017 
1 
Update #09 

CALGB 50904 
 
 
Alliance Protocol Operations Program Office 
125 South Wacker Drive, Suite 1600 
Chicago, IL 60606 
Tel: 773-702-9171 
Fax: 312-345-0117 
allianceforclinicaltrialsinoncology.org 
 
Alliance Statistics and Data Center 
Mayo Clinic 
RO FF-3-24-CC/NW Clinic 
200 First Street SW 
Rochester, MN 55905 
 
 
Alliance Biorepository at Ohio State University 
The Ohio State University 
Innovation Centre 
2001 Polaris Parkway 
Columbus, OH 43240 
Tel: 614-293-7073 
Fax: 614-293-7967 
 
Alliance Imaging Core Laboratory 
Wright Center of Innovation 
The Ohio State University 
395 West 12th Avenue, Room 414 
Columbus, OH  43210 
Tel: 614-293-2929 or 614-366-0807 
  Fax: 614-293-9275 
calgb50904@imagingcorelab.com 
 
 
OPEN 
(Oncology Patient Enrollment Network) 
https://open.ctsu.org 
 
Alliance Registration Office 
Tel: 507-284-4130  Fax: 507-284-0885 
Medidata Rave® iMedidata portal 
https://login.imedidata.com 
Alliance Biospecimen Management System (BioMS)  
http://bioms.wustl.edu/bioms 
1-855-55-BIOMS 
AE Reporting  
https://eapps-ctep.nci.nih.gov/ctepaers/ 
 
Pharmacy Contact 
LeAnne Kennedy, PharmD, BCOP 
Tel: 336-713-3416 
Fax: 336-713-3401 
lakenned@wakehealth.edu 
Barbara Todaro, PharmD 
Tel: 716-845-8676 
Fax: 716-845-8726 
barbara.todaro@roswellpark.org 
 
Nurse Contact 
Sharon G. Levy, RN, BSN 
Tel: 202-687-8921  Fax 202-784-4344 
sgl5@georgetown.edu 
Document History 
Activation Date: 4/8/11 
Update #1: 2/15/12 
Update #4:  
5/15/13  
Update #7: 
09/11/14 
Update #2: 4/15/12 
Update #5: 
8/15/13  
Update #8: 
08/01/15 
Update #3: 5/15/12 
Update #6: 
08/15/14 
Update #9 
XX/XX/17 
Version Date: 08/23/2017 
2 
Update #09 

 
 
CALGB 50904 
CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION 
To submit site registration 
documents: 
For patient enrollments:  
Submit study data:  
CTSU Regulatory Office 
1818 Market Street, Suite 
1100 
Philadelphia, PA 19103 
Phone – 1-866-651-CTSU 
Fax – 215-569-0206 
 
Email: 
CTSURegulatory@ctsu.cocc
g.org (for submitting 
regulatory documents only) 
Please refer to the patient 
enrollment section of the 
protocol for instructions on 
using the Oncology Patient 
Enrollment Network (OPEN) 
which can be accessed at 
https://www.ctsu.org/OPEN_
SYSTEM/ or 
https://OPEN.ctsu.org. 
 
Contact the CTSU Help Desk 
with any OPEN-related 
questions at 
ctsucontact@westat.com. 
 
Data collection for this study will be 
done exclusively through Medidata 
Rave. Please see the data submission 
section of the protocol for further 
instructions. 
The most current version of the study protocol and all supporting documents must be downloaded 
from the protocol-specific Web page of the CTSU Member Web site located at https://www.ctsu.org.  
Access to the CTSU members’ website is managed through the Cancer Therapy and Evaluation 
Program - Identity and Access Management (CTEP-IAM) registration system and requires user log on 
with CTEP-IAM username and password. 
For clinical questions (i.e. patient eligibility or treatment-related) contact the Alliance Study Chair. 
For non-clinical questions (i.e. unrelated to patient eligibility, treatment, or clinical data 
submission) contact the CTSU Help Desk by phone or e-mail:  
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com.  All calls and 
correspondence will be triaged to the appropriate CTSU representative. 
For detailed information on the regulatory and monitoring procedures for CTSU sites please 
review the CTSU Regulatory and Monitoring Procedures policy located on the CTSU members’ 
website   https://www.ctsu.org  > education and resources tab > CTSU Operations Information >CTSU 
Regulatory and Monitoring Policy 
The CTSU Web site is located at https://www.ctsu.org. 
Version Date: 08/23/2017 
3 
Update #09 

CALGB 50904 
A RANDOMIZED PHASE II TRIAL OF OFATUMUMAB AND BENDAMUSTINE VS. OFATUMUMAB, 
BORTEZOMIB (NSC #681239, IND #58443) AND BENDAMUSTINE IN PATIENTS WITH UNTREATED 
FOLLICULAR LYMPHOMA 
Schema Page 1 of 1 
Eligibility Criteria 
Required Laboratory Values 
Histologically confirmed follicular non-Hodgkin lymphoma, WHO classification grade 1, 2, 
or 3a (> 15 centroblasts per high power field with centrocytes present) 
Granulocytes: 
≥ 1,000/µl 
Platelet Count: 
≥ 75,000/µl 
Follicular Lymphoma International Prognostic Index (FLIPI) score ≥ 3 (see Section 4.1.2) 
or FLIPI score of 2 with at least 1 tumor mass/lymph node > 6 cm 
Creatinine: 
≤ 2.0 mg/dL 
No prior treatment (see Section 4.2) 
AST and ALT: 
≤ 2.5 x ULN 
No prior cytotoxic chemotherapy, radiotherapy, immunotherapy or radioimmunotherapy 
Bilirubin: 
≤ 2 x ULN 
No corticosteroids are permitted, except for maintenance therapy for a non-malignant 
disease 
 
 
Age ≥ 18 years 
 
 
ECOG performance status 0-2 
 
 
Measurable disease (see Section 4.3) 
 
 
No known CNS involvement by lymphoma 
 
 
Non-pregnant and non-nursing  
 
 
Patients with HIV infection are eligible provided they meet the parameters in Section 4.8 
 
No active hepatitis B or C infection (see Section 4.9) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
* In Arms A and B, restage patients with CT or MRI of the chest, abdomen, and pelvis and FDG-PET/CT after cycles 
2 and 6 of induction therapy. Additionally, in Arms A and B, restaging with CT or MRI of the chest, abdomen, and 
pelvis is performed after 4 cycles of induction. During maintenance therapy, restage every 4 months with CT or MRI 
of chest, abdomen and pelvis. After the completion of therapy, restage every 4 months with CT or MRI of the chest, 
abdomen, and pelvis for two years and then every 6 months until disease progression or for a maximum of 10 years 
from study entry. 
** See Sections 8.1.1, 8.1.2, 8.2.1, and 8.2.2 for induction and maintenance premedication. 
 
 
R
E
G
/ 
R
A
N
D
O
M
I 
Z
A
T 
I
O
N 
ARM A* 
Induction**  
• Ofatumumab 300 mg (IV) on day 1 of cycle 1and 1000 mg on day 1 of cycles 2-6, immediately prior to 
bendamustine.  
• Bendamustine 90 mg/m2 (IV) over 30-60 minutes on days 1 and 2 of each cycle.  
Cycles will be repeated every 35 days for up to 6 cycles.  
 
Maintenance** 
Starting 8 weeks after cycle 6 day 1 of induction therapy in patients without disease progression.  
• Ofatumumab 1000 mg (IV) on day 1 of each cycle. 
Cycles will be repeated every 56 days for up to 4 cycles.  
ARM B* 
Induction**  
• Ofatumumab 300 mg (IV) on day 1 of cycle 1 and 1000 mg on day 1 of cycles 2-6 immediately prior to 
bortezomib and bendamustine.  
• Bendamustine 90 mg/m2 (IV) on days 1 and 2 of each cycle.  
• Bortezomib 1.6 mg/m2 (IV or SC) on days 1, 8, 15, and 22 of each cycle  
Cycles will be repeated every 35 days for up to 6 cycles.  
 
Maintenance**  
Starting 8 weeks after cycle 6 day 1 of induction therapy in patients without disease progression. 
• Ofatumumab 1000 mg (IV) on day 1 of each cycle (immediately prior to bortezomib).  
• Bortezomib 1.6 mg/m2 (IV or SC) on days 1, 8, 15, and 22 of each cycle. 
Cycles will be repeated every 56 days for up to 4 cycles. 
Version Date: 08/23/2017 
4 
Update #09 

CALGB 50904 
TABLE OF CONTENTS 
1.0 
INTRODUCTION ........................................................................................................................... 7 
1.1 
PROGNOSIS AND TREATMENT OPTIONS IN FOLLICULAR LYMPHOMA ............................................ 7 
1.2 
OFATUMUMAB IN FOLLICULAR LYMPHOMA ................................................................................. 7 
1.3 
VERTICAL REGIMEN IN FOLLICULAR LYMPHOMA ......................................................................... 8 
1.4 
MAINTENANCE THERAPY IN FOLLICULAR LYMPHOMA ................................................................. 9 
1.5 
FDG-PET IMAGING....................................................................................................................... 9 
1.6 
STUDY RATIONALE ....................................................................................................................... 9 
1.7 
INCLUSION OF WOMEN AND MINORITIES ................................................................................... 10 
2.0 
OBJECTIVES ............................................................................................................................... 10 
2.1 
PRIMARY OBJECTIVE .................................................................................................................. 10 
2.2 
SECONDARY OBJECTIVES ............................................................................................................ 11 
3.0 
ON-STUDY GUIDELINES .......................................................................................................... 11 
4.0 
ELIGIBILITY CRITERIA .......................................................................................................... 12 
4.1 
DOCUMENTATION OF DISEASE:................................................................................................... 12 
4.2 
PRIOR TREATMENT ..................................................................................................................... 12 
4.3 
MEASURABLE DISEASE ............................................................................................................... 12 
4.4 
CNS INVOLVEMENT .................................................................................................................... 13 
4.5 
AGE REQUIREMENT ..................................................................................................................... 13 
4.6 
ECOG PERFORMANCE STATUS ................................................................................................... 13 
4.7 
PREGNANCY AND NURSING STATUS ........................................................................................... 13 
4.8 
HIV STATUS ................................................................................................................................ 13 
4.9 
HEPATITIS B OR C ....................................................................................................................... 13 
4.10 
REQUIRED INITIAL LABORATORY VALUES ................................................................................. 13 
5.0 
REGISTRATION/RANDOMIZATION ..................................................................................... 14 
5.1 
REGISTRATION REQUIREMENTS .................................................................................................. 14 
6.0 
DATA SUBMISSION, HISTOLOGY REVIEW, AND CORRELATIVE SCIENCE 
SPECIMEN SUBMISSION ..................................................................................................................... 16 
6.1 
DATA SUBMISSION ...................................................................................................................... 16 
6.2 
ALLIANCE BIOSPECIMEN MANAGEMENT SYSTEM INSTRUCTIONS ............................................. 19 
6.3 
HISTOLOGIC REVIEW .................................................................................................................. 19 
6.4 
SPECIMEN SUBMISSION FOR CORRELATIVE STUDIES ................................................................. 19 
7.0 
REQUIRED DATA ....................................................................................................................... 23 
8.0 
TREATMENT PLAN ................................................................................................................... 25 
8.1 
INDUCTION .................................................................................................................................. 25 
8.2 
MAINTENANCE THERAPY ............................................................................................................ 26 
9.0 
DOSE MODIFICATIONS AND MANAGEMENT OF TOXICITY ....................................... 27 
9.1 
DOSE MODIFICATION FOR HEMATOLOGIC TOXICITY ................................................................. 27 
9.2 
GRADE 2-4 PERIPHERAL NEUROPATHY ...................................................................................... 29 
9.3 
OFATUMUMAB INFUSION AND HYPERSENSITIVITY REACTIONS ................................................. 29 
9.4 
DERMATOLOGIC TOXICITY OR HEPATITIS B REACTIVATION ..................................................... 29 
9.5 
OTHER GRADE 3-4 NON-HEMATOLOGIC TOXICITY .................................................................... 29 
9.6 
DOSE MODIFICATIONS FOR OBESE PATIENTS ............................................................................. 29 
9.7 
HBV REACTIVATION .................................................................................................................. 30 
10.0 
ANCILLARY THERAPY ............................................................................................................ 30 
10.1 
CALGB POLICY CONCERNING THE USE OF GROWTH FACTORS ................................................ 30 
Version Date: 08/23/2017 
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Update #09 

CALGB 50904 
11.0 
FDG-PET IMAGING, INTERPRETATION, QUALITATIVE AND SEMI-
QUANTITATIVE ANALYSES ............................................................................................................... 30 
11.1 
INSTITUTION CREDENTIALING PROCEDURES FOR FDG-PET/CT IMAGING ................................ 30 
11.2 
FDG-PET/CT IMAGING .............................................................................................................. 32 
12.0 
CORRELATIVE SCIENCE COMPANION STUDY (CALGB 151005) ................................ 36 
12.1 
SINGLE NUCLEOTIDE POLYMORPHISM ANALYSIS ...................................................................... 37 
12.2 
IMMUNOHISTOCHEMICAL MARKERS .......................................................................................... 37 
12.3 
VALIDATION OF GENE SIGNATURES IN LYMPHOMA ................................................................... 38 
13.0 
DRUG FORMULATION, AVAILABILITY AND PREPARATION ..................................... 39 
13.1 
OFATUMUMAB ............................................................................................................................ 39 
13.2 
BENDAMUSTINE .......................................................................................................................... 40 
13.3 
BORTEZOMIB (NSC #681239, IND #58443) ............................................................................... 41 
14.0 
CRITERIA FOR RESPONSE, PROGRESSION AND RELAPSE ......................................... 43 
14.1 
DEFINITIONS OF RESPONSE [23] .................................................................................................. 43 
14.2 
GUIDELINES FOR EVALUATION OF MEASURABLE DISEASE ........................................................ 45 
15.0 
REMOVAL OF PATIENTS FROM PROTOCOL THERAPY ............................................... 45 
15.1 
DURATION OF TREATMENT ......................................................................................................... 45 
15.2 
EXTRAORDINARY MEDICAL CIRCUMSTANCES ........................................................................... 45 
16.0 
STATISTICAL CONSIDERATIONS ........................................................................................ 45 
16.1 
RANDOMIZATION ........................................................................................................................ 45 
16.2 
PRIMARY ENDPOINT .................................................................................................................... 45 
16.3 
ADVERSE EVENT MONITORING................................................................................................... 46 
16.4 
SECONDARY ENDPOINTS ............................................................................................................. 47 
16.5 
ACCRUAL AND FOLLOW-UP ........................................................................................................ 48 
16.6 
SAFETY CONSIDERATIONS .......................................................................................................... 48 
16.7 
CDUS REPOSTING ....................................................................................................................... 48 
17.0 
ADVERSE EVENT REPORTING (AER).................................................................................. 48 
17.1 
CALGB 50904 REPORTING REQUIREMENTS .............................................................................. 48 
17.2 
ADDITIONAL INSTRUCTIONS OR EXCLUSIONS TO CTEP-AERS EXPEDITED REPORTING 
REQUIREMENTS FOR PHASE 2 AND 3 TRIALS UTILIZING AN AGENT UNDER A CTEP IND OR NON-CTEP 
IND: 49 
17.3 
CAEPR FOR BORTEZOMIB (PS-341, NSC 681239) .................................................................... 50 
18.0 
REFERENCES .............................................................................................................................. 55 
APPENDIX I 
COLLABORATIVE AGREEMENT PROVISIONS ................................................ 58 
APPENDIX II 
CALGB 50904 PET/CT INSTRUMENT ................................................................ 60 
APPENDIX III 
CALGB 50904 IMAGING SITE PERSONNEL FORM ....................................... 65 
 
 
Version Date: 08/23/2017 
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Update #09 

CALGB 50904 
1.0 
INTRODUCTION 
1.1 
Prognosis and treatment options in follicular lymphoma 
The follicular lymphoma international prognostic index (FLIPI) identifies three prognostic 
groups in patients with follicular non-Hodgkin lymphoma (NHL) on the basis of the 
presence of 5 different risk factors: age > 60 years of age, stage III-IV disease, hemoglobin 
< 12 g/dL, elevated LDH, or involvement of 4 or more nodal sites. For those patients with 
3 or more of these adverse risk factors, predicted overall survival (OS) is 52% at 5 years 
and 35% at 10 years, compared to a 10 year OS of 70% in the low risk group [1]. More 
recently, a second prognostic index, FLIPI 2, has been developed and may be more accurate 
than the original FLIPI. FLIPI2 identifies age > 60 years, bone marrow involvement, 
hemoglobin < 12 g/dL, elevated β2-microglobulin, or bulky disease > 6 cm as adverse 
prognostic factors associated with PFS and OS [2]. Newer therapies and treatment 
paradigms need to be developed for these patients with a high-risk FLIPI 1 and FLIPI 2 
scores at diagnosis in order to improve responses and most importantly, prolong response 
duration.  
As front-line therapy for patients with follicular non-Hodgkin lymphoma, rituximab, 
cyclophosphamide, vincristine, and prednisone (RCHOP) results in an overall response 
rate (ORR) of 100%, with 87% of patients obtaining a complete response (CR) or complete 
response unconfirmed (CRu) [3]. With this regimen, the median time to disease 
progression is 82.3 months [3]. However, in those patients with poor risk FLIPI scores, the 
median time to progression following RCHOP is significantly shorter, at only 30.05 
months, compared to 83.5 and 51.95 months for patients with 0-1 or 2 adverse risk factors, 
respectively [3].  
Recently, several studies have demonstrated that rituximab in combination with the unique 
alkylating agent, bendamustine, has similar efficacy and an improved toxicity profile in 
comparison to CHOP in the treatment of patients with newly diagnosed and relapsed 
indolent NHL [4-7]. In the relapsed setting, response rates of 77-92%, complete responses 
of 15-60%, and progression-free survivals of 6.7-24 months have been noted [4, 5, 7]. 
Toxicities have been minimal consisting of grade 3-4 myelosuppression in 16-54% in 
relapsed patients, with increased toxicity at the 120 mg/m2 dose level of bendamustine (120 
mg/m2 on days 1 and 2) compared to the 90 mg/m2 dose [4, 5, 7]. In a randomized phase 
III trial of rituximab-bendamustine vs. RCHOP in patients with untreated indolent NHL, 
including 55% follicular lymphoma patients, the overall response rate was similar between 
the rituximab-bendamustine and RCHOP treatment arms at 93.8% and 93.5%, respectively 
[7]. However, toxicity was significantly less in the rituximab-bendamustine arm with only 
15% alopecia, a 36.5% rate of infection, and 10.7% risk of grade 3-4 neutropenia, 
compared to 62%, 47.8%, and 46.5 % alopecia, infection, and neutropenia rates with 
RCHOP [7]. The median PFS with R-bendamustine was 54 months compared to 34.8 
months with R-CHOP (p=0.0002). Therefore, although RCHOP and R-bendamustine have 
similar response rates in untreated patients with follicular lymphoma, the toxicity profile 
and prolonged PFS significantly favors the use of R-bendamustine in this population. 
1.2 
Ofatumumab in follicular lymphoma 
One possible approach to improve remission duration and increase molecular responses in 
these high-risk follicular lymphoma patients is to consider the use of novel monoclonal 
antibody therapy in combination with chemotherapy regimens such as CHOP or 
bendamustine. Ofatumumab is fully humanized anti-CD20 monoclonal antibody that 
targets a novel epitope of the CD20 molecule and releases much more slowly from the 
antigen than rituximab. Compared with rituximab, ofatumumab appears to have more 
Version Date: 08/23/2017 
7 
Update #09 

CALGB 50904 
potent complement-dependent cytotoxicity and is able to induce lysis in B-cell lymphoma 
cell lines that are resistant to rituximab [8, 9].  There is also increased NK-cell mediated 
ADCC potency with ofatumumab, when compared to rituximab [10]. In a phase 1/2 clinical 
trial of ofatumumab in patients with relapsed or refractory follicular lymphoma, responses 
were observed at doses ranging from 300-1000 mg of ofatumumab given once a week for 
4 weekly doses [11]. The response rate did not appear to be dose dependent, with responses 
across all dose levels and adjusted for body surface area. Therefore, a fixed dose of 1000 
mg has been selected for future phase II trials. In addition, toxicity consists primarily of 
infusion reactions, and sustained B-cell depletion occurs from 6-10 months after 
ofatumumab dosing.  
Some responses have also been noted in patients who are refractory to rituximab [12]. In a 
phase II study of ofatumumab at doses of 500 - 1000 mg in 116 patients with relapsed 
follicular NHL that was refractory to rituximab (defined as failure to achieve a PR, disease 
progression during rituximab treatment, or disease progression within 6 months of a 
rituximab-containing treatment), the ORR was 11% in all patients, and was 22% in patients 
who were refractory to rituximab containing monotherapy [12].  Although this ORR was 
low, what is encouraging is that 47% of patients on this study had high-risk follicular NHL, 
with FLIPI scores of 3 or higher, and responses were observed in refractory patients 
including at least 1 CR. In addition, toxicity was mild and consisted of grade 3-4 infusion 
reactions in only 3 patients. Furthermore, additional studies have suggested that 
combination therapy with chemotherapy and ofatumumab is well-tolerated. In patients 
with previously untreated CLL, combination therapy with ofatumumab, fludarabine, and 
cyclophosphamide is well-tolerated without grade 3-4 infusion toxicity and with no 
unexpected increase in myelosuppression or infectious toxicity [13]. In addition, a higher 
CR was observed in patients receiving 1000 mg of ofatumumab compared to 500 mg when 
combined with fludarabine and cyclophosphamide [13]. Although additional comparative 
studies between rituximab and ofatumumab are needed, it currently appears that 
combination therapy with ofatumumab and nucleoside analogues is feasible and that 
ofatumumab has efficacy in patients with high-risk follicular lymphoma who are refractory 
to rituximab.  
1.3 
Vertical regimen in follicular lymphoma  
In a multi-center phase I study, 16 patients with relapsed follicular lymphoma and a median 
of 3 prior therapies (including 31% who were previously transplanted) received rituximab 
375 mg/m2 IV on days 1, 8, 15, and 22 of cycle 1 and then on day 1 of cycles 2-5, 
bortezomib 1.6 mg/m2 on days 1, 8, 15, and 22, and bendamustine 60-90 mg/m2 on days 
1-2 of a 35 day cycle [14]. Doses up to 90-mg/m2 bendamustine were well tolerated. 
Toxicities consisted of grade 3-4 neutropenia in 25% of patients and grade 4 
thrombocytopenia in 6% of patients. Other events included grade 3 diarrhea (31%), fatigue 
(25%), vomiting (13%), and nausea (13%).  
In a subsequent phase II trial with this regimen, the ORR in 49 patients with relapsed and 
refractory follicular NHL was 84%, and 35% of these patients had high-risk FLIPI scores 
at the time of study enrollment. Grade 3-4 toxicities were uncommon and included 
neutropenia in 25% of patients, thrombocytopenia in 6%, peripheral neuropathy in 6%, 
febrile neutropenia in 5%, and herpes zoster in 1 patient [15]. Therefore, the vertical 
regimen combining rituximab, bortezomib, and bendamustine appears well-tolerated with 
preliminary efficacy in patients with relapsed follicular lymphoma and should be explored 
as front-line therapy. 
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1.4 
Maintenance therapy in follicular lymphoma 
Another approach to improve remission duration and improve response rate in high-risk 
follicular lymphoma patients is to consider the addition of maintenance therapy to 
chemotherapy combination regimens. In newly diagnosed and relapsed patients, 
maintenance rituximab following either single agent rituximab or combination 
chemotherapy improves response duration, progression-free survival (PFS), and OS [16-
19]. Following initial therapy with 4 weekly doses of rituximab, rituximab maintenance at 
least doubles event-free and progression-free survival from ranges of 7.4-12 months to 23-
31 months [17, 18]. Following RCHOP in the relapsed setting, those patients receiving 
maintenance rituximab had an improvement in 3 year OS from 77% to 85% [19]. Although 
a variety of rituximab maintenance schedules exist, every 2 month dosing proposed by 
Ghielmini et al. reflects known rituximab pharmacokinetic data, where it has been observed 
that the consistent antibody concentrations in the blood correlate with patient response, and 
that continuous drug exposure may be more crucial than achieving maximal serum levels 
[17]. To date, maintenance therapy with the novel CD20 monoclonal antibody ofatumumab 
has not been explored, and little data is available regarding the outcomes of maintenance 
therapy in patients with high-risk follicular lymphoma. 
1.5 
FDG-PET Imaging 
Preliminary studies with FDG-PET in follicular lymphoma indicate that FDG-PET detects 
disease in 95-98% of untreated and relapsed follicular lymphoma patients [20, 21], and that 
persistent PET positivity after chemotherapy correlates with progression-free survival [20, 
22]. In a retrospective analysis of 31 patients with follicular grade 1-2 NHL, PET was both 
specific (88%) and sensitive (95%) [20]. Bishu et al. reported that in 2 of 16 patients who 
remained PET positive after completion of chemotherapy, PFS was 5.8 months, compared 
to 29.5 months for their PET negative counterparts [20]. Similarly, Zinzani et al. noted that 
2-year PFS for previously untreated patients with follicular lymphoma receiving CHOP or 
a fludarabine-containing induction was 20% in 6 of 45 patients who were PET positive at 
the completion of therapy, compared to 90% in the PET negative group [22]. Therefore, as 
in diffuse large cell lymphoma and Hodgkin lymphoma, it appears that PET positivity at 
the completion of therapy does correlate with outcomes; however, these studies are 
currently small. We propose evaluating FDG-PET at baseline, after 2 cycles and at the end 
of induction chemotherapy (6-8 weeks after cycle 6 day 1) as part of this trial to determine 
prospectively in a large subset of uniformly treated patients with follicular lymphoma if 
PET positivity correlates with PFS. 
1.6 
Study Rationale 
On the basis of the considerable success of rituximab-bendamustine in the front-line 
treatment of follicular NHL, the improvements in toxicity with bendamustine-containing 
therapy, the tolerability and efficacy of the vertical regimen in patients with untreated 
follicular lymphoma, and the potential improvement in efficacy with the novel monoclonal 
antibody ofatumumab, we propose a randomized phase II study of ofatumumab-
bendamustine compared to ofatumumab-bortezomib-bendamustine in patients with 
untreated, high-risk follicular NHL. The primary endpoint is to determine the complete 
response rate with ofatumumab-bendamustine and ofatumumab, bortezomib, and 
bendamustine in patients with high-risk follicular lymphoma in order to generate 
prospective data of expected outcomes in this population with bulky disease or adverse 
FLIPI risk factors. Although it is known in the high-risk FLIPI patients that RCHOP leads 
to a median PFS of 30 months [3], it is unclear if similar outcomes will be observed in 
untreated follicular lymphoma patients with adverse risk factors receiving ofatumumab and 
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bendamustine front-line. In addition, with the preliminary efficacy of the vertical regimen 
in patients with relapsed follicular lymphoma [14], the addition of bortezomib to 
ofatumumab and bendamustine may further improve complete response rate, overall 
response rate and progression-free survival in high-risk, previously untreated patients. 
We propose examining ofatumumab and bendamustine (ARM A) and ofatumumab, 
bortezomib, and bendamustine (ARM B) to determine the optimal front-line therapeutic 
approach in high-risk follicular lymphoma. We postulate that intensifying therapy with the 
addition of bortezomib to the ofatumumab-bendamustine regimen in patients with high-
risk follicular lymphoma will improve complete response rates and ultimately progression-
free survival. For ARM B, we have elected to follow the previously published rituximab, 
bortezomib, and bendamustine schedule in untreated indolent lymphoma as previously 
described in the vertical study [14], although only 1 dose of ofatumumab will be given 
during cycle 1 (as opposed to 4 doses of rituximab) in order to ensure that total doses of 
ofatumumab are similar between ARMS A and B. For ARMs A and B, we will use the 
previously published 1000 mg dose of ofatumumab in combination with bendamustine, 
that has been shown to be tolerable in CLL and follicular lymphoma and in combination 
with chemotherapy [11-13], and is associated with a higher CR-rate in patients with CLL 
[13]. In addition, with the proven efficacy of maintenance rituximab in prolonging 
progression-free survival in patients with untreated and relapsed follicular lymphoma [16-
19], we will also explore the role of maintenance ofatumumab (ARM A) or maintenance 
ofatumumab and bortezomib (ARM B) in patients who respond to induction therapy. 
1.7 
Inclusion of Women and Minorities 
It is the intent of CALGB/the Alliance to enroll patients regardless of gender or race. Both 
men and women of all races and ethnic groups are eligible for this study. In the 
development of this protocol, the possibility of inherent gender or racial/ethnic differences 
in treatment response has been considered.  
Accrual Targets 
Ethnic Category 
Sex/Gender 
Females 
 
Males 
 
Total 
Hispanic or Latino 
2 
+ 2 
= 4 
Not Hispanic or Latino 
59 
+ 67 
= 126 
Ethnic Category: Total of all subjects 
61 
(A1) 
+ 69 
(B1) 
= 130 
(C1) 
Racial Category 
 
American Indian or Alaskan Native 
0 
+ 0 
= 0 
Asian 
2 
+ 2 
= 4 
Black or African American 
3 
+ 3 
= 6 
Native Hawaiian or other Pacific Islander 
0 
+ 0 
= 0 
White 
56 
+ 64 
= 120 
Racial Category: Total of all subjects 
61 
(A2) 
+ 68 
(B2) 
= 130 
(C2) 
 
(A1 = A2) 
 
(B1 = B2) 
 
(C1 = C2) 
2.0 
OBJECTIVES  
2.1 
Primary Objective  
To determine the complete response (CR) rate in newly diagnosed untreated follicular 
lymphoma patients receiving 6 cycles of ofatumumab-bendamustine (ARM A) and 6 
cycles of ofatumumab, bortezomib, and bendamustine (ARM B) using International 
Harmonization Project Response Criteria [23]. 
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2.2 
Secondary Objectives 
2.2.1 
To determine progression-free survival (PFS) in patients with untreated follicular 
lymphoma after 6 cycles of ofatumumab-bendamustine (ARM A) followed by 
maintenance ofatumumab and after 6 cycles of ofatumumab, bortezomib, and 
bendamustine followed by maintenance ofatumumab and bortezomib (ARM B) 
2.2.2 
To determine the toxicity profile of ofatumumab and bendamustine and 
ofatumumab, bortezomib, and bendamustine in patients with untreated high-risk 
follicular lymphoma 
2.2.3 
To determine if changes in both qualitative and semi-quantitative FDG-PET 
findings at baseline, after cycle 2 (day 32-35), and at end of therapy (6-8 weeks 
after the last cycle of induction chemotherapy but prior to maintenance therapy) 
with ofatumumab-bendamustine and ofatumumab, bortezomib, and bendamustine 
correlate with response and PFS in patients with high-risk follicular lymphoma 
2.2.4 
To assess if a combinatorial approach using both qualitative and semi-quantitative 
changes in FDG-PET and CT or MRI studies at baseline, after cycle 2 (day 32-35), 
and at end of therapy (6-8 weeks after the last cycle of induction chemotherapy 
prior to maintenance therapy) would result in a higher predictive value for response 
and PFS in patients with high-risk follicular lymphoma 
2.2.5 
To correlate all molecular parameters with FDG-PET parameters in determination 
of response and PFS 
2.2.6 
To correlate pre-treatment single nucleotide polymorphisms with response and 
PFS following ofatumumab-bendamustine and ofatumumab, bortezomib, and 
bendamustine therapy in patients with untreated high-risk follicular lymphoma 
2.2.7 
To correlate CD-68, bcl-2, Ki-67, FOXP3, activated cytotoxic T-cells, lymphoma 
associated macrophages (LAM), MUM1, CD10, nuclear p65 and cREL subunits 
of NFkB, and selected genetic translocations by FISH analysis (such as Bcl-2 and 
Bcl-6) with response and PFS in patients receiving initial therapy for high-risk 
follicular lymphoma 
2.2.8 
To determine whether immune gene signatures previously identified as prognostic 
factors in follicular lymphoma can be applied to paraffin embedded tissues in 
ofatumumab and bendamustine or ofatumumab, bendamustine, and bortezomib 
treated patients; evaluate microRNA signatures associated with these gene 
signatures and outcome 
3.0 
ON-STUDY GUIDELINES 
This clinical trial can fulfill its objectives only if patients appropriate for this trial are enrolled. All 
relevant medical and other considerations should be taken into account when deciding whether this 
protocol is appropriate for a particular patient. Physicians should consider the risks and benefits of 
any therapy, and therefore only enroll patients for whom this treatment is appropriate. Although 
they will not be considered formal eligibility (exclusion) criteria, physicians should recognize that 
the following may seriously increase the risk to the patient entering this protocol: 
• 
Psychiatric illness that would prevent the patient from giving informed consent. 
• 
Medical condition such as uncontrolled infection, uncontrolled diabetes mellitus or cardiac 
disease, which, in the opinion of the treating physician, would make this protocol unreasonably 
hazardous for the patient. 
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• 
Patients with a “currently active” second malignancy other than non-melanoma skin cancers. 
Patients are not considered to have a “currently active” malignancy if they have completed 
therapy and are free of disease for ≥ 3 years.  
4.0 
ELIGIBILITY CRITERIA 
All questions regarding eligibility criteria should be directed to the Study Chair. Please note that 
the Study Chair cannot grant waivers to eligibility requirements.  
4.1 
Documentation of Disease:  
4.1.1 
Histologic Documentation:  
Histologically confirmed follicular non-Hodgkin lymphoma, WHO classification 
grade 1, 2, or 3a (>15 centroblasts per high power field with centrocytes present). 
Bone marrow biopsies as the sole means of diagnosis are not acceptable, but they 
may be submitted in conjunction with nodal biopsies. Fine needle aspirates are 
not acceptable. 
Failure to submit pathology within 60 days of patient registration will be 
considered a major protocol violation.  
4.1.2 
Patients must have at least one of the following indicators of poor risk disease: 
≥ 3 risk factors by the Follicular Lymphoma International Prognostic Index, or 
2 risk factors by the Follicular Lymphoma International Prognostic Index and at 
least one bulky mass or lymph node > 6 cm in size 
Follicular Lymphoma International Prognostic Index (FLIPI score) [1, 23]:  
1. Age > 60 years 
2. Involvement of > 4 nodal sites 
3. Stage III-IV disease 
4. Hemoglobin < 12.0 g/dL 
5. LDH > Upper limit of normal (ULN) 
0-1 of the above risk factors: 
Low Risk 
2 risk factors: 
Intermediate Risk 
≥ 3 risk factors: 
Poor Risk 
4.2 
Prior Treatment 
4.2.1 
No 
prior 
cytotoxic 
chemotherapy, 
radiotherapy, 
immunotherapy, 
or 
radioimmunotherapy. 
4.2.2 
No corticosteroids are permitted, except for maintenance therapy for a non-
malignant disease or to prevent treatment-related ofatumumab reactions. 
(Maintenance therapy dose must not exceed 20 mg/day prednisone or equivalent). 
4.3 
Measurable Disease 
Measurable disease must be present either on physical examination or imaging studies. 
Non-measurable disease alone is not acceptable. Any tumor mass > 1 cm is acceptable. 
Lesions that are considered non-measurable include the following: 
• 
Bone lesions 
• 
Leptomeningeal disease 
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• 
Ascites 
• 
Pleural/pericardial effusion 
• 
Inflammatory breast disease 
• 
Lymphangitis cutis/pulmonis 
• 
Bone marrow involvement (involvement by non-Hodgkin lymphoma should be noted) 
4.4 
CNS Involvement  
Patients must have no known CNS involvement by lymphoma. 
4.5 
Age Requirement 
Patients must be ≥ 18 years of age. 
4.6 
ECOG Performance Status  
Patients must have ECOG performance status of 0-2. 
4.7 
Pregnancy and Nursing Status 
Patients must be non-pregnant and non-nursing. Due to the unknown teratogenic potential 
of this regimen, pregnant or nursing patients may not be enrolled. Women of childbearing 
potential must have a negative serum or urine pregnancy test within 14 days prior to 
registration. In addition, women and men of childbearing potential must commit to use an 
effective form of contraception throughout their participation in this study due to the 
teratogenic potential of the therapy utilized in this trial. Appropriate methods of birth 
control include abstinence, oral contraceptives, implantable hormonal contraceptives 
(Norplant), or double barrier method (diaphragm plus condom). 
4.8 
HIV Status 
Patients with HIV infection are eligible. Patients with HIV infection must meet the 
following: no evidence of co-infection with hepatitis B or C; CD4+ count > 400/µl; no 
evidence of resistant strains of HIV; on anti-HIV therapy with an HIV viral load < 50 
copies HIV RNA/mL; no history of AIDS-defining conditions. No safety data are available 
regarding HIV positive individuals treated with ofatumumab. No zidvoudine or stavudine 
are allowed owing to overlapping toxicity with chemotherapy. 
4.9 
Hepatitis B or C 
Patients must have no evidence of active hepatitis B or C infection (i.e., no positive 
serology for anti-HBc or anti-HCV antibodies). HBV seropositive patients (HBsAg +) are 
eligible if HBV DNA is undetectable at baseline and they are closely monitored for 
evidence of active HBV infection by HBV DNA testing at each treatment cycle. After 
completing treatment, HBsAg + patients must be monitored by HBV DNA testing every 2 
months for 6 months post-treatment, while continuing lamivudine (see Section 10.0). 
4.10 
Required Initial Laboratory Values 
Granulocytes 
≥1,000/µl 
Platelet count 
≥75,000/µl 
Creatinine  
< 2.0 mg/dL 
AST and ALT 
< 2.5 x upper limits of normal (ULN) 
Bilirubin 
≤ 2 x ULN 
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5.0 
REGISTRATION/RANDOMIZATION 
5.1 
Registration Requirements 
Informed Consent: The patient must be aware of the neoplastic nature of his/her disease 
and willingly consent after being informed of the procedure to be followed, the 
experimental nature of the therapy, alternatives, potential benefits, side-effects, risks, and 
discomforts. Human protection committee approval of this protocol and a consent form is 
required. 
Monthly Conference Call Participation: One representative from each institution with a 
patient enrolled in this protocol must participate in a monthly (once a month) conference 
call to discuss toxicity (see Section 16.3 Adverse Event Monitoring). This will occur for 
the first 40 patients enrolled on the study (20 in ARM A and 20 in ARM B). Institutions 
with patients enrolled on this protocol that do not participate in the conference calls may 
be denied future registrations to this trial.  
5.1.1 
CTSU Registration Requirements 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). Study 
documents 
and 
forms 
can 
be 
accessed 
on 
the 
Alliance 
website: 
www.allianceforclinicaltrialsinoncology.org. 
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>. 
5.1.2 
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. 
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CALGB 50904 
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>. 
5.1.3 
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 
members’ website by entering credentials at https://www.ctsu.org.  For sites under 
the CIRB initiative, IRB data will automatically load to RSS. 
Downloading Site Registration Documents: 
Site registration forms may be downloaded from the CALGB 50904 protocol page 
located on the CTSU members’ website. Go to https://www.ctsu.org and log in to 
the members’ area using your CTEP-IAM username and password 
• 
Click on the Protocols tab in the upper left of your screen 
• 
Under RSS Browser, select ‘Regulatory and Roster Forms and Resources’ to 
expand this menu, then select the ‘Printable CTSU Forms’ folder 
• 
Download the required CTSU Site Registration forms 
Requirements For CALGB 50904 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 
E-mail: CTSURegulatory@ctsu.coccg.org (for regulatory document 
submission only) 
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 
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CALGB 50904 
• 
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 
5.1.4 
Patient Enrollment  
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 and upon enrollment, 
initializes the patient in the Rave database.. 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. 
5.1.5 
Additional Required Regulatory Documentation 
The following documentation is required and should be submitted at the time of 
IRB approval. Participation and drug shipment (bendamustine, ofatumumab) are 
contingent upon the receipt of the following documentation by the Regulatory 
Support System (RSS): 
• 
Documentation of IRB approval of the protocol and informed consent 
document 
• 
Copy of IRB approved consent form 
• 
Pharmacy license with the address for drug shipment 
• 
CV of investigator(s) 
5.1.6 
Registration to Correlative Study 
There is one correlative study within CALGB 50904 (CALGB 151005). This 
correlative science study must be offered to all patients enrolled on CALGB 50904, 
although patients may opt not to participate. The three components of this 
correlative study are: 
• 
Single Nucleotide Polymorphism Analysis (Section 12.1). 
• 
Immunohistochemical Markers (Section 12.2). 
• 
Validation of Gene Signatures in Lymphoma (Section 12.3). 
• 
If a patient answers “yes” to model consent questions #1 and/or #2, then the 
patient should be registered to CALGB 151005 at the same time that s/he is 
registered to the treatment trial (50904) with samples submitted per Section 
6.4. 
6.0 
DATA SUBMISSION, HISTOLOGY REVIEW, AND CORRELATIVE SCIENCE SPECIMEN 
SUBMISSION  
6.1 
Data Submission 
Forms should be submitted to the Alliance Statistics and Data Center in compliance with 
the Data Submission schedule below. Forms that use the Teleform barcode and 
cornerstones should be submitted electronically using the “Submit to CALGB” button 
located at the bottom of the last page of each form. Original forms should not be submitted 
by fax or mail. 
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Amended forms and supporting documentation (e.g., reports or flow sheets) should be 
submitted by mail to: 
Alliance Statistics and Data Center 
Attn: Andy Johnson 
RO FF-3-24-CC/NW Clinic  
200 First Street SW 
Rochester, MN 55905 
For the most up-to-date forms for this study, please refer to the Alliance Web site at 
https://www.allianceforclinicaltrialsinoncology.org/.
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CALGB 50904 
Form* 
 
Submission Schedule 
Baseline 
C-2024 
50904 On-Study Form 
Submit within one month of registration. 
C-2028 
50904 Lymphoma Measurement Form 
C-2029 
50904 FDG-PET Adjunctive Data Sheet 
Report 
Imaging and Pathology reports 
 
 
 
Treatment 
C-2025 
50904 Treatment Summary Form 
Submit at the completion of each cycle 
during Induction and Maintenance. 
C-2027 
50904 Adverse Event Form** 
 
 
 
C-2026 
50904 Follow-up Form 
Submit following cycle 2 (FDG-PET and 
CT/MRI), cycle 4 (CT/MRI only), and 
cycle 6 (FDG-PET and CT/MRI) during 
induction.   
C-2028 
50904 Lymphoma Measurement Form 
C-2029 
50904 FDG-PET Adjunctive Data Sheet 
Report 
Imaging and Pathology reports 
 
 
 
C-2026 
50904 Follow-up Form 
Submit every 4 months during 
Maintenance. 
C-2028 
50904 Lymphoma Measurement Form 
Report 
Imaging and Pathology reports 
 
 
 
Follow-up (Post-treatment) 
C-2026 
50904 Follow-up Form 
Submit every 4 months for 2 years, then 
every 6 months until disease progression or 
for a maximum of 10 years from study 
entry. 
C-2028 
50904 Lymphoma Measurement Form 
Report 
Imaging and Pathology reports 
 
 
 
Other 
C-300 
Off Treatment Form 
Submit at end of all protocol treatment. 
 
 
 
C-113 
Notification of Death 
Submit at time of death. 
 
 
 
C-1001  
New Malignancy Form 
Submit at time of diagnosis of new 
malignancy. 
 
 
 
C-1820 
Adverse Events Addendum Form 
Complete if additional space is needed to 
report other adverse events.  See form for 
instructions. 
* 
Use CALGB Remarks Addenda (C-260) if additional comments are necessary or additional writing space is needed.   
† 
If patient never starts treatment and is not randomized, then the patient will be cancelled.  No data submission is 
required.  If the patient never starts treatment, but has been randomized, then submit all Baseline forms, Post-
Treatment Follow-up forms, and other forms.  
** Submit AE form until all protocol treatment related events have resolved or until non-protocol treatment begins. If 
patient death is reported via CTEP-AERS, report a Grade 5 event on the AE form even if the patient is off protocol 
treatment.  
Common Terminology Criteria for Adverse Events (CTCAE): This study will utilize the 
Common Terminology Criteria for Adverse Events version 4.0 for toxicity and adverse 
event reporting. 
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CALGB 50904 
6.2 
Alliance Biospecimen Management System Instructions 
USE OF THE ALLIANCE BIOSPECIMEN MANAGEMENT SYSTEM (BioMS) IS 
MANDATORY AND ALL SPECIMENS MUST BE LOGGED AND SHIPPED VIA 
THIS SYSTEM.  
BioMS is a web-based system for logging and tracking all biospecimens collected on 
Alliance trials. Authorized individuals may access BioMS at the following URL: 
http://bioms.wustl.edu/bioms, using most standard web browsers (Safari, Firefox, Internet 
Explorer). For information on using the BioMS system, please refer to the ‘Help’ links on 
the BioMS web page to access the on-line user manual, FAQs, and training videos. To 
report technical problems, such as login issues or application errors, please contact: 1-855-
55-BIOMS.  For assistance in using the application or questions or problems related to 
specific specimen logging, please contact: 1-855-55-BIOMS. 
After logging collected specimens in BioMS, the system will create a shipping manifest. 
This shipping manifest must be printed and placed in the shipment container with the 
specimens. 
6.3 
Histologic Review 
Submission of a tissue block is critical for confirmation of lymphoma diagnosis. High 
quality hematoxylin and eosin-stained sections and any required confirmatory studies (such 
as immunohistochemistry and in situ hybridization) may be done most efficiently from the 
tissue block in laboratories of the Alliance Biorepository at Ohio State University (OSU). 
Within 60 days of registration, send a formalin-fixed, paraffin-embedded block of well-
fixed lymphoma tissue containing adequate material for histologic confirmation of 
diagnosis. A block at least 1 cm x 1 cm x 2 mm is preferable, although smaller is acceptable 
if no other block is suitable. If only one block exists, and the tissue is sufficiently large, it 
is acceptable to split the block into two and submit one. Contact Dr. Eric Hsi (216-444-
5230) with questions. 
Samples should be logged and shipped via the Biospecimen Management System see 
Section 6.2 for instructions. The requested tissue block should be labeled with the 
protocol number (50904), institutional surgical pathology number, study patient ID, 
institution, date of acquisition, and tissue source. A copy of the BioMS shipping manifest 
must be printed and placed in the shipment with the specimens. In addition to the pathology 
specimen and the shipping manifest, send a copy of the pathology report (include 
consultative pathology reports, if available) to OSU. 
Failure to submit pathology materials within 60 days of patient registration will be 
considered a major protocol violation.  
If a patient has consented to participate in the research studies proposed (model consent 
question #2), only one tissue block need be submitted to accommodate both histologic 
confirmation of diagnosis and correlative science studies (see Section 6.4.2). 
The CALGB/Alliance has instituted special considerations for the small percentage of 
institutions whose policies prohibit release of any blocks. If, due to institutional policy, a 
block cannot be sent, please call 614-293-7073 to obtain a protocol for submission of 
representative tissue from your institution. 
6.4 
Specimen Submission for Correlative Studies 
All participating institutions must ask patients for their consent to participate in the 
correlative substudy (CALGB 151005) planned for CALGB 50904, although patient 
participation is optional. Single nucleotide polymorphism analysis, immunohistochemical 
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CALGB 50904 
staining, and validation of gene signatures will be performed. Rationale and methods for 
the scientific components of these studies are described in Section 12.0. For patients who 
consent to participate, specimens will be collected at the following time points for these 
studies: 
 
Time Points 
 
Sample Type 
Prior to Treatment  
Progression or Relapse 
Ship to: 
Whole Blood  
(lavender top) 
1 x 10 mL 1 
 
OSU 
FFPE tissue 
1 block 2 
1 block 3 
OSU 
1 For patients who consent (Question #1) to companion study 151005, described in Section 12.1. 
2 Diagnostic tissue block is required for all patients registered to CALGB 50904. For patients who 
consent (Question #2) to companion study 151005, only one tissue block need be submitted to 
accommodate both histologic confirmations of diagnosis and correlative science studies as described 
in Sections 12.2 and 12.3. 
3 If biopsy has been performed, for patients who consent (Question #3 and/or #4). 
6.4.1 
Whole Blood Submission 
For patients who consent to participate (model consent question #1), whole blood 
will be used for the single nucleotide polymorphism analysis described in Section 
12.1. 
Whole blood will be collected prior to initiation of therapy only. Collect 10 mL of 
whole blood in lavender top tube. The tube should be inverted 8-10 times to mix 
the tube additive, and then refrigerated until shipped. Samples should be packaged 
to prevent breakage and shipped on a cold pack for processing and cell 
cryopreservation for later DNA extraction. 
Specimens should be logged and shipped via the Biospecimen Management 
System (BioMS), see Section 6.2 for instructions. A copy of the shipping manifest 
produced by BioMS must be printed and placed in the shipment with the 
specimens. All submitted specimens must be labeled with the protocol number 
(50904), study patient ID, patient’s initials, date and time of specimen collection 
and type of specimen collected (e.g., whole blood). 
Ship samples by overnight courier the same day they are collected. If shipping 
on Friday, FedEx or UPS must be used and the air bill must be marked “For 
Saturday delivery.” Do not ship specimens on Saturdays. Ship specimens to the 
OSU: 
Alliance Biorepository at Ohio State University 
Innovation Center 
2001 Polaris Parkway 
Columbus, OH 43240 
Tel: 614-293-7073 
Fax: 614-293-7967 
path.calgb@osumc.edu 
6.4.2 
Paraffin-Embedded Tissue Block Submission 
Paraffin embedded tissue will be used for immunohistochemical evaluation of 
markers of angiogenesis, cell of origin, lymphoma associated macrophages, and 
tumor infiltrating T-cells (Tregs), and validation of gene signatures in lymphoma. 
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Furthermore, the CALGB/Alliance Lymphoma Committee is committed to 
conducting correlative science studies utilizing tissue from consenting patients 
enrolled on treatment trials, and has chosen tissue microarrays (TMAs) as the 
method of archiving tissue. TMAs are constructed by removing two 1 mm diameter 
tissue cores from the lymphoma tissue block using a specially designed instrument 
(Beecher Instruments, Sun Prairie, WI). The resulting tissue array can contain 100 
cases in a single tissue block, and allows rapid, high throughput analysis of markers 
by immunohistochemistry or in situ hybridization. The original tissue block 
remains intact with only a small amount of tissue removed with no significant 
distortion. The original block may then be returned to the submitting institution. 
Samples should be logged and shipped via the Biospecimen Management System 
(BioMS), see Section 6.2 for instructions. A copy of the shipping manifest 
produced by BioMS must be printed and placed in the shipment with the 
specimens. All submitted specimens must be labeled with the protocol number 
(50904), study patient ID, patient’s initials, date and time of specimen collection 
and type of specimen collected (e.g., FFPE block). 
Please be sure to use a method of shipping that is secure and traceable. Ship 
specimens Monday through Thursday by overnight service to assure receipt. Do 
not ship specimens on Fridays or Saturdays. 
For patients who consent to participate (model consent question #2), send a 
formalin-fixed, paraffin-embedded block of well-fixed lymphoma tissue to OSU: 
Alliance Biorepository at Ohio State University 
Innovation Center 
2001 Polaris Parkway 
Columbus, OH 43240 
Tel: 614-293-7073 
Fax: 614-293-7967 
path.calgb@osumc.edu 
If a patient has consented to participate (model consent question #2), only one 
tissue block need be submitted to accommodate both histologic confirmation of 
diagnosis and correlative science studies (see Section 6.4). 
6.4.3 
Progression or Relapse Specimen Submission 
Samples should be logged and shipped via the Biospecimen Management System 
(BioMS), see Section 6.2 for instructions. A copy of the shipping manifest 
produced by BioMS must be printed and placed in the shipment with the 
specimens. All submitted specimens must be labeled with the protocol number 
(50904), study patient ID, patient’s initials, date and time of specimen collection 
and type of specimen collected (e.g., FFPE). 
Please be sure to use a method of shipping that is secure and traceable. Ship 
specimens Monday through Thursday by overnight service to assure receipt. Do 
not ship specimens on Fridays or Saturdays. 
At the time of progression or relapse, if a patient has consented to allow tissue to 
be kept for future research (model consent question # 3 and/or 4), and if a biopsy 
has been performed, please submit a formalin-fixed, paraffin-embedded block of 
well-fixed lymphoma tissue for pathology review and future correlative science to 
OSU: 
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Alliance Biorepository at Ohio State University 
Innovation Center 
2001 Polaris Parkway 
Columbus, OH 43240 
Tel: 614-293-7073 
Fax: 614-293-7967 
path.calgb@osumc.edu 
 
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7.0 
REQUIRED DATA 
Guidelines for Pre-Study Testing 
To be completed within 16 DAYS before registration: 
- 
All blood work*** 
- 
History and physical 
To be completed within 28 DAYS before registration: 
- 
Any radiologic exam, scan of any type (e.g., PET, CT or MRI) or ultrasound, which is 
utilized for tumor measurement  
To be completed within 42 DAYS before registration: 
- 
Any baseline exams used for screening,  
- 
Any radiologic exam, scan of any type or ultrasound of uninvolved organs that is not 
utilized for tumor measurement 
- 
Bone marrow aspirate & biopsy (bilateral preferred) 
Tests & Observations 
Prior to 
Registration 
Day 1 of each 
induction 
cycle 
Day 1 of each 
maintenance 
cycle 
Time of 
Restaging*  
Post 
Treatment 
Follow 
up** 
History and Progress notes 
X 
X 
X 
 
X 
Physical Examination (physician visit) 
X 
X 
X 
 
X 
Pulse, Blood Pressure 
X 
X 
X 
 
 
Height 
X 
 
 
 
 
Weight/Body Surface Area† 
X 
X† 
X† 
 
 
Performance Status 
X 
X 
X 
 
X 
Tumor Measurements 
X 
A 
A 
A 
A 
Drug Toxicity Assessment  
 
X 
X 
 
X 
Laboratory Studies 
 
 
 
 
 
CBC, Differential, Platelets 
X 
B 
B 
 
X 
Serum Creatinine, BUN 
X 
X 
X 
 
X 
Serum Electrolytes, Ca++ 
 
X 
X 
 
X 
AST, ALT, ALK Phos, Bilirubin 
X 
X 
X 
 
X 
Uric Acid, LDH 
X 
H 
H 
 
H 
β2 microglobulin 
X 
 
 
 
 
Serum or urine βHCG 
X*** 
 
 
 
 
HBsAg, HBsAB, HB core antibody 
C 
 
 
 
 
HBV DNA testing 
D 
D 
D 
 
D 
HCV testing 
X 
 
 
 
 
HIV (if required, see Section 4.9) 
X 
 
 
 
 
Staging 
 
 
 
 
 
CT scan/MRI (chest/abd/pelvis) 
X 
 
 
X†† 
X 
CT scan/MRI neck 
E 
 
 
E 
E 
FDG-PET/CT scan 
F1 
 
 
F2 
 
Bone Marrow Asp & Bx (bilateral 
preferred) 
X 
 
 
G 
G 
Histologic Review 
X 
 
 
 
 
* 
Restage after cycles 2, 4, and 6 during induction and then every 4 months during maintenance therapy.  
**  
At least every 4 months for 2 years, then every 6 months until disease progression or for a maximum of 10 
years from study entry. 
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*** 
Within 14 days prior to registration for females of childbearing potential. 
† 
Although doses are recalculated prior to each treatment, the actual dose given need not be changed unless the 
difference is ≥ 10%. 
†† 
Repeat CT of the chest/abdomen/pelvis or MRI scan after cycle 2, cycle 4, cycle 6 and every 4 months during 
maintenance therapy.  
A 
As indicated to follow measurable disease.   
B 
Obtain on day 1 of each cycle for patients in ARM A; Obtain on days 1 and 15 of each cycle for patients in 
ARM B. 
C 
All patients must be screened for hepatitis B before starting treatment. Carriers of hepatitis B should be 
carefully monitored, including HBV DNA testing, for evidence of active HBV infection every 2 months for 
at least 6 months after ofatumumab treatment ends. For patients with evidence of prior HBV infection, i.e. 
HBsAg positive, lamuvidine or other HBV suppressive therapy is required (see Section 10.0).  
D 
HBV DNA testing should be performed at baseline, at the start of each induction and maintenance cycle, and 
then every 2 months for up to 6 months from the last oftumumab dose for patients who are carriers of hepatitis 
B or who have had prior HBV infection.  
E 
Perform if nodes are palpable prior to treatment. 
F1 
Perform PET/CT at baseline, within 4 weeks of treatment initiation (see Section 11.0). 
F2 
Restage with PET/CT after cycle 2 (perform between days 32-35) and cycle 6 (perform 6-8 weeks after the 
start of cycle 6). PET/CT is not required during maintenance therapy or post-treatment follow-up (see Section 
11.0). 
G 
If initially positive, repeat only in patients who are demonstrated to be in CR by all other criteria. 
H 
LDH only. Uric acid is only required at baseline (prior to registration). 
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8.0 
TREATMENT PLAN 
Protocol treatment is to begin within 7 days of registration (unless otherwise specified by Study 
Chair). Questions regarding treatment should be directed to the Study Chair. 
All dosing is to be determined by actual weight. Please see Section 9.0 for dose modifications, 
Section 10.0 for ancillary therapy, and Section 13.0 for drug formulation, availability and 
preparation. 
8.1 
Induction  
Eligible patients will be randomized to receive either 6 cycles of ofatumumab with 
bendamustine (ARM A) or 6 cycles of ofatumumab, bendamustine, and bortezomib (ARM 
B). Response will be assessed by CT or MRI and/or FDG-PET/CT scan according to 
International Harmonization Criteria [23] after 2 (CT/MRI and FDG-PET/CT), 4 (CT/MRI 
only) and 6 (CT/MRI and FDG-PET/CT) cycles of ofatumumab-bendamustine (ARM A) 
or ofatumumab, bortezomib, and bendamustine (ARM B). Patients without evidence of 
disease progression by CT scan after 2 and 4 cycles will continue for a maximum of 6 
cycles. 
8.1.1 
ARM A: Ofatumumab and Bendamustine Induction 
Premedication: 
Acetaminophen 
(or 
equivalent) 
650 
mg 
orally 
and 
diphenhydramine (or equivalent) 50-100 mg orally or by IV 30-60 minutes prior 
to each ofatumumab infusion. On day 1 of cycle 1 only, administer 20 mg IV 
dexamethasone (or acceptable equivalent steroid). Additional acetaminophen, 
diphenhydramine, and glucocorticoids may be provided at the treating physician’s 
discretion for the management of ofatumumab-related infusion reactions. 
Ofatumumab 300 mg IV on day 1 of cycle 1, and then 1000 mg IV on day 1 of 
cycles 2-6 (immediately prior to bendamustine).  
The initial rate during the first cycle should be 25 mL/hr during the first hour. The 
rate may be increased, if tolerated, by 50 mL/hr increments every 30 minutes to a 
maximum of 400 mL/hr. If administration is well-tolerated during the first cycle, 
the initial rate during subsequent cycles of therapy may be increased to 50 mL/hr 
for the first hour. If tolerated, the rate may be increased by 100 mL/hr increments 
every 30 minutes to a maximum rate of 400 mL/hr. 
Note: The plan for rate escalation is based on mL/hr and not mg/hr. 
Bendamustine 90 mg/m2 IV over 30-60 minutes on days 1 and 2 of each cycle. 
Cycles will be repeated every 35 days for a total of 6 cycles. To begin a cycle 
the ANC > 1000/µL and platelets > 75,000/µL. Remove the patient form the 
protocol for treatment delays exceeding 3 weeks. 
See Section 9.0 for dose modifications and management of toxicity. See Section 
10.0 for ancillary therapy. 
8.1.2 
ARM B: Ofatumumab, Bortezomib, and Bendamustine Induction 
Premedication: 
Acetaminophen 
(or 
equivalent) 
650 
mg 
orally 
and 
diphenhydramine (or equivalent) 50-100 mg orally or by IV 30-60 minutes prior 
to each ofatumumab infusion. On day 1 of cycle 1 only, administer 20 mg IV 
dexamethasone (or acceptable equivalent steroid). Additional acetaminophen, 
diphenhydramine, and glucocorticoids may be provided at the treating physician’s 
discretion for the management of ofatumumab-related infusion reactions. 
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Ofatumumab 300 mg IV on day 1 of cycle 1, and 1000 mg IV on day 1 of cycles 
2-6 (immediately prior to bortezomib and bendamustine).  
The initial rate during the first cycle should be 25 mL/hr during the first hour. The 
rate may be increased, if tolerated, by 50 mL/hr increments every 30 minutes to a 
maximum of 400 mL/hr. If administration is well-tolerated during the first cycle, 
the initial rate during subsequent cycles of therapy may be increased to 50 mL/hr 
for the first hour. If tolerated, the rate may be increased by 100 mL/hr increments 
every 30 minutes to a maximum rate of 400 mL/hr. 
Note: The plan for rate escalation is based on mL/hr and not mg/hr. 
Bendamustine 90 mg/m2 IV over 30-60 minutes on days 1 and 2 of each cycle. 
Bortezomib 1.6 mg/m2 by IV over 3-5 seconds or by subcutaneous injection on 
days 1, 8, 15, and 22 of each cycle. 
Cycles will be repeated every 35 days for a total of 6 cycles. To begin a cycle 
the ANC ≥ 1000/µL and platelets ≥ 75,000/µL. Remove the patient from the 
protocol for treatment delays exceeding 3 weeks. 
See Section 9.0 for dose modifications and management of toxicity. See Section 
10.0 for ancillary therapy. 
8.2 
Maintenance therapy  
Patients without evidence of disease progression after 6 cycles of ofatumumab with 
bendamustine (ARM A) or 6 cycles of ofatumumab, bendamustine, and bortezomib (ARM 
B) may continue to receive either ofatumumab alone (ARM A) or ofatumumab and 
bortezomib maintenance therapy (ARM B). Maintenance therapy will start 2 months (8 
weeks) after cycle 6 day 1 of induction therapy. Maintenance therapy will be administered 
every 2 months for a total of 4 cycles. Response will be assessed by CT or MRI scans 
according to International Harmonization Criteria[23] every 4 months during maintenance 
therapy. Patients without evidence of disease progression will continue for a maximum of 
4 cycles (8 months) of maintenance therapy. 
8.2.1 
ARM A: Ofatumumab Maintenance 
Premedication: 
Acetaminophen 
(or 
equivalent) 
650 
mg 
orally 
and 
diphenhydramine (or equivalent) 50-100 mg orally or by IV 30-60 minutes prior 
to each ofatumumab infusion. Additional acetaminophen, diphenhydramine, and 
glucocorticoids may be provided at the treating physician’s discretion for the 
management of ofatumumab-related infusion reactions. 
Ofatumumab 1000 mg IV on day 1 of each cycle. 
The infusion rate can start at 50 mL/hr. If tolerated, the rate may be increased by 
100 mL/hr increments every 30 minutes to a maximum rate of 400 mL/hr. 
Note: The plan for rate escalation is based on mL/hr and not mg/hr. The 
administration schedule and rates of infusion in this study are different from those 
described in the package literature. 
Cycles will be repeated every 56 days (2 months) for a total of 4 cycles. To 
begin a cycle the ANC must be ≥ 1000/µL and platelets must be ≥ 75,000/µL. 
Remove the patient from the protocol for treatment delays exceeding 3 weeks. 
See Section 9.0 for dose modifications and management of toxicity. See Section 
10.0 for ancillary therapy. 
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8.2.2 
ARM B: Ofatumumab and Bortezomib Maintenance 
Premedication: 
Acetaminophen 
(or 
equivalent) 
650 
mg 
orally 
and 
diphenhydramine (or equivalent) 50-100 mg orally or by IV 30-60 minutes prior 
to each ofatumumab infusion. Additional acetaminophen, diphenhydramine, and 
glucocorticoids may be provided at the treating physician’s discretion for the 
management of ofatumumab related infusion reactions. 
Ofatumumab 1000 mg IV on day 1 of each cycle (immediately prior to 
bortezomib). The infusion rate can start at 50 mL/hr. If tolerated, the rate may be 
increased by 100 mL/hr increments every 30 minutes to a maximum rate of 400 
mL/hr. 
Note: The plan for rate escalation is based on mL/hr and not mg/hr. The 
administration schedule and rates of infusion in this study are different from those 
described in the package literature. 
Bortezomib 1.6 mg/m2 by IV over 3-5 seconds or by subcutaneous injection on 
days 1, 8, 15, and 22 of each cycle. 
Cycles will be repeated every 56 days (2 months) for a total of 4 cycles. To 
begin a cycle the ANC must be ≥ 1000/µL and platelets must be ≥ 75,000/µL. 
Remove the patient from the protocol for treatment delays exceeding 3 weeks. 
See Section 9.0 for dose modifications and management of toxicity. See Section 
10.0 for ancillary therapy. 
9.0 
DOSE MODIFICATIONS AND MANAGEMENT OF TOXICITY 
Dose Levels 
 
Starting Dose 
Dose Level -1 
Dose Level -2 
Ofatumumab (Arms A and B) 
1000 mg 
1000 mg 
1000 mg 
Bendamustine (Arms A and B) 
90 mg/m2 
60 mg/m2 
45 mg/m2 
Bortezomib (Arm B only) 
1.6 mg/m2 
1.3 mg/m2 
1 mg/m2 
9.1 
Dose Modification for Hematologic Toxicity 
Patients with treatment delays greater than 3 weeks should be removed from protocol 
therapy. 
The following dose modifications should be made for febrile neutropenia and blood counts 
obtained within 2 days prior to each cycle. If more than one of these applies, use the most 
stringent (i.e., the greatest dose reduction.) 
9.1.1 
Neutropenia  
For ANC < 1000 on Day 1 (or within 48 hours of day 1) of induction therapy, 
delay treatment until ANC ≥ 1000. 
If induction treatment is delayed for ANC < 1000 on day 1, administer filgrastim 
or pegfilgrastim beginning on day 3 (Arm A) or day 23 (Arm B) of all subsequent 
induction cycles.  
For recurrent ANC < 1000 during induction therapy, despite a colony stimulating 
factor, decrease dose of bendamustine (Arms A and B) by one dose level for all 
subsequent induction cycles, and decrease the dose of bortezomib (Arm B) by one 
dose level for all subsequent induction cycles.  
For ANC < 1000 on Day 1 (or within 48 hours of day 1) of maintenance therapy, 
delay treatment until ANC ≥ 1000. 
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If maintenance treatment is delayed for ANC < 1000 on day 1, decrease the dose 
of bortezomib (Arm B) by one dose level for all subsequent maintenance cycles.  
Use of pegfilgrastim or filgrastim is not permitted during maintenance, except in 
the event of serious infection per ASCO guidelines. 
During induction or maintenance, there are no dose reductions below dose level 
-2 if dose reduction below dose level -2 is required for neutropenia, discontinue all 
protocol therapy.  
During induction or maintenance, remove the patient from the protocol for delays 
exceeding 3 weeks. 
9.1.2 
Thrombocytopenia 
For platelets < 75,000 on Day 1 of induction or maintenance therapy, delay 
treatment until platelets ≥ 75,000. 
Resume treatment when thrombocytopenia improves to ≥ 75,000 with one dose 
level reduction of bendamustine (Arm A and B, induction only) and one dose level 
reduction of bortezomib (Arm B, induction and maintenance) for all subsequent 
cycles. 
During induction or maintenance, there are no dose reductions below dose level 
-2. If dose reduction below dose level -2 is required for thrombocytopenia, 
discontinue all protocol therapy. 
During induction or maintenance, remove the patient from the protocol for delays 
exceeding 3 weeks. 
9.1.3 
Febrile Neutropenia 
For febrile neutropenia (defined as temperature ≥ 38.5° C [101° F] sustained for 
more than one hour concomitant with an ANC < 500/µL) during induction, hold 
therapy until resolution. 
Administer filgrastim or pegfilgrastim starting on day 3 (Arm A) or day 23 (Arm 
B) of all subsequent induction cycles.  
For recurrent febrile neutropenia despite filgrastim or pegfilgrastim support during 
induction, reduce the dose of bendamustine (Arms A and B) by one dose level for 
all subsequent induction cycles, and decrease the dose of bortezomib (Arm B) by 
one dose level for all subsequent induction cycles.  
For febrile neutropenia (defined as temperature ≥ 38.5° C [101° F] sustained for 
more than one hour concomitant with an ANC < 500/µL) during maintenance, 
hold therapy until resolution. 
After resolution of the febrile neutropenia, reduce the dose of bortezomib (Arm B) 
by one dose level for all subsequent maintenance cycles.  
Use of pegfilgrastim or filgrastim is not permitted during maintenance, except in 
the event of serious infection per ASCO guidelines. 
During induction or maintenance, there are no dose reductions below dose level 
-2. If dose reductions below dose level -2 are required, discontinue all protocol 
therapy. 
During induction or maintenance, remove the patient from the protocol for delays 
exceeding 3 weeks. 
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9.2 
Grade 2-4 Peripheral Neuropathy  
For grade 2 peripheral neuropathy during induction or maintenance, decrease bortezomib 
by one dose level for all subsequent cycles.  
For grade 3 peripheral neuropathy during induction or maintenance, hold protocol 
therapy until the toxicity resolves to grade 1 or less. Delay cycle up to 2 weeks for 
resolution of the adverse event. Contact the study chair for delays exceeding 2 weeks. 
When toxicity resolves to grade 1 or less, resume protocol therapy and reduce the 
bortezomib (Arm B) by one dose level for all subsequent cycles. Remove the patient from 
protocol for treatment delays exceeding 3 weeks. 
For grade 4 peripheral neuropathy during induction or maintenance, discontinue 
bortezomib. Therapy with ofatumumab and bendamustine may continue.  
During induction or maintenance, there are no dose reductions below dose level -2. If 
dose reduction below dose level -2 is required for neurotoxicity, discontinue bortezomib. 
9.3 
Ofatumumab Infusion and Hypersensitivity Reactions  
Ofatumumab infusions must be interrupted if any infusion reactions (fever, chills, dyspnea, 
rash, etc.) ≥ grade 1 occur. Appropriate supportive care including acetaminophen, 
diphenhydramine, albuterol, and glucocorticoids may be administered according to 
institutional infusion reaction protocols. When the symptoms have resolved completely, 
the infusion may be restarted at half the previous rate. If tolerated, ofatumumab may be 
gradually re-escalated to the initial infusion rate. If the patient experiences a second 
infusion reaction, the ofatumumab infusion should be stopped. At the investigator’s 
discretion, patients unable to complete the full dose of ofatumumab may resume the 
incomplete treatment on the same or following day after dexamethasone 20 mg orally or 
IV (or equivalent) is given 30-60 minutes prior to re-treatment. 
9.4 
Dermatologic Toxicity or Hepatitis B Reactivation 
In the instance of ≥ grade 3 erythema multiforme or hepatitis B re-activation (i.e., 
detectable HBV DNA), remove the patient from all protocol therapy.  
9.5 
Other Grade 3-4 Non-Hematologic Toxicity  
For other grade 3-4 non-hematologic toxicity that occurs during induction or 
maintenance considered at least possibly related to bendamustine or bortezomib, hold 
bortezomib (Arm B) and bendamustine (Arm A and B) until toxicity improves to grade 1 
or less. Delay cycle up to 2 weeks for resolution of the adverse event. Contact the study 
chair for delays exceeding 2 weeks.  
Once the toxicity has resolved to grade 1 or less, resume treatment with one dose level 
reduction for bendamustine (Arms A and B), and one dose level reduction for bortezomib 
for all subsequent induction and maintenance cycles.  
During induction or maintenance, there are no dose levels below dose level -2. If dose 
reduction below dose level -2 is required for other grade 3 or 4 toxicity, discontinue all 
protocol therapy. 
During induction or maintenance, remove the patient from the protocol for delays 
exceeding 3 weeks. 
9.6 
Dose Modifications for Obese Patients 
There is no clearly documented adverse impact of treatment of obese patients when dosing 
is performed according to actual body weight. Therefore, all dosing is to be determined 
solely by actual weight without any modification. This will eliminate the risk of calculation 
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CALGB 50904 
error and the possible introduction of variability in dose administration. Failure to use 
actual body weight in the calculation of drug dosages will be considered a major protocol 
deviation. Physicians who are uncomfortable with calculating doses based on actual body 
weight should recognize that doing otherwise would be a protocol violation 
9.7 
HBV Reactivation 
Discontinue ofatumumab in patients with prior HBV infection if HBV DNA testing reveals 
evidence of reactivation. 
10.0 
ANCILLARY THERAPY 
Patients should receive full supportive care, including transfusions of blood and blood products, 
erythropoietin, antibiotics, antiemetics (non-steroidal), etc., when appropriate. The reason(s) for 
treatment, dosage, and the dates of treatment should be recorded on CALGB Remarks Addenda 
(form C-260). 
Treatment with hormones or other chemotherapeutic agents may not be administered. 
Prophylaxis against herpes zoster reactivation according to institutional guidelines is recommended 
for patients in arm A. Due to high risk of herpes zoster with bortezomib use, prophylaxis against 
herpes zoster reactivation utilizing valacylovir, acyclovir, or famciclovir is required for patients in 
Arm B for up to 6 months after final bortezomib dose. 
Hepatitis B surface antigen positive patients will receive lamivudine 100 mg/day orally (or 
acceptable alternative) until 6 months after the last ofatumumab dose. HBV DNA testing will occur 
at the start of each induction and maintenance cycle and then will continue every 2 months until 6 
months after the last ofatumumab dose. 
Anti-emetic prophylaxis (non-steroidal) may be provided prior to bortezomib and bendamustine 
infusions. Supportive care with anti-emetics, anti-diarrheals, and stool softeners is permitted for 
the treatment of gastrointestinal adverse events.  
10.1 
CALGB Policy Concerning the Use of Growth Factors 
The use of an erythropoiesis-stimulating agent (ESA) is allowed. If an ESA is used, it 
should be within the context of the most current guidelines. 
The use of filgrastim or pegfilgrastim in CALGB 50904 is described in Sections 9.1.1 and 
9.1.3. 
11.0 
FDG-PET IMAGING, INTERPRETATION, QUALITATIVE AND SEMI-QUANTITATIVE ANALYSES  
11.1 
Institution Credentialing Procedures for FDG-PET/CT Imaging 
Prior to enrollment of patients, institutions must be credentialed to participate in the trial 
by the Alliance Imaging Core Laboratory (ICL) at the Ohio State University Medical 
Center if they have not previously been credentialed for any other CALGB trials. The 
Imaging Core Lab will provide a site manual that outlines all of the details as they relate to 
the image acquisition and reconstruction. 
11.1.1 FDG-PET/CT Requirements for Participation 
1) The participating center must have, or have access to, a facility with an 
integrated positron-emission tomography and computed tomography 
(PET/CT) scanner. 
2) The participating center must have the ability to submit PET and CT studies 
electronically to the ICL in digital DICOM format (other formats: BITMAP, 
JPG). Hardcopy or scanned files are not acceptable. 
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3) Participating sites must be credentialed by the ICL so that the performance 
characteristics and infrastructure requirements are met: 
If a site has been credentialed by either the ICL, or ACRIN, or ACR CQIE, only a 
protocol refresher will be needed for participating in CALGB 50904. 
If a site has never been credentialed by any of the above institutions, however they 
either participated in other CALGB PET/CT trials or successfully completed 
certain protocol refresher processes (i.e., CALGB 50604, CALGB 50801) by the 
ICL, a protocol refresher (and/or WebEx Site Visit, if necessary) is required for 
50904 participation. 
If an institution has never been credentialed by the ICL or any of the above 
institutions, and has not participated in a CALGB trial with a PET/CT component, 
the ICL will adhere to the ACRIN criteria for PET imaging approval procedures. 
In order for an institution to be approved to participate in this study, they are 
required to submit the following for technical and quality review by the ICL: 
i) 
Two test patient studies (for all PET/CT instruments utilized) 
Images of two unidentified patients shall consist of three volume or multislice 
files as follows: a) Whole body CT from PET/CT scanner; b) Whole body 
(torso) emission with attenuation correction (A/C); and c) Whole body (torso) 
emission without A/C. 
ii) 
Uniform phantom data with the SUV measurement of the phantom (for all 
PET/CT instruments utilized): 
Water-fillable uniform phantom: The phantom must be filled with water, and 
a known amount of F-18 (either as fluoride or as FDG) should be injected 
into the phantom. The activity injected should be determined by measurement 
of the syringe before and after the injection in a properly calibrated dose 
calibrator. The injected activity should be chosen to result in an activity 
concentration similar to that encountered in clinical FDG imaging (i.e., 1-1.5 
mCi of F-18 should be added to the 6,283 mL phantom: 2 mCi for the 9.293 
mL phantom). After thoroughly mixing the phantom, the phantom must be 
scanned with the same protocol used for the patient imaging. The images also 
must be reconstructed with the same algorithm and filters used for patient 
imaging. A circular or elliptical region of interest (ROI) covering most of the 
interior of the phantom must be drawn over all slices, and the average SUV 
and standard deviation must be measured and reported in the PET/CT 
Instrument Technical Specifications Form (Appendix II). The expected SUV 
for the uniform phantom is 1.0 and the acceptable range is 0.9 to 1.1. 
(Alternatively) Ge-68/Ga-68 calibration phantom: This phantom can readily 
be scanned with the same protocol used for patient imaging. The assay date 
and activity from the calibration certificate of this phantom must be reported 
on the PET/CT Instrument Technical Specifications Form (Appendix II). The 
images must be reconstructed with the same algorithm and filters used for 
patient imaging. A circular or elliptical ROI covering most of the interior of 
the phantom must be drawn over all slices, and the average SUV and standard 
deviation must be measured and reported in the PET Instrument Technical 
Specification form. The expected SUV for the uniform phantom is 1.0 and 
the acceptable range is 0.9 to 1.1. 
iii) Appendix II: PET/CT Instrument Technical Specifications Form (for all 
PET/CT instruments utilized) 
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iv) Appendix III: Imaging Site Personnel Form 
11.2 
FDG-PET/CT Imaging 
A PET/CT scan will be obtained pre-treatment (baseline), after cycle 2 (day 32-35), and at 
the end of therapy (6-8 weeks after cycle 6, day 1 after the last cycle of induction 
chemotherapy). 
As several series do support the utility of FDG-PET in assessing residual disease and 
predicting PFS in follicular NHL [20, 22], these 3 PET scans will be considered standard 
of care.  
Semi-quantitative and qualitative PET analysis will be performed by the Alliance Imaging 
Committee using absolute values of and changes in SUVs, as well as various reading 
schemes using various references such as mediastinal blood pool and the liver. PET/CT 
results at the completion of induction therapy will be correlated with response and PFS 
with maintenance therapy. PET results will also be evaluated in combination with changes 
seen on dedicated CT or MRI studies between baseline and after 2 cycles, 6 cycles, and 
end of therapy to assess if a combinatorial approach using both metabolic and morphologic 
changes would result in a higher predictive value for response and PFS. 
All PET scans should be obtained on integrated PET/CT machines. 
The following PET/CT images will be collected digitally for archival use: 
• 
Baseline (within 4 weeks of treatment initiation) 
• 
After cycle 2 (day 32-35)  
• 
End of treatment (6-8 weeks after cycle 6, day 1)  
11.2.1 FDG-PET/CT Imaging Procedures 
11.2.1.1 Patient Preparation 
Patients must fast for at least four hours before the PET/CT scan. Oral 
hydration is strongly encouraged prior to and during injection of 18F-FDG 
(250-500 mL water can be given PO during the uptake period) and during 
the uptake period after administration of 18F-FDG. IV furosemide (10 mg) 
may be administered (but is not mandatory) to increase urinary elimination 
of the tracer and minimize image artifacts caused by urinary stasis in the 
abdomen and pelvis. Intravenous fluids containing dextrose or parenteral 
feeding should be withheld for at least 6 hours prior to the injection of 18F-
FDG. No steroid administration is allowed for at least 7 days prior to 
FDG-PET imaging. Active exercise should be discouraged for at least 24 
hours prior to the study. Muscle stress, tension, chewing, and movement 
during the uptake period should be minimized to decrease muscle uptake. 
Patients should not speak during the injection and uptake period. 
Interviews with the patient should be withheld until after completion of 
the imaging study. 
The blood glucose level should be checked before 18F-FDG injection. 
Blood sugar (measured by glucometer) must be less than 200 mg/dL at the 
time of the FDG-PET/CT study. If the blood glucose level is greater than 
200 mg/dL, the FDG-PET/CT imaging should be rescheduled. If the blood 
glucose level still exceeds 200 mg/dL on the following scheduled day for 
PET scanning, the patient will not be included in the trial. Insulin 
administration immediately before the PET/CT study to reduce the 
glucose levels is not allowed. Patients with diabetes should continue to 
adhere to their oral agents or insulin routines. These medications should 
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not be administered near the 18F-FDG injection time. In insulin-dependent 
patients, insulin should be administered at least 5 hours prior to the 18F-
FDG injection. Patients with diabetes who are on diabetic medication 
should take their medication 4-5 hours prior to the test. If blood sugar 
exceeds 150 mg/dL (but less than 200 mg/dL), a note should be made in 
on the case report form. 
Metallic objects should be removed from the patients whenever possible. 
Patients should be kept in a warm waiting room prior to 18F-FDG injection 
to avoid brown adipose tissue uptake. In anxious and claustrophobic 
patients, administration of oral diazepam (0.06-0.10 mg/kg) is 
recommended 30-40 minutes prior to the initiation of the imaging study. 
Weight (kg), height (cm), blood glucose (mg/dL), and the date and time of 
chemotherapy and colony stimulating administration (e.g., GCSF, 
GMCSF) will be recorded prior to the injection of 18F-FDG. 
10-20 mCi of 18F-FDG will be administered IV, depending on the 
manufacturer’s recommendation. A 10-20 mL saline flush is 
recommended in reducing the venous retention of 18F-FDG. The patient 
must wait for at least 60 minutes prior to the initiation of the PET/CT 
acquisition for all PET/CT scans (both pre-and post-therapy scans). The 
wait period should be kept with a minimal variation of 10 minutes among 
patients. The wait period must not exceed 75 minutes at baseline. It is 
NOT acceptable to start imaging with wait periods of less than 60 
minutes and longer than 75 minutes. The time difference between 
baseline and other PET studies (after cycles 2 and 6) should not be > 10 
minutes. A time difference of > 15 minutes between PET/CT studies is 
NOT acceptable. 
The imaging will start after voiding the bladder. 150-200 mL of water must 
be given to the patient immediately prior to the study acquisition before 
they are positioned on the table to distend stomach and avoid physiologic 
stomach uptake. 
11.2.1.2 FDG Dosing and Administration 
The administered activity of FDG should be based on the PET/CT scanner 
manufacturer’s recommendation. The recommended FDG dose is 0.14-
0.21 mCi/kg. The actual FDG dose should be a bolus of 10-20 mCi, 
followed by a saline flush (per institutional procedure). A dose at the 
higher end of the range is recommended, if feasible, with appropriate 
reduction in the per kilogram dose for heavier patients (in accordance with 
the manufacturer’s recommendation). The effective FDG dose injected 
and time of injection should be documented on CALGB form C-2029 
(50904 FDG-PET Adjunctive Data Sheet). 
11.2.2 FDG-PET/CT Image Acquisition 
Patients will be positioned on the table in a headfirst, supine position with arms 
elevated above the abdomen to reduce beam-hardening artifacts at the level of the 
liver. A separate head and neck imaging will be pursued for those whose primary 
disease site is in the neck with the arms positioned along the side. The use of IV 
and oral contrast is at the discretion of each facility. However, IV-contrast CT 
acquisition should follow PET imaging acquired with non-contrast CT to avoid 
variations in FDG uptake in the blood pool and the tumor that is caused by the 
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contrast agent. If IV contrast is not used, CT should be acquired using a current of 
not less than 120 mA/second to allow for sufficient resolution for definition of 
anatomic structures. Immediately after CT scanning, a PET emission scan will be 
obtained. 
Six to seven contiguous volumes will be chosen, depending on the patient’s height, 
to ensure data acquisition of the entire region of interest (ROI), the level of the 
skull base to the 1/3 proximal femurs. The time/bed position should be in 
accordance with the manufacturer’s recommendations for optimal imaging. 
Adjacent fields of view should share overlapping slices. 
It is critical that follow-up emission scans be performed in an identical way to the 
baseline scan, with the same scanner, same scan direction (skull to thighs or thighs 
to skull), and consistent arm positioning (arms up or arms down).  
It is NOT acceptable to start imaging with wait periods of less than 60 minutes 
and longer than 75 minutes. The time difference between baseline and other PET 
studies (after cycles 2 and 6) should not be > 10 minutes. A time difference of > 
15 minutes between PET/CT studies is NOT acceptable. 
11.2.3 Qualitative PET Analysis 
Semi-quantitative and qualitative PET analysis will be performed by the Alliance 
Imaging Committee. 
Tumor selection: Up to 6 lesions (target lesions) demonstrating highest (or 
relatively higher compared to other lesions) FDG uptake will be selected for 
analyses at baseline. Their locations and size (length and width) will be defined. 
Tumor #1 will be the tumor site with highest FDG uptake; the others will be 
selected in descending order of uptake. On the integrated PET/CT scan, the 
location and dimensions of the index tumors will be determined at the baseline 
scan and at all subsequent studies. For all reading scales, the interpreter’s degree 
of suspicion for an abnormality will be recorded with the use of a 5-point ordinal 
categoric scale. 
The evaluation will be performed using the three different sets of criteria as 
follows: 
• 
using mediastinum blood pool (MBP) as the reference organ [24]. 
• 
using liver as the reference organ [25]. 
• 
measurements of SUVmax normalized to body weight 
Mediastinum blood pool (MBP) is evaluated at the aortic arch level. Negative 
post-therapy PET scan (metabolic responders): Upon qualitative evaluation, tumor 
FDG uptake that is less than or equal to the MBP in target tumors, regardless of 
uptake in non-target tumors (if any), will be considered negative for the presence 
of residual lymphoma. Positive post-therapy PET scan: Upon qualitative 
evaluation, diffuse of focal uptake in target tumors exceeding that seen in the MBP 
will be considered positive for residual tumor. 
Liver uptake will be evaluated on axial slices.  
Negative and positive post-therapy PET scans with respective criteria set are 
defined as follows.  
The following criteria will be used for the 5-point ordinal scale: 
MBP-based Assessment (IHP criteria) 
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1) 
No uptake visible for assessed lesion 
2) 
Increased lesion uptake, but < MBP uptake 
3) 
Increased lesion uptake, but equal to MBP uptake 
4) 
Lesion uptake moderately increased compared with MBP 
5) 
Lesion uptake markedly increased compared with MBP 
Liver-based Assessment (London criteria) 
1) 
No uptake 
2) 
Increased lesion uptake ≤ MBP 
3) 
Increased lesion uptake >MBP and ≤ liver 
4) 
Lesion uptake moderately increased compared with liver 
5) 
Lesion uptake markedly increased compared with liver 
Interpretation of ultimate positivity/negativity: Negative is scores of 0-3; 
Positive is scores of 4-5. Additionally, after therapy if any residual uptake is 
observed in non-target lesions, these lesions will be evaluated in the same fashion 
as the target organs. 
SUV Assessment: Circular or volumetric regions of interest (ROI) will be placed 
over the target lesions, in mid-segment of the liver and MBP. When circular ROI 
are used, care must be taken that the ROI is drawn on the slice with the highest 
FDG uptake. When volumetric ROI are used, care must be taken that the region is 
confined to the lesion and does not include adjacent structures with high 
physiologic FDG uptake (e.g., renal collecting system, bone marrow after GCSF). 
Percent change between baseline and after therapy at all points as well as absolute 
SUVs will be determined at all points. 
11.2.4 FDG-PET/CT and CT/MRI Data Archiving, Storage, and Submission 
Once the image acquisition has been completed, the entire study (complete 
PET/CT data in digital DICOM format), along with CALGB form C-2029 (50904 
FDG-PET Adjunctive Data Sheet) and CALGB form C-2028 (50904 Lymphoma 
Measurement Form), must be submitted to the Imaging Core Laboratory within 
no more than 3 business days. Institutions must also send CALGB forms C-2029 
and C-2028 to the Alliance Statistical Center, Data Operations at Duke University. 
The complete PET/CT and CT/MRI scans will be submitted to the Imaging Core 
Lab in digital DICOM format. BMP files, JPG files, or hard copies (films) are not 
acceptable. The raw data of the entire study should be saved until the scan is 
accepted by the Imaging Core Lab. De-identify the patient data using institutional 
procedures to remove patient name and medical record number while preserving 
the study patient ID number and protocol number. The de-identified digital images 
may be burned to a CD or transferred to a PC-based system. The following datasets 
must be sent: 
• 
Transmission CT data 
• 
Emission data with CT attenuation correction 
• 
Emission data without CT attenuation correction 
Data may be transferred by 1) Web Transfer; 2) FTP transfer; 3) 
Shipment/Mail Transfer. Once the data submission is complete, you must send 
an e-mail to the Imaging Core Lab at CALGB50904@imagingcorelab.com to 
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inform them that the images have been sent from your institution. Please include 
the study patient ID number and the date of the scan. 
1) Web Transfer: 
Any PCs with Internet access and web browser (e.g., Internet Explorer, Mozilla 
Firefox) can be used to web transfer DICOM images and other required files to the 
Imaging Core Lab. The standard Web Transfer information will be provided 
separately through the specific trial e-mail CALGB50904@ImagingCoreLab.com, 
per the request by participating sites before their first data submission. 
2) FTP Transfer:  
Any FTP software can be used to initiate access to the secure FTP Server of the 
Imaging Core Laboratory. The standard FTP access information will be provided 
separately through the specific trial e-mail CALGB50904@ImagingCoreLab.com, 
per the request by participating sites before their first data submission. 
3) Shipment/Mail Transfer: 
If FTP data transfers cannot be achieved, the de-identified images in digital 
DICOM format should be burned to a CD and mailed to the Imaging Core Lab. 
Please submit only one patient’s images per CD, with the patient’s study patient 
ID number, study type (i.e., PET baseline, after cycle 2 or end of treatment), date 
of scans, date of first study treatment, and name of submitting institution. 
Submit these data to: 
Alliance Imaging Core Lab 
Attn: CALGB50904 
The Ohio State University 
395 W. 12th Avenue, Suite 414 
Columbus, Ohio, 43210 
Tel: 614-293-9151 
Fax: 614/293-9275 
CALGB50904@imagingcorelab.com 
If there are any difficulties or questions concerning the FDG-PET and CT/MRI 
data submission, please contact the Imaging Core Lab.  
The Alliance Imaging Core Lab will acknowledge receipt of the imaging data via 
email confirmation to the institution within 1 business day of receipt. The data 
will be reviewed for quality. After completion of the quality check, another e-mail 
assessing the protocol compliance will be sent to the institution within 3 business 
days. 
12.0 
CORRELATIVE SCIENCE COMPANION STUDY (CALGB 151005) 
There are three components to the CALGB 151005 correlative science companion study that must 
be presented to all patients, though patients may opt not to participate. The first component will be 
to evaluate Fc receptor polymorphisms and to correlate clinical outcomes in patients with 
previously untreated, high-risk follicular NHL treated with ofatumumab and bendamustine or 
ofatumumab, bendamustine, and bortezomib. The second component will be to correlate CD-68, 
bcl-2, Ki-67, FOXP3, Granzyme B, activated cytotoxic T-cells, lymphoma-associated 
macrophages (LAM), MUM1, CD10, and selected genetic translocations by FISH analysis 
(including Bcl-2 and Bcl-6) with response and progression-free survival following RCHOP and 
maintenance therapy in previously untreated patients with high-risk follicular lymphoma. The third 
component will be to determine whether immune gene signatures previously identified as 
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prognostic factors in follicular lymphoma can be applied to paraffin-embedded tissues in patients 
treated with either ofatumumab and bendamustine or ofatumumab, bendamustine, and bortezomib. 
12.1 
Single Nucleotide Polymorphism Analysis 
12.1.1 Background 
This study will correlate single nucleotide polymorphisms (SNPs) in the Fc gamma 
receptors 2A and 3A with response to ofatumumab-bendamustine (ARM A) or 
ofatumumab, bortezomib, and bendamustine (ARM B) and subsequent 
maintenance therapy in patients with previously untreated follicular NHL.  
12.1.2 Objective 
To correlate pre-treatment single nucleotide polymorphisms with response and 
PFS following ofatumumab-bendamustine and ofatumumab, bortezomib, and 
bendamustine therapy in patients with untreated high-risk follicular lymphoma. 
12.1.3 Methods 
SNP analysis will be performed at The Ohio State University in the laboratory of 
Dr. John Byrd, M.D., according to published protocols [26, 27]. Briefly, genomic 
DNA will be extracted and quantified, and 250 ng will be amplified in a standard 
polymerase chain reaction (PCR). PCR products will then be digested using 
restriction enzymes, and products will be analyzed by agarose gel electrophoresis. 
Results are compared to published data. 
12.2 
Immunohistochemical Markers 
12.2.1 Background 
Recent data have also suggested that the host immune response may affect the 
clinical course and survival of patients with follicular lymphoma. Dave et al. used 
gene-expression profiling in a series of follicular lymphomas, and found that a 
survival-predictor score could be generated using expression of immune response 
genes [28]. Genes associated with a favorable prognosis (termed “immune 
response 1”) included many genes expressed by T cells and macrophages, while 
genes associated with a poor prognosis (“immune response 2”) included many 
expressed by macrophages and dendritic cells. The combination of both immune 
response signatures was highly predictive of survival [28]. A subsequent study 
using a different group of patients demonstrated that lymphoma associated 
macrophages (LAMs) as recognized by expression of CD68 correlated with a poor 
prognosis, while expression of the T-cell antigens CD3, CD4, and CD8 did not 
correlate with clinical outcome [29]. Presence of immune modulating T-cells, 
regulatory T-cells (Tregs) as determined by FOXP3 expression, has also been 
studied with variable results, possibly related to patient populations and different 
methods of assessment of FOXP3. In one study, FOXP3 expression pattern has 
been suggested to be associated with poor outcome [30], while in others the 
number or pattern of FOXP3+ cells has been associated with favorable outcome 
[31]. Another subset of immune modulating T-cells (TFH) cells, recognized by 
PD-1, have also been shown to correlate with favorable survival [32]. These 
cellular components of the inflammatory infiltrate have not been examined 
together in the setting of a multi-institutional trial, and are of particular interest in 
CALGB phase II rituximab and immunotherapy based studies in which treatment-
naïve patient response to biologic therapies is monitored by PET. 
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With regard to the tumor cells themselves, MUM1 expression in follicular 
lymphoma (FL) cells has recently been demonstrated.  This post-germinal 
center/activated B-cell markers has not been previously known to be expressed to 
any degree in FL. Correlates of MUM1 have been suggested such as higher 
cytologic grade, lack of CD10, BCL6 amplification, and Ki67 [30, 33]; however, 
the clinical significance of MUM1+ FL has not been characterized.  We have data 
to suggest a more aggressive clinical course as evidenced by the need to treat at 
diagnosis, as opposed to watchful waiting [21]. Furthermore, our preliminary data 
derived from SWOG cohorts suggests that MUM1+ FL (>20% of cells) has a poor 
OS compared to MUM1- FL in newly diagnosed patients receiving CHOP with 
monoclonal antibody [34]. Thus, this CALGB patient population is of particular 
interest to follow-up and confirm this observation in an independent data set. 
12.2.2 Objective 
To correlate CD-68, bcl-2, Ki-67, FOXP3, activated cytotoxic T-cells, lymphoma 
associated macrophages (LAM), MUM1, CD10, nuclear p65 and cREL subunits 
of NFkB, and selected genetic translocations by FISH analysis (such as Bcl-2 and 
Bcl-6) with response and PFS in patients receiving initial therapy for high-risk 
follicular lymphoma. 
12.2.3 Methods 
In patients who consent, tissue microarrays (TMA) will be constructed from 
paraffin-embedded 
tissue 
collected 
prior 
to 
initiation 
of 
therapy. 
Immunohistochemistry for FOXP3 (22510, Abcam), granzyme B (GrB7, Accurate 
Chemical), and CD68 (PGM1, Dako) will be performed using an automated 
immunostainer (Ventana Medical Systems, Tucson, AZ), with tonsil used as a 
positive control tissue. Pattern of FOXP3 (perifollicular versus other) and number 
of FOXP3/1000x high power field (average of five fields) will be scored using a 
“hotspot” counting method. Granzyme B will be quantitated in a similar manner. 
Ki-67 will be analyzed by image analysis (Aperio) within follicles. BCL2, MUM1, 
CD10 will also be performed using automated stainers (Ventana) and scored in 
tumor cells as negative (5%), weakly positive (6-20%), or strongly positive (> 
20%). In an attempt to standardize analysis, we will also perform image analysis 
to quantitate the number of positive cells. FISH analysis will be performed with 
specific break-apart probes (Vysis) on TMAs according to standard procedures 
with cutoffs (positive, negative, and aneuploid) set by the central laboratory. Only 
those cells demonstrating nuclear staining will be counted.  
Pre-treatment levels of NFkB activity will be assessed by evaluation of nuclear 
(active) p65 and cREL subunits of NFkB by automated immunohistochemistry 
using TMAs in the laboratory of Dr. Hsi.  Nuclear staining will be scored via image 
analysis (Aperio) in the laboratory of Dr. Said (lymphoma pathology cadre) and 
correlated with outcome. 
12.3 
Validation of Gene Signatures in Lymphoma 
12.3.1 Background 
Specific expression profiles have been discovered and have been proven useful in 
subclassfication and outcome prediction in lymphoma, including follicular 
lymphoma [28, 35-38]. However, these signatures have yet to be validated in 
independent patient cohorts from routinely processed tissues in modern (anti 
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CD20-containing) regimens. Such validation is of interest in this study. In addition 
to these established signatures, there is emerging evidence that expression of 
micro-RNAs are of pathogenetic importance in lymphoma. These micro-RNAs, 
which regulate gene expression, are differentially expressed in lymphocytes 
subsets, lymphoma subtypes, and may also be useful biomarkers [39-45]. Indeed 
a comprehensive profile of normal B-cell micro-RNA profiles has been established 
[45]. In order to further explore micro-RNA expression profiles and relationships 
with established gene signatures and outcome, we will also interrogate microRNA 
signatures that may correlate with these key gene signatures in this study.  
12.3.2 Objectives 
To determine whether immune gene signatures previously identified as prognostic 
factors in FL can be applied to paraffin embedded tissues in ofatumumab and 
bendamustine or in ofatumumab, bendamustine, and bortezomib treated patients; 
to evaluate microRNA signatures associated with these gene signatures and 
outcome. 
12.3.3 Methods 
Published gene signatures will be validated, focusing on immune response that 
have been associated with outcome in follicular lymphoma [28], on the paraffin 
embedded tissue collected on this trial. 
Microarrays, quantitative real-time PCR, serial analysis of gene expression 
(SAGE) or similar methods will be used to generate gene expression profiles of 
tumors. Additional correlative studies may be done in conjunction with molecular 
profiling to assess genomic and protein changes using additional standard methods 
such as sequencing, polymerase chain reaction (PCR), immunophenotyping, 
Southern, Northern and Western Blot. 
13.0 
DRUG FORMULATION, AVAILABILITY AND PREPARATION 
Qualified personnel who are familiar with procedures that minimize undue exposure to themselves 
and to the environment should undertake the preparation, handling, and safe disposal of 
chemotherapeutic agents in a self-contained, protective environment. 
Discard unused portions of injectable chemotherapeutic agents that do not contain a bacteriostatic 
agent or are prepared with unpreserved diluents (i.e., Sterile Water for Injection USP or 0.9% 
Sodium Chloride for Injection USP) within eight hours of vial entry to minimize the risk of bacterial 
contamination. 
The total administered dose of chemotherapy may be rounded up or down within a range of 5% of 
the actual calculated dose. 
It is not necessary to change the doses of ofatumumab, bendamustine, or bortezomib due to changes 
in weight unless the calculated dose changes by ≥10%. 
13.1 
Ofatumumab  
Please review the ofatumumab prescribing information. 
AVAILABILITY 
Ofatumumab will be supplied by GlaxoSmithKline and distributed by Biologics. It may be 
ordered using the Drug Order Form on the CALGB 50904 study page, on the Alliance web 
site. Ofatumumab will be supplied in vials containing 100 mg or 1000 mg, at a 
concentration of 20 mg/mL. Please refer to the agent’s package insert for additional 
information. 
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STORAGE & STABILITY 
Intact vials of ofatumumab should be stored under refrigeration. Vials do not contain a 
preservative and are intended for single use. Diluted solutions should also be stored under 
refrigeration if they are not used immediately after preparation. 
At the end of the study, institutions should provide a copy of the local drug destruction 
policies to the Alliance protocol office, and then destroy all unused drug onsite. 
PREPARATION 
For the 300 mg dose, withdraw and discard 15 mL from 1000 mL of 0.9% NaCl. Then add 
300 mg to the 1000 mL bag, for IV infusion. For the 1000 mg dose, withdraw and discard 
50 mL from 1000 mL of 0.9% NaCl. Then add 1000 mg to the 1000 mL bag, for IV 
infusion. 
ADMINISTRATION 
In this study, ofatumumab will be administered as an IV infusion, at the rate(s) specified 
in Section 8.0. Maintenance doses should begin at the initial rate of 50 mL/hr followed by 
rate increase by 50 mL/hr every 30 minutes until a maximum rate of 400 mL/hr, because 
of the time elapsed between doses. 
TOXICITIES 
In the published reports of Phase I/II studies, the most commonly occurring adverse events 
(AEs) were infusion-related AEs. In these studies, infusion-related AEs were defined as 
those events occurring on the day of drug administration. Infusion-related AEs (e.g., 
hypersensitivity reactions, cytokine release syndrome) include fever, chills, fatigue, 
dyspnea, pharyngolaryngeal pain, cough, pruritus, rash and urticaria. The majority of these 
events were of grade 1 and 2 severity. Other reported AEs include headache, hypotension 
and nausea. Most AEs were noted on the day of ofatumumab administration; infusion-
related AEs were generally seen within the first few hours of the start of the ofatumumab 
infusion. The number of AEs reported decreased with each subsequent dose.  
As with rituximab, serious infections have been reported infrequently with ofatumumab. 
Exacerbation or reactivation of viral infections (e.g., JC virus reactivation leading to 
progressive multifocal leukoencephalopathy [PML], hepatitis B reactivation) have been 
reported in patients with CLL or follicular lymphoma, and less so in patients with 
rheumatoid arthritis. Patients presenting with new neurologic findings (e.g., major changes 
in vision, unusual eye movements, loss of balance or coordination, confusion) should be 
evaluated for PML.  
Tumor lysis syndrome and small bowel obstruction have also been reported. Tumor lysis 
syndrome may be more likely in patients with high numbers of circulating malignant cells, 
as has been seen with rituximab. 
Cardiac toxicity, including heart failure and myocardial infarction, were reported rarely in 
patients with CLL who received ofatumumab. 
13.2 
Bendamustine  
Please review the bendamustine prescribing information. 
AVAILABILITY 
Bendamustine will be supplied and distributed by Cephalon. It may be ordered using the 
Drug Order Form on the CALGB 50904 study page, on the Alliance web site. 
Bendamustine will be supplied in vials containing 100 mg as a lyophilized powder. Please 
refer to the agent’s package insert for additional information. 
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STORAGE AND STABILITY 
Intact vials should be stored at room temperature and protected from light. Once 
reconstituted or further diluted for infusion, bendamustine is stable for 24 hours when 
stored refrigerated (2-8°C or 36-47°C) or for 3 hours when stored at room temperature (15-
30°C or 59-86°F) and room light. 
At the end of the study, institutions should provide a copy of the local drug destruction 
policies to the Alliance protocol office, and then destroy all unused drug onsite. 
PREPARATION 
Add 5 mL of sterile water for injection to a 25 mg vial or 20 mL of sterile water for injection 
in a 100 mg vial to yield a concentration of 5 mg/mL. The desired volume should be 
withdrawn from the vial, and injected into 500 mL of 0.9% NaCl or 2.5% 
dextrose/0.45%NaCl for IV infusion.  
ADMINISTRATION 
In this study, bendamustine will be administered as an IV infusion over 30-60 minutes, 
following ofatumumab (Arm A) or bortezomib (Arm B). 
TOXICITIES 
The most common adverse events reported with bendamustine include myelosuppression, 
GI toxicity, fatigue, fever and chills, and infection. Grade 3 or 4 neutropenia is reported in 
60% of patients but febrile neutropenia is less common. Grade 3 or 4 thrombocytopenia is 
reported in 25% of patients. Dose delays due to myelosuppression were common in a study 
of bendamustine given every 21 days to patients with rituximab refractory NHL. Nausea 
and vomiting are seen in approximately 77% and 40% of patients, respectively. Most of 
these events are grade 1 or 2. Infusion reactions during or shortly after bendamustine 
administration have been reported in as many as 15% of patients. Reactions consist of fever 
and 
chills, 
and 
less 
frequently, 
shortness 
of 
breath, 
hypotension 
or 
anaphylactic/anaphylactoid reactions. Pre-medication with steroids following mild 
infusion reactions may prevent further reactions with subsequent doses. Fatigue has been 
reported in 57% of patients. Less commonly, severe skin reactions (e.g. TEN, SJS) and 
second malignancies have been seen. In some cases, skin reactions have been seen in 
patients who also received other medications associated with severe skin toxicity (e.g., 
allopurinol). In addition, extravasation reactions including erythema, swelling and pain 
have been described. 
As in the case with other alkylators, secondary malignancies including MDS and AML 
have also been reported. 
13.3 
Bortezomib (NSC #681239, IND #58443) 
AVAILABILITY 
NCI-supplied agents may be requested by the Principal Investigator (or their authorized 
designee) at each participating institution.  Pharmaceutical Management Branch (PMB) 
policy requires that agent be shipped directly to the institution where the patient is to be 
treated.  PMB does not permit the transfer of agents between institutions (unless prior 
approval from PMB is obtained).  The CTEP-assigned protocol number must be used for 
ordering all CTEP-supplied investigational agents.  The responsible investigator at each 
participating institution must be registered with CTEP, DCTD through an annual 
submission of FDA Form 1572 (Statement of Investigator), Curriculum Vitae, 
Supplemental Investigator Data Form (IDF), and Financial Disclosure Form (FDF).  If 
there are several participating investigators at one institution, CTEP-supplied 
investigational agents for the study should be ordered under the name of one lead 
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investigator at that institution. 
Active CTEP-registered investigators and investigator-designated shipping designees and 
ordering designees can submit agent requests through the PMB Online Agent Order 
Processing (OAOP) application (https://eapps-ctep.nci.nih.gov/OAOP/pages/login.jspx).  
Access to OAOP requires the establishment of a CTEP Identity and Access Management 
(IAM) account (https://eapps-ctep.nci.nih.gov/iam/) and the maintenance of an “active” 
account status and a “current” password.  For questions about drug orders, transfers, 
returns, or accountability, call (240) 276-6575 Monday through Friday between 8:30 am 
and 4:30 pm (ET) or email PMBAfterHours@mail.nih.gov anytime. 
PREPARATION 
IV preparation: Each vial should be reconstituted with 3.5 mL normal (0.9%) saline, 
resulting in a bortezomib solution of 1 mg/mL. 
SC preparation: Each vial should be reconstituted with 1.4 mL normal (0.9%) saline, 
resulting in a bortezomib solution of 2.5 mg/mL. 
STORAGE AND STABILITY 
Intact vials should be stored at room temperature and protected from light. Solutions 
reconstituted as instructed are stable for at least 8 hours at room temperature. 
At the end of the study, all unused (including expired) drug should be returned to the PMB. 
ADMINISTRATION 
IV administration: The desired volume of bortezomib reconstituted solution is 
administered as a rapid IV injection over 3 to 5 seconds. 
SC administration: The desired volume of bortezomib reconstituted solution is 
administered as a subcutaneous injection in the thigh or abdomen. Rotate sites at least 1 
inch away from old sites. 
TOXICITIES 
The most frequently reported adverse events associated with bortezomib to date include 
gastrointestinal events, fatigue, and thrombocytopenia. Gastrointestinal events include 
nausea, vomiting, anorexia, diarrhea, and constipation. Most GI events have been grade 1 
or 2 and they occurred early in treatment, persisting for several cycles. Occasional grade 4 
vomiting and diarrhea have been noted. Prophylaxis against GI events is not thought to be 
necessary with the first cycle of treatment. Ileus and abdominal pain/cramping have also 
been reported. Fatigue is also predominantly of grade 1 or 2 severity and has onset early in 
treatment (i.e. during the first and second cycles). Thrombocytopenia, although occurring 
in 38% of patients in phase II studies, is reported to be transient (resolution during the rest 
period in each cycle) and uncomplicated. Thrombocytopenia of grade 3 severity was seen 
in 25% of patients. 
Peripheral neuropathy was noted in 35% of patients in phase II studies (grade 3 in 13% and 
grade 4 in < 1%). Peripheral neuropathy is primarily sensory and appears to be more severe 
in patients with pre-existing sensory signs or symptoms. It does not seem to be related to 
cumulative dose, in that new onset or worsening of existing neuropathy was noted 
throughout the cycles of treatment. Recently motor neuropathy has also been described. 
Peripheral neuropathy may or may not be completely reversible. 
Grade 3 neutropenia was described in 10% of patients in phase II studies. Febrile 
neutropenia occurred in 4%. Clinically significant infections (distinct from neutropenia) 
were reported in 13%. Fever was reported in 36% of patients; severity of grades 3 or 4 in 
4%.  
Hypotension, the mechanism of which is unknown, was reported in 11% of patients in 
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phase II studies. Most patients were orthostatic. Hypotension required pharmacologic 
treatment and a small number of patients had syncopal events. Orthostatic hypotension was 
not acutely related to bolus injection of bortezomib.  
Other reported adverse events and potential risks include anemia, rash/desquamation, 
vasculitis, headache, lymphopenia, granulocytopenia, dyspnea, constipation, edema, and 
pruritis.  
Also reported on bortezomib trials but with the relationship to bortezomib still 
undetermined: hyponatremia, hypokalemia, hyperkalemia, hypertension, tachycardia, 
bradycardia, atrial flutter, myalgia, and instances of various pain, clotting abnormalities, 
renal dysfunction, abnormal liver function tests and certain central nervous system 
abnormalities (confusion and altered mentor status). 
For a comprehensive adverse events and potential risks list (CAEPR), see Section 17.3. 
14.0 
CRITERIA FOR RESPONSE, PROGRESSION AND RELAPSE  
For the purposes of this study, patients will be restaged using CT or MRI scan and/or FDG-PET/CT 
according to Section 7.0 after cycles 2, 4, and 6 of induction therapy, every 4 months during 
maintenance therapy, every 4 months for 2 years after completion of therapy, and then every 6 
months until disease progression or for a maximum of 10 years from study entry. 
14.1 
Definitions of Response [23] 
14.1.1 Complete Response (CR): 
Complete disappearance of all detectable clinical evidence of disease and disease-
related symptoms if present before therapy. 
In patients with no pre-treatment PET scan, or if the PET scan was positive before 
therapy, a post-treatment residual mass of any size is permitted as long as it is PET-
negative. 
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 should be considered normal size by imaging studies, and nodules related to 
lymphoma should disappear. However, determination of splenic involvement is 
not always reliable because a spleen considered normal in size may still contain 
lymphoma, whereas an enlarged spleen may reflect variations in anatomy, blood 
volume, the use of hematopoietic growth factors, or causes other than lymphoma. 
If the bone marrow was involved by lymphoma before 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 
that demonstrates 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. 
14.1.2 Partial Response (PR): 
At least a 50% decrease in the sum of the product of the diameters (SPD) of up to 
six of the largest dominant nodes or nodal masses. These nodes or masses should 
be selected prior to initiation of therapy according to all of the following: a) they 
should be clearly measurable in at least two perpendicular dimensions; b) if 
possible, they should be from disparate regions of the body; and c) they should 
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include mediastinal and retroperitoneal areas of disease whenever these sites are 
involved. 
No increase should be observed in the size of other nodes, liver, or spleen. 
Splenic and hepatic nodules must regress by ≥ 50% in their SPD, or, for single 
nodules, in the greatest transverse diameter. 
With the exception of splenic and hepatic nodules, involvement of other organs is 
usually assessable and no measurable disease should be present. 
Bone marrow assessment is irrelevant for determination of a PR if the sample was 
positive before treatment. However, if positive, the cell type should be specified 
(e.g., large-cell lymphoma or small neoplastic B cells). Patients who achieve a CR 
by the above criteria, but who have persistent morphologic bone marrow 
involvement, will be considered partial responders. When the bone marrow was 
involved before therapy and a clinical CR was achieved, but with no bone marrow 
assessment after treatment, patients should be considered partial responders. 
No new sites of disease should be observed. 
For patients with no pre-treatment PET scan, or if the PET scan was positive before 
therapy, the post-treatment PET should be positive in at least one previously 
involved site. 
14.1.3 Stable Disease (SD) 
Stable disease is defined as patient fails to attain the criteria needed for a CR or 
PR, but does not fulfill those for progressive disease (see below). The PET should 
be positive at prior sites of disease, with no new areas of involvement on the post-
treatment CT or PET. 
14.1.4 Progression (PD) or Relapse: 
Lymph nodes should be considered abnormal if the long axis is > 1.5 cm, 
regardless of the short axis. If a lymph node has a long axis of 1.1 to 1.5 cm, it 
should only be considered abnormal if its short axis is > 1.0. Lymph nodes ≤ 1.0 
cm by ≤ 1.0 cm will not be considered as abnormal for relapse or progressive 
disease. 
Appearance of any new lesion > 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. 
At least a 50% increase from nadir in the SPD of any previously involved nodes, 
or in a single involved node, or the size of other lesions (e.g., splenic or hepatic 
nodules). To be considered progressive disease, a lymph node with a diameter of 
the short axis of < 1.0 cm must increase by ≥ 50% and to a size of 1.5 x 1.5 cm, or 
> 1.5 cm in the long axis. 
At least a 50% increase in the longest diameter of any single previously identified 
node > 1.0 cm in its short axis. 
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Lesions should be PET-positive if a typical FDG-avid lymphoma or the lesion was 
PET-positive prior to therapy unless the lesion is too small to be detected with 
current PET systems (< 1.5 cm in its long axis by CT). 
14.2 
Guidelines for Evaluation of Measurable Disease 
Clinical Lesions will only be considered measurable when they are superficial (e.g., skin 
nodules, palpable lymph nodes). 
Chest X-ray: Lesions on chest X-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung. However, CT is preferable. 
Conventional CT and MRI should be performed with cuts of 10 mm or less in slice 
thickness contiguously. Spiral CT should be performed using a 5 mm contiguous 
reconstruction algorithm. This applies to the chest, abdomen, and pelvis. Head & neck and 
extremities usually require specific protocols. 
Ultrasound (US) should not be used to measure tumor lesions that are clinically not easily 
accessible when the primary endpoint of the study is objective response evaluation. It is a 
possible alternative to clinical measurements of superficial palpable nodes, subcutaneous 
lesions, and thyroid nodules. US might also be useful to confirm the complete 
disappearance of superficial lesions usually assessed by clinical examination. 
15.0 
REMOVAL OF PATIENTS FROM PROTOCOL THERAPY 
15.1 
Duration of Treatment 
Remove patients from protocol therapy who have disease progression after cycles 2, 4, or 
6 of induction therapy. During maintenance therapy, patients may remain on study therapy 
for the planned duration of protocol treatment provided there is no evidence of disease 
progression or unacceptable toxicity. Remove from all protocol therapy any patient with 
rapid or documented disease progression. 
15.2 
Extraordinary Medical Circumstances 
If, at any time the constraints of this protocol are detrimental to the patient's health and/or 
the patient no longer wishes to continue protocol therapy, protocol therapy shall be 
discontinued. In this event: 
• 
Notify the Study Chair. 
• 
Document the reason(s) for discontinuation of therapy in patient records and CALGB 
form C-300 (Off Treatment Form). 
• 
Follow the patient for relapse, progression, survival, and secondary malignancy or 
new primaries. 
16.0 
STATISTICAL CONSIDERATIONS 
16.1 
Randomization 
One hundred thirty (65 per arm) newly diagnosed high-risk follicular lymphoma patients 
will be randomized between  
Arm A: 6 cycles of ofatumumab-bendamustine  
Arm B: 6 cycles of ofatumumab, bortezomib, and bendamustine  
16.2 
Primary Endpoint 
The primary endpoint of this trial is to determine the CR rate in newly diagnosed high-risk 
follicular lymphoma patients. Arm A (control) has not been rigorously investigated in this 
high-risk patient population, so that we employ a randomized phase II trial design. In the 
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up-front setting, the CR rate with R-bendamustine in a subset of patients with high-risk 
untreated follicular NHL (FLIPI > 2) was estimated as 41% [6]. Therefore, based on 
available CR and ORR data with rituximab-bendamustine in front-line therapy for patients 
with intermediate to high-risk FLIPI scores, we anticipate a CR rate following induction 
therapy of about 40% for patients in Arm A. Improvement in CR rate to 60% with 
combined ofatumumab, bortezomib, and bendamustine (Arm B) would be of interest for 
further study of this therapy in follicular lymphoma.  
Let PA and PB denote the CR rates of Arms A and B, respectively. Following a two-stage 
design with one-sided alpha=15% for H0: PA=PB vs. H1: PA<PB requires N=122 eligible 
patients (61 patients per arm) for 84% power under H1: PA=40%, PB=60%. This design 
is based on the two-stage Fisher’s exact test [45].  
Stage 1: Thirty patients will be randomized to each arm. Let X1 and Y1 denote the number 
of complete responders from Arms A and B, respectively. If Y1-X1 is larger than or equal 
to 0, then the study will proceed to the second stage. Otherwise, the study will be stopped. 
Stage 2: An additional 31 patients will be randomized to each arm. Let X and Y denote the 
number of complete responders among the cumulative 61 patients of Arms A and B, 
respectively. If Y-X is larger than or equal to the critical value a, then Arm B will be 
accepted for further investigation. The critical value a for Y-X after the 2nd stage will be 
determined based on the total number of complete responders (CR) from the two arms for 
15% of one-sided alpha reflecting the two-stage testing. Note that the Fisher’s exact test is 
valid (i.e. accurately control the type I error) even when PA is different from 40% since it 
tests on the odds ratio between PA and PB. The specification of PA and PB is required 
only to calculate the sample sizes.  
16.3 
Adverse Event Monitoring 
Monthly conference calls to monitor toxicity will be held until the first 40 patients (20 per 
arm) have completed the induction therapy. As far as the monthly conference calls 
continue, we will monitor all toxicity data available from the patients.  
We will closely monitor grade 3-4 infusion reactions and peripheral neuropathy in addition 
to all other types of toxicities. Four statistical interim looks will be when the first 5, 10, 15 
and 20 patients complete the protocol therapy for each arm. 
Infusion Reactions: Expected rate of grade 3-4 reactions is only about 20-30% as a single 
agent but may be a bit higher in previously untreated patients. As a result, a rate of 50% of 
grade 3-4 reactions will be considered acceptable while 75% or above will be considered 
unacceptable for each arm. Grade 3-4 reactions will be evaluated independently for each 
arm. We will consider stopping the study for amendment if 5 of the first 5, 8 or more of 
the first 10, 12 or more of the first 15, or 14 or more of the first 20, patients experience 
grade 3-4 reactions for either arm. This monitoring rule has 10%, 48%, 66% and 82% 
probability to stop the trial if an arm has 50%, 65%, 70% and 75% grade 3-4 reaction rate, 
respectively.  
Peripheral Neuropathy: Grade 3-4 peripheral neuropathy will be monitored for each arm.  
Arm A: The expected rate of grade 3-4 peripheral neuropathy in the control arm is about 
5%. We will consider stopping the study for amendment if 2 or more of the first 5, 3 or 
more of the first 10, 3 or more of the first 15, or 3 or more of the first 20 patients experience 
grade 3-4 peripheral neuropathy for arm A. This monitoring rule has 8.5%, 34%, 61% and 
80% probability to stop the trial if arm A has 5%, 10%, 15% and 20% grade 3-4 peripheral 
neuropathy rate, respectively. 
Arm B: The expected rate of grade 3-4 peripheral neuropathy in arm B is about 20%. We 
will consider stopping the study for amendment if 3 or more of the first 5, 5 or more of the 
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first 10, 7 or more of the first 15, or 8 or more of the first 20 patients experience grade 3-4 
peripheral neuropathy for arm B. This monitoring rule has 10%, 33%, 66% and 90% 
probability to stop the trial if arm A has 20%, 30%, 40% and 50% grade 3-4 peripheral 
neuropathy rate, respectively. 
16.4 
Secondary Endpoints 
PFS: Kaplan-Meier curves of PFS and OS will be generated for the two arms. The p-values 
of the log-rank test will be calculated to compare PFS and OS between the two arms. 
Toxicity: The toxicity profile of the two arms will be summarized using frequency tables. 
The chi-squared test will be conducted to compare the toxicity rate of grade 3 or higher 
between the two arms.  
Pre-treatment single nucleotide polymorphisms (SNP): The PFS will be compared among 
the three genotype groups of each SNP using the log-rank tests. A max-type test will be 
used by taking the maximum value of the log-rank tests under dominant, recessive, and 
proportional hazard model. The critical value (or p-value) of the max test will be obtained 
by a permutation method. No multiple testing adjustment may be applied because of the 
small sample size. 
Immunohistochemical (IHC) Markers: The IHC markers will be correlated with response 
(using the two-sample t-test) and PFS (using the Cox regression method) data. No multiple 
testing adjustment will be applied because of the small sample size.  
Predictive value of FDG-PET: In analysis, the ratio between the SUVmax after cycle 2 and 
the SUVmax at baseline will be used as the observation for each patient. (A ratio smaller 
than 1 means decrease in post-therapy SUVmax from the baseline). The ratio will be 
correlated with response (using the two-sample t-test) and PFS (using the Cox regression 
method) data. In addition, FDG-PET ratios between baseline and after 2 cycles will be 
evaluated in combination with changes obtained from dedicated CT or MRI studies to 
determine if a combinatorial approach using both metabolic and morphologic changes 
would result in a higher predictive value for response and PFS. We will regress response 
on FDG-PET (or CT or MRI), treatment arm and their interaction using the logistic 
regression method. We will conduct an analysis on the pooled data if the treatment effect 
and the interaction between treatment are not significant. The association of the imaging 
data with PFS will be similarly analyzed using Cox regression method.  
We will compare the predictive values between FDG-PET and FDG-PET plus CT or MRI. 
For some patients the MRI may be positive but CT or MRI may be negative, and vice versa. 
These patients will contribute only one data point to the analysis. However those patients 
with positivity (negativity) for both FDG-PET and MRI/CT will contribute paired data 
points to the analysis of positive (negative) predictive value. In order to handle the partially 
correlated binary data, we will use a GEE-type approach in the statistical testing. 
Qualitative analyses using various reading schemes will also be performed to determine 
changes in FDG-PET positivity or negativity. Similar analyses will be conducted using 
FDG-PET data after cycle 6 and at the end of therapy. A transformation (such as logarithm) 
of the FDG-PET outcomes may be considered to improve the normality of error terms 
and/or linearity of the time trajectory. 
In another set of data analysis, the change rate (slope) of the time trajectory of FDG-PET 
findings will be calculated for each patient and correlated with response (using two-sample 
t-test) and PFS (using Cox regression method). Similar analyses will be conducted with 
PET findings combined with CT or MRI. 
Dave et al. discovered gene signature associated with overall survival from 191 patients. 
The gene signature will be validated with respect to CR rate, progression-free survival 
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(PFS) and overall survival (OS). In order to test for the association of the gene expression 
signatures with response to treatment, we will median-center and divide our patients into 
high and low expressors of the gene expression signature. We will test the association 
between the gene signature and the response in this study by chi-squared test for a 2x2 
table. Based on our experience from 150711 (59 of 60 patients participated), we expect that 
most of n=122 eligible patients will participate in this correlative study. If the CR rate for 
the high- and low-risk groups are 35% and 65%, respectively, then we are going to have 
91% power to validate the association with a two-sided alpha=5%. The log-rank test will 
be used to compare the PFS between high and low-risk groups as defined by the gene 
signature. The association with OS will be validated similarly. This validation will also be 
conducted within each arm. 
16.5 
Accrual and Follow-up 
Accounting for possible dropouts and ineligible patients, we will accrue a total of 130 
patients to this study. Ineligible patients will be excluded in the final analysis. With an 
expected accrual of 3 patients per month, it will take about 44 months to complete the 
accrual. For analyzing PFS OS, each patient will be followed until disease progression or 
death, or for a maximum of 10 years from study entry.  
16.6 
Safety Considerations 
Toxicity will be assessed according to NCI criteria for adverse events, version 4.0. As there 
are no phase I data available regarding the combination of ofatumumab with bendamustine 
or bortezomib, monthly conference calls will be conducted among participating 
investigators, the study chair, and the study statistician to monitor adverse events in the 
first 40 patients enrolled (20 enrolled on Arm A and Arm B).  
16.7 
CDUS Reposting 
The Alliance Statistical Center at Duke University will submit quarterly reports to CTEP 
by electronic means using the Clinical Data Update System (CDUS). 
17.0 
ADVERSE EVENT REPORTING (AER) 
Investigators are required by Federal Regulations to report serious adverse events as defined below. 
Investigators are required to notify the Investigational Drug Branch, the Alliance Central Protocol 
Operations Program Office, the Study Chair, and their Institutional Review Board (IRB) if a patient 
has an adverse event requiring expedited reporting. All such events must be reported in an expedited 
manner using the CTEP Adverse Event Expedited Reporting System (CTEP-AERS). 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 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).  
The Alliance requires investigators to route all expedited adverse event reports (AERs) through the 
Central Protocol Operations Program Office for CALGB or Alliance-coordinated studies. 
Note: Please be sure to read this entire protocol section, as requirements are described in both the 
table below and the bullet points following the table. Note that the table and the additional 
instructions or exclusions are protocol-specific, and in the case of a conflict, the additional 
instructions or exclusions supersede the table.  
17.1 
CALGB 50904 Reporting Requirements 
Late Phase 2 and Phase 3 Studies: Expedited Reporting Requirements for Adverse Events 
that Occur on Studies under an IND within 30 Days of the Last Day of Treatment  
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FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or not 
they are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
 An adverse event is considered serious if it results in ANY of the following outcomes:   
1) 
Death 
2) 
A life-threatening adverse event  
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 
hours  
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
5) 
A congenital anomaly/birth defect.  
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization 
may be considered serious when, based upon medical judgment, they may jeopardize the patient or 
subject and may require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported via CTEP-AERS within 
the timeframes detailed in the table below. 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 Timeframes 
Grade 3 Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 
Calendar Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
10 Calendar Days 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-AERS within 
24 hours of learning of the AE, followed by a complete expedited report within 5 calendar 
days of the initial 24-hour report. 
o “10 Calendar Days” - A complete expedited report on the AE must be submitted within 10 
calendar days of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last day of treatment require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• All Grade 4, and Grade 5 AEs that are at least possibly related to treatment 
Expedited 10 calendar day reports for: 
• Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization and that are at 
least possibly related to treatment 
• Grade 3 adverse events that are at least possibly related to treatment 
Effective Date:  May 5, 2011 
17.2 
Additional Instructions or Exclusions to CTEP-AERS Expedited Reporting 
Requirements for Phase 2 and 3 Trials Utilizing an Agent Under a CTEP IND or non-
CTEP IND: 
• 
CALGB 50904 uses a drug under a CTEP IND. The reporting requirements for 
investigational agents under a CTEP IND should be followed for all agents (any arm) 
in this trial. 
• 
Treatment expected adverse events include those listed in Section 9.0 and in the 
package inserts for ofatumumab, bendamustine and in the CAEPR (see below) for 
bortezomib. Note: the ASAEL column of the bortezomib CAEPR has been replaced 
with the specific protocol exceptions to expedited reporting (SPEER) list. This list now 
includes "expected" severity grades in addition to event terms. 
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• 
Grade 3/4 hematosuppression and hospitalization resulting from such do not require 
CTEP-AERS, but must be reported as part of study results.  
• 
Febrile neutropenia and hospitalization resulting from such do not require CTEP-
AERS, but must be reported as part of study results. 
• 
Grade 3 nausea or grade 3/4 vomiting and hospitalization resulting from such do not 
require CTEP-AERS, but must be reported as part of study results. 
• 
Grade 3/4 peripheral neuropathy and hospitalization resulting from such do not require 
CTEP-AERS, but must be reported as part of study results. 
• 
Grade 3/4 infusion reactions or hypersensitivity reactions and hospitalization from 
such do not require CTEP-AERS, but must be reported as part of study results. 
• 
Grade 3 fatigue and hospitalization resulting from such do not require CTEP-AERS, 
but must be reported as part of study results. 
• 
All adverse events reported via CTEP-AERS (i.e., serious adverse events) should also 
be forwarded to your local IRB, according to local IRB policy 
• 
Deaths clearly due to progressive disease do not require CTEP-AERS, but must be 
reported as part of study results via routine reporting 
17.3 
CAEPR for Bortezomib (Velcade, NSC 681239) 
The Comprehensive Adverse Events 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. In addition to the comprehensive list, a 
subset, the Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a 
separate column and is identified with bold and italicized text. This subset of AEs (SPEER) 
contains events that are considered 'expected' for expedited reporting purposes only. Refer 
to 
the 
'CTEP, 
NCI 
Guidelines: 
Adverse 
Event 
Reporting 
Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pd
f for further clarification. Frequency is provided based on 2084 patients. Below is the 
CAEPR for bortezomib (Velcade). 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses 
next to the AE in the SPEER. If this CAEPR is part of a combination protocol using 
multiple investigational agents and has an AE listed on different SPEERs, use the lower of 
the grades to determine if expedited reporting is required. 
Version 2.6, May 25, 20171 
 
 Adverse Events with Possible  
 Relationship to Bortezomib (Velcade) 
 (CTCAE 4.0 Term) 
[n= 2084] 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
Anemia 
 
 
 Anemia (Gr 3) 
CARDIAC DISORDERS 
  
 
 
Heart failure 
  
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
 Abdominal pain (Gr 3) 
Constipation 
 
 
 Constipation (Gr 3) 
Diarrhea 
 
 
 Diarrhea (Gr 3) 
 
Dyspepsia 
 
 Dyspepsia (Gr 2) 
 
Gastrointestinal hemorrhage2  
  
 
 
Gastrointestinal perforation3 
  
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CALGB 50904 
 
 Adverse Events with Possible  
 Relationship to Bortezomib (Velcade) 
 (CTCAE 4.0 Term) 
[n= 2084] 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
Ileus 
 
 Ileus (Gr 3) 
Nausea 
 
 
 Nausea (Gr 3) 
Vomiting 
 
 
 Vomiting (Gr 3) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
Chills 
 
 Chills (Gr 2) 
 
Edema limbs 
 
 Edema limbs (Gr 3) 
Fatigue 
 
 
 Fatigue (Gr 3) 
Fever 
 
 
 Fever (Gr 3) 
HEPATOBILIARY DISORDERS 
  
 
 
Hepatic failure4 
  
 
 
Hepatobiliary disorders - Other 
(hepatitis)4 
  
INFECTIONS AND INFESTATIONS 
  
Infection5 
 
 
 Infection5 (Gr 4) 
INVESTIGATIONS 
  
 
 
Alanine aminotransferase 
increased4 
  
 
 
Alkaline phosphatase 
increased4 
  
 
 
Aspartate aminotransferase 
increased4 
  
 
 
Blood bilirubin increased4 
  
 
 
GGT increased4 
  
 
 
INR increased4 
  
 
 
Investigations - Other 
(albumin)4 
  
 
Neutrophil count decreased 
 
 Neutrophil count decreased 
(Gr 4) 
Platelet count decreased 
 
 
 Platelet count decreased  
(Gr 4) 
 
Weight loss 
 
  
METABOLISM AND NUTRITION DISORDERS 
  
Anorexia 
 
 
 Anorexia (Gr 3) 
 
Dehydration 
 
  
 
 
Tumor lysis syndrome 
  
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia 
 
 Arthralgia (Gr 3) 
 
Back pain 
 
 Back pain (Gr 3) 
 
Bone pain 
 
 Bone pain (Gr 2) 
 
Musculoskeletal and 
connective tissue disorder - 
Other (muscle spasms) 
 
  
 
Myalgia 
 
 Myalgia (Gr 3) 
 
Pain in extremity 
 
 Pain in extremity (Gr 3) 
NERVOUS SYSTEM DISORDERS 
  
 
Dizziness 
 
 Dizziness (Gr 3) 
 
Headache 
 
 Headache (Gr 3) 
 
 
Leukoencephalopathy 
  
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 Adverse Events with Possible  
 Relationship to Bortezomib (Velcade) 
 (CTCAE 4.0 Term) 
[n= 2084] 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
Neuralgia 
 
 Neuralgia (Gr 3) 
 
Paresthesia 
 
  
Peripheral motor neuropathy 
 
 
 Peripheral motor neuropathy 
(Gr 3) 
Peripheral sensory neuropathy  
 
 Peripheral sensory 
neuropathy (Gr 3) 
 
 
Reversible posterior 
leukoencephalopathy syndrome 
  
PSYCHIATRIC DISORDERS 
  
 
Anxiety 
 
  
 
Insomnia 
 
 Insomnia (Gr 2) 
RENAL AND URINARY DISORDERS 
  
 
 
Acute kidney injury 
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
 
Adult respiratory distress 
syndrome 
  
 
Cough 
 
 Cough (Gr 2) 
 
Dyspnea 
 
 Dyspnea (Gr 3) 
 
Pharyngeal mucositis 
 
 Pharyngeal mucositis (Gr 2) 
 
 
Pulmonary hypertension 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Rash maculo-papular 
 
 Rash maculo-papular (Gr 3) 
VASCULAR DISORDERS 
  
 
Hypotension 
 
 Hypotension (Gr 4) 
 
1This table will be updated as the toxicity profile of the agent is revised. Updates will be distributed to all Principal 
Investigators at the time of revision.  The current version can be obtained by contacting PIO@CTEP.NCI.NIH.GOV.  
Your name, the name of the investigator, the protocol and the agent should be included in the e-mail. 
 
2Gastrointestinal 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. 
 
3Gastrointestinal 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. 
 
4Cases of acute liver failure have been reported in patients receiving multiple concomitant medications and with 
serious underlying medical conditions. Other reported hepatic reactions include hepatitis, increases in liver enzymes, 
and hyperbilirubinemia. 
 
5Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC. 
 
Adverse events reported on bortezomib (Velcade) trials, but for which there is insufficient evidence to suggest 
that there was a reasonable possibility that bortezomib (Velcade) caused the adverse event: 
 
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BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system disorders - Other (hematocrit 
low); Blood and lymphatic system disorders - Other (lymphadenopathy); 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 - 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; 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; 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) 
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 
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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: 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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18.0 
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APPENDIX I COLLABORATIVE AGREEMENT PROVISIONS 
 
The agent supplied by CTEP, DCTD, NCI used in this protocol (bortezomib) is provided to the 
NCI under a Collaborative Agreement (CRADA, CTA, CSA) between Millennium 
Pharmaceuticals, Inc. (hereinafter referred to as Collaborator) and the NCI Division of Cancer 
Treatment and Diagnosis. Therefore, the following obligations/guidelines, in addition to the 
provisions 
in 
the 
“Intellectual 
Property 
Option 
to 
Collaborator” 
(http://ctep.cancer.gov/industry/ipo.html) contained within the terms of the award, apply to the use 
of the Agents in this study: 
1. 
Agent may not be used for any purpose outside the scope of this protocol, nor can Agent be 
transferred or licensed to any party not participating in the clinical study. Collaborator’s data 
for Agent are confidential and proprietary to Collaborator and Provider and should be 
maintained as such by the investigators. The protocol documents for studies utilizing 
investigational Agents contain confidential information and should not be shared or 
distributed without the permission of the NCI. If a copy of this protocol is requested by a 
patient or a patient’s family member participating on the study, the individual should sign a 
confidentiality agreement. A suitable model agreement can be downloaded from 
http://ctep.cancer.gov. 
2. 
For a clinical protocol where there is an investigational Agent used in combination with 
(an)other investigational Agent(s), each the subject of different agreements, the access to and 
use of data by Collaborator shall be as follows: (data pertaining to such combination use shall 
hereinafter be referred to as “Multi-Party Data.”) 
a. NCI will provide Collaborator with prior written notice regarding the existence and nature 
of any agreements governing their collaboration with NIH, the design of the proposed 
combination protocol, and the existence of any obligations that would tend to restrict the 
NCI’s participation in the proposed combination protocol.  
b. Each Collaborator shall agree to permit the use of the Multi-Party Data from the clinical 
trial by any other Collaborator solely to the extent necessary to allow said other Collaborator 
to develop, obtain regulatory approval, or commercialize its own investigational Agent. 
c. Any Collaborator having the right to use the Multi-Party Data from these trials must agree 
in writing prior to the commencement of the trials that it will use the Multi-Party Data solely 
for the development, regulatory approval, and commercialization of its own investigational 
agent. 
3. Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement 
will be made available to Collaborator, the NCI, and the FDA, as appropriate and unless 
additional disclosure is required by law or court order as described in the IP Option to 
Collaborator 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm). 
Additionally, all Clinical Data and Results and Raw Data will be collected, used, and disclosed 
consistent with all applicable federal statutes and regulations for the protection of human 
subjects, including, if applicable, the Standards for Privacy of Individually Identifiable Health 
Information set forth in 45 C.F.R. Part 164. 
4. When a Collaborator wishes to initiate a data request, the request should first be sent to the 
NCI, who will then notify the appropriate investigators (Group Chair for Cooperative Group 
studies, or PI for other studies) of Collaborator’s wish to contact them.  
5. Any data provided to Collaborator for phase III studies must be in accordance with the 
guidelines and policies of the responsible Data Monitoring Committee (DMC), if there is a 
DMC for this clinical trial. 
6. Any manuscripts reporting the results of this clinical trial should be provided to CTEP by 
the Group Office for Cooperative Group Studies or by the investigator for non-Cooperative 
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Group Studies for immediate delivery to Collaborator for advisory review and comment prior 
to submission for publication. Collaborator will have 30 days from the date of receipt for 
review. Collaborator shall have the right to request that publication be delayed for up to an 
additional 30 days in order to ensure that Collaborator’s intellectual property rights, are 
protected. Copies of abstracts should be provided CTEP for forwarding to Collaborator for 
courtesy review as soon as possible and preferably at least three (3) days prior to submission, 
but in any case, prior to presentation at the meeting or publication in the proceedings. Press 
releases and other media presentations must also be forwarded to CTEP prior to release. 
Copies of any manuscript, abstract and/or press release should be sent to: 
Regulatory Affairs Branch, CTEP, DCTD, NCI 
Executive Plaza North, Suite 7111 
Bethesda, Maryland 20892 
Fax: 301-402-1584 
Email: anshers@mail.nih.gov 
The Regulatory Affairs Branch will then distribute them to Collaborator. No publication, 
manuscript or other form of public disclosure shall contain any of Collaborator’s 
confidential/proprietary information. 
 
 
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CALGB 50904 
APPENDIX II 
CALGB 50904 PET/CT INSTRUMENT  
Technical Specifications Form 
(From ACRIN Credentialing Application, 2005) 
 
Page 1 of 5 
 
 
Institution:  
 
 
 
 
 
Date: 
 
Institution Address: 
 
 
Institution Contact Name and Telephone Number: 
 
E-mail: 
 
 
 
 
 
 
Fax: 
 
 
 
PET Center Name:  
 
 
 
 
Date: 
 
PET Center Address: 
 
 
PET Center Contact Name and Telephone Number: 
 
E-mail: 
 
 
 
 
 
 
Fax: 
 
 
 
Type of Scanner: 
(e.g., GE Discovery ST, Siemens Biograph, Philips Gemini, GE Advance, Siemens/CTI ECAT, etc.) 
 
Transmission Source: 
(e.g., 68GE-rods, 137Cs-point, CT) 
 
Method of Attenuation Correction: 
(e.g., segmentation, subtraction of emission contribution to transmission scan, CTAC) 
 
 
Routine QC Testing Performed 
 
Daily: 
 
Monthly: 
 
Quarterly: 
 
Yearly: 
Other: 
 
 
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CALGB 50904 
CALGB 50904 PET/CT INSTRUMENT TECHNICAL SPECIFICATIONS FORM 
(From ACRIN Credentialing Application, 2005) 
 
Page 2 of 5 
 
 
UNIFORM PHANTOM SCAN INFORMATION 
 
Phantom Length: 
 
 
 
Phantom Diameter: 
 
Phantom Volume: 
 
Radionuclide: 
 
Scan Date: 
 
 
Scan Time: 
 
 
 
Scan Duration: 
 
For Water-Fillable Phantoms, Provide the Following Data: 
 
Assayed Activity in Syringe before injection: 
mCi 
 
Time: 
 
Assayed Activity in Syringe after injection: 
mCi 
 
Time: 
 
 
 
For Ge-68/Ga-68 Calibration Phantoms, Provide the Following Data: 
Calibration Date: 
 
 
 
Time: 
 
Calibration Activity: 
mCi  
Time: 
 
 
 
 
 
 
 
 
 
 
 
 
Std Dev of SUV 
Number of Pixels in 
Slice # 
Average SUV in ROI1 
 
  (if available) 
ROI: 
 
 
1 
 
 
________ 
 
     ________ 
 
 
2 
 
 
________ 
 
     ________ 
 
 
3 
 
 
________ 
 
     ________ 
 
 
4 
 
 
________ 
 
     ________ 
 
 
5 
 
 
________ 
 
     ________ 
 
 
6 
 
 
________ 
 
     ________ 
 
 
7 
 
 
________ 
 
     ________ 
 
 
8 
 
 
________ 
 
     ________ 
Report info for EVERY 
9 
 
 
________ 
 
     ________ 
slice of the phantom 
10 
 
 
________ 
 
     ________ 
 
 
11 
 
 
________ 
 
     ________ 
 
 
12 
 
 
________ 
 
     ________ 
 
 
13 
 
 
________ 
 
     ________ 
 
 
14 
 
 
________ 
 
     ________ 
 
 
15 
 
 
________ 
 
     ________ 
 
 
16 
 
 
________ 
 
     ________ 
 
 
17 
 
 
________ 
 
     ________ 
 
 
18 
 
 
________ 
 
     ________ 
 
 
19 
 
 
________ 
 
     ________ 
 
 
20 
 
 
________ 
 
     ________ 
1 A circular or elliptical region of interest (ROI) covering most of the interior of the phantom. 
 
 
 
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CALGB 50904 PET/CT INSTRUMENT TECHNICAL SPECIFICATIONS FORM 
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Page 3 of 5 
 
 
 
FOR IMAGING CORE LABORTORY USE ONLY: 
 
Phantom Images Review: 
 
Date: 
Comments: 
 
 
 
 
 
 
        Approved 
 
        Disapproved 
 
 
_________________________________________        ___________________ 
 Signature                                                            Date 
 
 
 
 
 
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CALGB 50904 PET/CT INSTRUMENT TECHNICAL SPECIFICATIONS FORM 
(From ACRIN Credentialing Application, 2005) 
Page 4 of 5 
 
 
WHOLE BODY FDG-PET TEST PATIENT #1: 
 
 
File Name: 
 
 
 
Patient Height: 
Patient Weight: 
 
FDG Dose (mCi): 
 
 
Dose Assay Time: 
 
Blood glucose prior to FDG administration (mg/dL): 
 
Injection Time: 
 
 
Start Time of Emission Scan: 
 
ACQUISITION No. of Bed Positions: 
 
 
EMISSION TIME (MIN/BED): 
 
TRANSMISSION TIME (MIN/BED): 
 
 
RECONSTRUCTION ALGORITHM: 
(e.g., 2D FBP, 2D OSEM, 3D FORE/OSEM, 3D RAMLA) 
PIXEL SIZE (mm) 
X-Y: 
 
Z: 
 
 
Scatter Correction Applied: 
 
  Yes 
 
No 
 
(Include algorithm type, e.g., model-based, tail-fit, Bergstrom): 
 
Randoms Correction Applied:   Online 
Smoothed Randoms (offline)   None 
 
 
FOR IMAGING CORE LABORTORY USE ONLY: 
 
Test Patient #1 Review: 
Date: 
Comments: 
 
 
        Approved 
 
        Disapproved 
 
_________________________________________        ___________________ 
 Signature                                                            Date 
 
 
 
 
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CALGB 50904 PET/CT INSTRUMENT TECHNICAL SPECIFICATIONS FORM 
(From ACRIN Credentialing Application, 2005) 
Page 5 of 5 
 
 
WHOLE BODY FDG-PET TEST PATIENT #2: 
 
 
File Name: 
 
 
 
Patient Height: 
Patient Weight: 
 
FDG Dose (mCi): 
 
 
Dose Assay Time: 
 
Blood glucose prior to FDG administration (mg/dL): 
 
Injection Time: 
 
 
Start Time of Emission Scan: 
 
ACQUISITION No. of Bed Positions: 
 
EMISSION TIME (MIN/BED): 
 
TRANSMISSION TIME (MIN/BED): 
 
RECONSTRUCTION ALGORITHM: 
(e.g., 2D FBP, 2D OSEM, 3D FORE/OSEM, 3D RAMLA) 
PIXEL SIZE (mm) 
X-Y: 
 
Z: 
 
 
Scatter Correction Applied: 
 
  Yes 
 
No 
 
(Include algorithm type, e.g., model-based, tail-fit, Bergstrom): 
 
Randoms Correction Applied:   Online 
Smoothed Randoms (offline)   None 
 
 
 
FOR IMAGING CORE LABORTORY USE ONLY: 
 
Test Patient #2 Review: 
 
Date: 
Comments: 
 
 
        Approved 
 
        Disapproved 
 
_________________________________________        ___________________ 
 Signature                                                            Date 
 
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CALGB 50904 
APPENDIX III CALGB 50904 IMAGING SITE PERSONNEL FORM 
 
 
Responsible CRA Contact 
Complete Address 
E-mail 
Phone Number 
Fax Number 
Radiology Department Contact 
Complete Address 
E-mail 
Phone Number 
Fax Number 
 
 
 
 
Please provide the information requested above. Provide the middle initial 
for individuals who commonly use them. Also, please add or correct the 
degree/title as necessary. This information will be retained by the Imaging 
Core Laboratory. 
 
Once completed, you may send this form to: 
 
  
Alliance Imaging Core Laboratory 
  
Attn: CALGB 50604 
  
Wright Center of Innovation 
  
The Ohio State University 
  
395 West 12th Avenue, Room 414 
  
Columbus, OH 43210 
  
Fax: 614-293-9275 
 
Call the Imaging Core Laboratory at 614-293-2929 or 614-366-0807 with 
any questions. Thank you for your assistance. 
 
 
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