Ofatumumab With or Without Bendamustine for Patients With Mantle Cell Lymphoma Ineligible for Autologous Stem Cell Transplant
Phase: PHASE2
Conditions: Mantle Cell Lymphoma
Sponsor: Memorial Sloan Kettering Cancer Center

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Page 1 of 59 
 
 
Ofatumumab with or without Bendamustine for Patients with Mantle Cell 
Lymphoma Ineligible for Autologous Stem Cell Transplant 
MSKCC THERAPEUTIC/DIAGNOSTIC PROTOCOL 
Principal Investigator/Department: 
Paul Hamlin, MD 
Medicine /Manhattan, Basking 
Ridge 
Co-Principal 
Investigator(s)/Department: 
Andrew Zelenetz, MD, PhD 
Medicine /Manhattan, West 
Harrison 
Investigator(s)/Department: 
Craig Moskowitz, MD 
Steven Horwitz, MD 
Ariela Noy, MD 
Lia Palomba, MD 
Carol Portlock, MD 
Alison Moskowitz, MD 
Matthew Matasar, MD 
David Straus, MD 
John Gerecitano, MD, PhD 
Craig Sauter, MD 
Anas Younes, MD 
Teresa Scardino 
Michelle Wisniewski 
Anita Kumar, MD 
Elina Tsyvkin, MD 
Connie Batlevi, MD, PhD 
Jillian Solomon 
Sharyn Kurtz 
Nadia Kralovic 
Jason Carter 
Christopher Y. Park, MD, PhD 
James Caravelli, MD 
Zhigang Zhang, PhD 
Ai Ni, PhD 
Ephraim Casper, MD 
Han Xiao, MD 
Audrey Hamilton, MD 
Mila Gorsky, MD 
Sree Chalasani, MD 
Asma Latif, MD 
Afsheen Iqbal. MD 
Regina Byrne 
Avni Desai, MD 
Julie Fasano, MD 
John Fiore, MD 
Steven Sugarman, MD 
Stuart Lichtman, MD 
Marisa Siebel, MD 
Kenneth Ng, MD 
Arlyn Apollo, MD 
Zoe Goldberg, MD 
Tiffany Troso-Sandoval, MD 
Pamela Drullinsky, MD 
Philip Caron, MD 
Medicine/ Manhattan 
Medicine/ Manhattan 
Medicine/ Manhattan 
Medicine/ Manhattan 
Medicine/ Manhattan 
Medicine/ Manhattan 
Medicine/Manhattan,Commack 
Medicine/ Manhattan 
Medicine/ Manhattan 
Medicine/ Manhattan 
Medicine/ Manhattan 
Medicine/ Manhattan 
Medicine/ Manhattan 
Medicine/ Manhattan 
Medicine/ Manhattan 
Medicine/ Manhattan 
Medicine/ Manhattan 
Medicine/ Manhattan 
Medicine/ Manhattan 
Medicine/ Manhattan 
Pathology 
Radiology 
Biostatistics 
Biostatistics 
Medicine/Basking Ridge 
Medicine/Basking Ridge 
Medicine/Basking Ridge 
Medicine/Basking Ridge 
Medicine/Basking Ridge 
Medicine/Basking Ridge 
Medicine/Basking Ridge 
Medicine/Basking Ridge 
Medicine/Commack 
Medicine/Commack 
Medicine/Commack 
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Medicine/Rockville Centre 
Medicine/Rockville Centre 
Medicine/Rockville Centre 
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Medicine/Rockville Centre 
Medicine/Sleepy Hollow 

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Stephanie Smith-Marrone, MD 
Carolyn Wasserheit-Lieblich,MD 
Nancy Mills, MD 
Michelle Boyar, MD 
Michael Fanucchi, MD 
Medicine/Sleepy Hollow 
Medicine/Sleepy Hollow 
Medicine/Sleepy Hollow 
Medicine/Sleepy Hollow 
Medicine/Sleepy Hollow 
Consenting 
Professional(s)/Department: 
Paul Hamlin, MD 
Andrew Zelenetz, MD, PhD 
Craig Moskowitz, MD 
Steven Horwitz, MD 
Ariela Noy, MD 
Lia Palomba, MD 
Carol Portlock, MD 
Alison Moskowitz, MD 
Matthew Matasar, MD 
David Straus, MD 
John Gerecitano, MD, PhD 
Craig Sauter, MD 
Anas Younes, MD 
Anita Kumar, MD 
Elina Tsyvkin, MD 
Ephraim Casper, MD 
Han Xiao, MD 
Audrey Hamilton, MD 
Mila Gorsky, MD 
Sree Chalasani, MD 
Asma Latif, MD 
Afsheen Iqbal. MD 
Avni Desai, MD 
Julie Fasano, MD 
John Fiore, MD 
Steven Sugarman, MD 
Stuart Lichtman, MD 
Marisa Siebel, MD 
Kenneth Ng, MD 
Arlyn Apollo, MD 
Zoe Goldberg, MD 
Tiffany Troso-Sandoval, MD 
Pamela Drullinsky, MD 
Philip Caron, MD 
Stephanie Smith-Marrone, MD 
Carolyn Wasserheit-Lieblich,MD 
Nancy Mills, MD 
Michelle Boyar, MD 
Michael Fanucchi, MD 
Medicine /Manhattan, Basking 
Ridge 
Medicine /Manhattan, West 
Harrison 
Medicine/ Manhattan 
Medicine/ Manhattan 
Medicine/ Manhattan 
Medicine/ Manhattan 
Medicine/ Manhattan 
Medicine/ Manhattan 
Medicine/Manhattan,Commack 
Medicine/ Manhattan 
Medicine/ Manhattan 
Medicine/ Manhattan 
Medicine/ Manhattan 
Medicine/ Manhattan 
Medicine/ Manhattan 
Medicine/Basking Ridge 
Medicine/Basking Ridge 
Medicine/Basking Ridge 
Medicine/Basking Ridge 
Medicine/Basking Ridge 
Medicine/Basking Ridge 
Medicine/Basking Ridge 
Medicine/Commack 
Medicine/Commack 
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Medicine/Commack 
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Medicine/Rockville Centre 
Medicine/Rockville Centre 
Medicine/Rockville Centre 
Medicine/Rockville Centre 
Medicine/Rockville Centre 
Medicine/Sleepy Hollow 
Medicine/Sleepy Hollow 
Medicine/Sleepy Hollow 
Medicine/Sleepy Hollow 
Medicine/Sleepy Hollow 
Medicine/Sleepy Hollow 
Please Note: A Consenting Professional must have completed the mandatory Human 
Subjects Education and Certification Program. 

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Memorial Sloan-Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 

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Table of Contents 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA ............................................................................... 3 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS ........................................................................................ 4 
3.0 
BACKGROUND AND RATIONALE .............................................................................................. 5 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION .................................................................... 12 
4.1 
Design ...................................................................................................................................... 12 
4.2 
Intervention ............................................................................................................................... 14 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS .................................................................................... 15 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY .................................................................................... 21 
6.1 
Subject Inclusion Criteria ......................................................................................................... 21 
6.2 
Subject Exclusion Criteria ........................................................................................................ 22 
7.0 
RECRUITMENT PLAN ................................................................................................................ 22 
8.0 
PRETREATMENT EVALUATION ............................................................................................... 23 
9.0 
TREATMENT/INTERVENTION PLAN ........................................................................................ 26 
10.0 
EVALUATION DURING TREATMENT/INTERVENTION ........................................................... 28 
11.0 
TOXICITIES/SIDE EFFECTS ...................................................................................................... 31 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT .............................. 33 
13.0 
CRITERIA FOR REMOVAL FROM STUDY ................................................................................ 37 
14.0 
BIOSTATISTICS .......................................................................................................................... 37 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES ....... 40 
15.1 
Research Participant Registration ............................................................................................ 40 
15.2 
Randomization ......................................................................................................................... 40 
16.0 
DATA MANAGEMENT ISSUES .................................................................................................. 40 
16.1 
Quality Assurance .................................................................................................................... 41 
16.2 
Data and Safety Monitoring ...................................................................................................... 41 
17.0 
PROTECTION OF HUMAN SUBJECTS ..................................................................................... 45 
17.1 
Privacy...................................................................................................................................... 45 
17.2 
Serious Adverse Event (SAE) Reporting ................................................................................. 45 
18.0 
INFORMED CONSENT PROCEDURES ..................................................................................... 46 
18.1 
Research Authorization ............................................................................................................ 46 
19.0 
REFERENCES ............................................................................................................................ 47 
20.0 
APPENDICES .............................................................................................................................. 52 

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Chemoimmunotherapy 
Restaging with CT CAP q 24 weeks+/- 2 week for 2 
years, then q 12 months (+/- 2 weeks) until POD 
(or a maximum of 5 years). 

Reassess with CT CAP 4-6 wks later 

Restaging with CT CAP q 24 weeks +/- 2 
years for 2 years, then q 12 months (+/- 2 
weeks) until POD (or a maximum of 5 years). 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
Immunotherapy: 
No GELF Criteria, bMIPI Low 
or Intermediate, No blastic 
morphology 
Week 1: 
Day 1: Ofatumumab 1000 mg 
Day 2: Ofatumumab 1000mg 
Weeks 2-4: Ofatumumab 1000 
mg Day 1 only 
 
 
 
 
Reassess with 
CT CAP 8-10 
wks later 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
< PR, SD or 
POD 
 
 
 
 
 
 
 
 
 
 
Chemoimmunotherapy: Any 
GELF Criteria, High bMIPI, 
blastic morphology, or POD on 
biologic induction 
Ofatumumab day 1 + 
Bendamustine days 1 & 2 x 6 
cycles q 28 days 
Cycle 1: 
Day 1: Ofatumumab 1000 mg 
followed by Bendamustine 90 
mg/m2 
Day 2: Ofatumumab 1000mg 
followed by Bendamustine 90 
mg/m2 
Cycles 2-6: Days 1 & 2: 
Ofatumumab 1000 mg day 1 only, 
Bendamustine 90 mg/m2 both days 
 
CR 
PR 
 
Immunotherapy 
induction 
Untreated non-transplant eligible 
Mantle Cell Lymphoma 
Assess Risk Factors: bMIPI, Blastic 
Phenotype, GELF Criteria 

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In order to improve on existing treatment strategies in the transplant ineligible and elderly 
patient with mantle cell lymphoma (MCL) a study is being proposed to investigate a novel anti- 
CD20 monoclonal antibody ofatumumab either alone or in conjunction with Bendamustine. This 
will be investigated in patients with newly diagnosed MCL who are not eligible for autologous 
stem cell transplant or 65 years or older. 
 
This regimen was selected because of the safety profile and efficacy of each agent 
independently. In the non transplant eligible/elderly patient population, goals of therapy are the 
induction of durable disease control using a program associated with a desirable safety profile 
while maintaining quality of life. Ofatumumab has the potential, based on better affinity in low 
CD20 expressing tumors and improved complement dependent cytotoxicity, to improve upon 
the outcomes of other single agent monoclonal antibodies used in lymphoma. Patients will be 
stratified based on the use of clinical and biologic risk factors. Patients at lower risk for early 
disease progression can be identified and stratified to monoclonal only therapy, while those 
patients with an immediate need for cytoreductive therapy (eg. symptomatic disease or higher 
risk) would be stratified to the combination regimen. 
 
 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS 
Primary Objective: 
• 
To determine the single agent efficacy (as determined by response rate) of the 
monoclonal antibody ofatumumab alone in low risk patients (as defined in this protocol 
by: 
1) absence of NCCN/GELF (appendix V) criteria for treatment, 2) low or 
intermediate 
risk 
bMIPI 
(based 
on 
calculation 
obtained 
from 
http://www.qxmd.com/calculate-online/hematology/prognosis-mantle-cell-lymphoma- 
mipi), 3) absence of blastic morphology, 4) Ki-67 <30%. 
• 
To determine the efficacy (as determined by response rate) of the combination 
ofatumumab + Bendamustine in high risk patients (as defined in this protocol by: 1) the 
presence of any NCCN/GELF (appendix V) criteria for treatment, 2) high risk bMIPI 
(based 
on 
calculation 
obtained 
from 
http://www.qxmd.com/calculate- 
online/hematology/prognosis-mantle-cell-lymphoma-mipi), 3) blastic morphology, 4) Ki- 
67 ≥30%, or 4) patients with <PR, SD or POD following immunotherapy induction. 

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Secondary Objectives: 
• 
To determine the duration of benefit for this stratified approach for all patients, based on 
progression free survival (PFS), remission duration (DR), and overall survival (OS). 
• 
In addition we will evaluate toxicity according to Common Terminology Criteria for 
Adverse Events, version 4.0 (CTCAE v4.0). We will investigate the baseline CGA tool 
as a mechanism to predict toxicity. 
• 
Evaluating microRNA expression in MCL tumor samples derived from this protocol and 
correlate these with the tumor proliferation index to determine their prognostic utility. 
• 
Through immunohistochemistry, we also intend to explore SOX11 expression as a 
possible predictor of indolent disease. 
Primary Endpoints: 
 
• 
Immunotherapy induction (low risk patients) the ORR (CR+PR) rate to ofatumumab 
• 
Chemoimmunotherapy induction (High Risk patients) the CR to ofatumumab + 
Bendamustine 
Secondary Endpoints: 
 
• 
OS, PFS, DFS, DR 
• 
Safety and toxicity profile 
 
3.0 
BACKGROUND AND RATIONALE 
INTRODUCTION 
Mantle cell lymphoma (MCL) is an uncommon, distinct clinical subtype of non-Hodgkin’s 
lymphoma that comprises approximately 8 % of all lymphoma diagnoses (approximately 5000 
cases per year) 1. The prognosis of patients with MCL is the poorest among B- cell lymphoma 
patients, with a median overall survival (OS) of 3-5 years, and time to treatment failure (TTF) of 
18 months 2.There are four histologic subtypes of mantle cell lymphoma (the small cell variant, 
the marginal zone–like variant, the blastoid variant, and the pleomorphic variant). The blastoid 
and pleomorphic variants are considered to have the worst prognosis among the subtypes. 
Since the histologic diagnosis of MCL is often challenging by morphology alone, accurate 
diagnosis relies on immunohistochemical staining for the purposes of immunophenotyping 3. It 
has been found to expresses B cell markers CD5+, CD 20+, CD43 +, cyclin D1 +, CD 10+/-, 

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and CD 23-1. There is variable CD2 and CD3 expression. The genetic hallmark of mantle cell 
lymphoma is the t(11;14)(q13;q32) chromosomal translocation leading to the upregulation of 
Cyclin D1, a critical regulator of the G1 phase of the cell cycle 2. 
 
MCL often presents in advanced stage, with involvement of the bone marrow 60% of the 
time and gastrointestinal tract 30 %-80% of the time. Gastrointestinal involvement often 
manifests as lymphomatous polyposis of the intestine and has been found to be present in many 
patients at a microscopic level involving macroscopically normal mucosa. It presents rarely in 
the CNS. MCL can however manifest itself in the skin, as well as in peripheral blood in a 
leukemic presentation. The latter can be detected through flow cytometry4. The demographic of 
affected patients is primarily older individuals, mostly men, with a male to female ratio of 2-4:1. 
 
BIOMARKERS 
Median survivals have improved over the past several years, but are still estimated to be 
in the 3-5 yr range 5. Biologic markers exist to assess increased aggressiveness in MCL. Among 
these is a clinical risk model called the mantle cell international prognostic index (MIPI), which 
discriminates patients into different risk categories with disparate survival outcomes. The 
strongest predictor of survival in patients with MCL was recently identified by gene expression 
profiling 6. Twenty proliferation associated genes were identified as being superior to other 
prognostic molecular markers alone or in combination. However routine gene expression 
profiling is neither readily available nor practical for clinical use. As such, Ki-67 has emerged as 
an important and clinically useful surrogate. Our group recently evaluated the use of 
quantitative image analysis as a method of accurately assessing the proliferative index in 
patients with MCL, with high reproducibility 7. Additional biomarkers include blastic morphology, 
the high cellular proliferative rate as determined by Ki-67 staining and dysregulation of p53. 
 
TREATMENT RATIONALE: 
Despite an increasing understanding of the underlying molecular biology of MCL, there 
remains no standard of care for upfront treatment and with the possible exception of allogeneic 
bone marrow transplantation there are no known curative options. Based on improved 
progression free survival (PFS) with intensive chemotherapy induction followed by high dose 
chemotherapy (HDT) and autologous stem cell transplant (ASCT) consolidation, this treatment 
strategy is often recommended for younger, eligible patients 8 and is directed at prolonging the 

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remission duration. However, given a median age at presentation in the sixth decade, more than 
half of patients are not considered eligible for transplantation secondary to medical co- 
morbidities. In this patient population the goals of therapy are disease control designed to 
maximize survival and concurrently maintain quality of life. 
 
For the older patient or in patients where HDT/ASCT is not a viable option, a variety of 
approaches have been utilized. In elderly patients without an immediate indication for therapy 
(eg. Low tumor burden as determined by absence of GELF/NCCN criteria), a period of 
expectant monitoring or single agent monoclonal antibody therapy is frequently employed. The 
activity of single agent rituximab in MCL, however, is quite modest with overall response rates in 
the range of 22-34% and median time to progression of less than 12 months. 32, 43, 44 The group 
at Cornell has reported their experience with deferred initial therapy, demonstrating that 
expectant monitoring is associated with a median time to therapy of 12 months (range 4-128 
months) in selected patients49. Additionally, the MIPI and Ki67% have been useful predictors for 
identifying patients with less biologically aggressive disease and longer survival outcomes. 
Consequently, an attractive risk stratified approach would incorporate less aggressive therapy 
initially for biologically less aggressive disease, reserving chemoimmunotherapy for later 
interventions. 
Nationwide, immuno chemotherapy combinations are most frequently utilized. When 
rituximab is combined with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) 
chemotherapy, as well as with mitoxantrone, chlorambucil, and prednisolone (MCP), response 
rates are slightly higher than either chemo or immunotherapy alone; however no improvements 
in overall survival (OS) or PFS have been found 9-11. Other more intensive therapies, such as 
with rituximab combined with cyclophosphamide, doxorubicin, vincristine, and dexamethasone 
alternating with methotrexate and cytarabine (R-Hyper CVAD/MA), have been associated with 
increased toxicity in those with MCL greater than 65 years and consequently are not generally 
feasible or recommended to elderly patients. With a median follow up time of 40 months, in 
younger patients the 3 year failure free survival (FFS) and OS rates for this regimen were 64% 
and 82%, respectively. These results are comparable to an ASCT approach, with similar toxicity 
(8% treatment related deaths)33. This same regimen was evaluated in patients 65 years or older 
by the same authors with lower doses of cytarabine. The median FFS for the entire group was 
15 months and there was significant hematologic toxicity 34. These approaches therefore are not 
feasible for a large proportion of patients with MCL. Modified intensive chemotherapy regimens 

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studied in older patients have been less toxic, but also less effective 11.Consequently, new 
strategies in this particular group of patients are urgently needed, and ideally, developing a 
treatment program utilizing alternative agents with improved activity and safety profile would be 
desirable. 
Bendamustine: 
Bendamustine (TreandaTM; Cephalon, Inc, Frazer PA) is a bifunctional alkylating agent 
consisting of a purine ring and nitrogen mustard moiety. Frequently used in Eastern Germany, it 
was approved in the United States by the U.S. Food and Drug Administration (FDA) in 2008 for 
treatment of chronic lymphocytic leukemia (CLL) based on a randomized trial comparing it to 
chlorambucil as treatment in the first line setting 22. Overall response rates and OS were higher 
with Bendamustine. Bendamustine was also approved for patients with indolent B-cell non- 
Hodgkin's lymphoma progressing during or within 6 months of treatment with rituximab or 
chemoimmunotherapy. 
In vitro studies of Bendamustine have demonstrated rapid production of DNA cross links and 
strand breaks, inhibition of mitotic checkpoints, and induction of mitotic catastrophe. 
Bendamustine has demonstrated activity in a broad range of lymphomas (CLL, indolent NHL, 
MCL), as well as in resistant tumors, including those harboring p53 dysregulation 24. Phase II 
single agent data of Bendamustine in rituximab refractory indolent and transformed NHL 
demonstrated an ORR of 77% (34 % CR/Cru) with a median duration of response of 6.7 
months45. 
Bendamustine Combinations: 
 
Three studies had investigated Bendamustine in conjunction with rituximab in MCL 35, 36. 
Rummel et al evaluated 63 patients with indolent NHL with previously treated or relapsed 
disease (16 of who had MCL). Median age of patients was 66, with 68% having stage IV 
disease. Prior rituximab exposure was not permitted in this study; hence these patients were 
rituximab naive. The response rates were encouraging, with 75% ORR, CR 50%, and PR 25%. 
This was replicated in a multicenter trial involving 66 patients 36; 12 of whom had MCL. Prior 
rituximab exposure was permitted in this group. Results were similar, with 92% ORR, 42% CR, 
17% unconfirmed CR (Cru), and 33% PR. The differences in CR here rate may be related to 
prior rituximab exposure. Given these promising results, Bendamustine and rituximab were 
brought to the first line setting in a phase III randomized trial performed by the StiL (Study 

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Group Indolent Lymphomas, Germany) comparing RCHOP to R-Bendamustine in indolent 
lymphoma. . Two hundred thirty two patients (45 of whom had MCL) received 6 cycles of BR. 
The median age of patients was 64 (23% > 70yrs), and most patients had advanced disease 
(77% stage IV). The overall response rate was 88% and CR was achieved in 42% of patients 
with mantle cell lymphoma, which was equivalent or better than the RCHOP arm and associated 
with a more favorable toxicity profile13. Consequently, rituximab-bendamustine was established 
as a viable front line therapy for elderly MCL patients. 
 
Ofatumumab: 
 
Ofatumumab is a novel, fully human anti-CD20 monoclonal antibody with demonstrated activity 
in CLL and non-Hodgkin’s lymphoma. Ofatumumab recognizes a CD20 epitope distinct from 
rituximab and is associated with similar antibody dependent cell mediated cytotoxicity (ADCC) 
and increased complement dependent cytotoxicity (CDC) 38. This activity has been seen even in 
settings with lower CD20 antigen density and in the presence of complement inhibitors. This 
improved activity may confer a theoretical advantage over rituximab is select situations (eg. CLL 
and MCL). In CLL, the safety and efficacy of ofatumumab was evaluated in a phase I/II trial of 
33 patients with relapsed or refractory disease 39. The FDA granted ofatumumab accelerated 
approval in 2009 for the treatment of CLL refractory to fludarabine and alemtuzumab based on 
the Hx-CD20-406 multicenter trial. Patients refractory to both fludarabine and alemtuzumab 
(double refractory, or DR) had an ORR of 51%, and those with bulky disease refractory to 
fludarabine (BFR) alone had an ORR of 44%40. In a recent update of this trial, ORR for BFR 
patients was 58% and 47% for DR patients 41. Ofatumumab has efficacy in NHL as well. In a 
phase I/II study involving patients with follicular lymphoma, the agent was demonstrated to be 
safe and associated with responses across a range of doses 23. Objective responses ranged 
from 20-63%, and these were not dose dependent. Five patients experienced CR. 
 
Ofatumumab was also recently evaluated in combination with CHOP chemotherapy. Fifty nine 
patients with relapsed or refractory FL were randomized to ofatumumab Day 1,500 mg (Group 
A) or 1,000 mg (Group B); cyclophosphamide Day 3, 750 mg/m2; doxorubicin Day 3, 50 mg/m2; 
vincristine Day 3, 1.4 mg/m2; and prednisolone Days 3-7, 100 mg every 3 weeks for 6 cycles. 
Overall response rates were 90% in Group A and 100% in Group B. Complete response (CR) + 
unconfirmed CR (CRu) was 69% in Group A and 55% in Group B. Overall, 16 of 21 pts (76%) 
with FLIPI score 3-5 attained CR/Cru 46. 

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Rationale for two treatment arms: 
As noted above, in recent years there have been a number of advances in identifying risk 
factors MCL patients regarding prognosis. The best candidates currently include NCCN/GELF 
criteria, MIPI, proliferative rate (Ki67) and blastic morphology. Furthermore, there is now 
evidence that subgroups of MCL patients may behave more indolently and that more 
conservative management, with a initial watch and wait period or less intensive treatment is 
rational rather than immediate chemoimmunotherapy in the absence of NCCN/GELF 
indications49. 
 
We have defined a low risk group as patients without an indication for immediate therapy as 
determined by no NCCN/GELF criteria for treatment. Additionally, we will utilize the prognostic 
markers of bMIPI and Ki67 to ensure patients have low to intermediate risk of progression or 
death. Patients treated with CHOP with Ki67%<10 and Ki67% of 10%-29% have median OS of 
112 and 59 months respectively, compared with patients whose Ki67 is 30% or greater where 
median OS is 35 months. For patients receiving RCHOP chemotherapy, the median OS was not 
reached for Ki67% <30%, but was 52 months for the high risk group Similarly, the MIPIb can 
predict overall survival with low risk patients (median OS not reached) and intermediate risk 
patients (median OS 58 months) having a more protracted disease course compared with high 
risk disease (median OS 37 months)50 . 
 
Low 
risk 
non-transplant 
eligible 
patients, 
therefore, 
may 
not 
require 
initial 
chemoimmunotherapy. Monoclonal antibody therapy alone is an attractive option from a toxicity 
standpoint, as there is the potential for disease control and prolonging PFS over monitoring 
alone with a delay in the need for chemotherapy. The currently available agent rituximab has 
had only modest activity in MCL as a single agent. We propose to investigate Ofatumumab in a 
population defined as low risk, as this agent has the potential for improved biologic activity over 
rituximab in MCL and a favorable safety profile. 
 
In high risk non-transplant eligible patients, where there is a clear indication for 
chemoimmunotherapy, rituximab+Bendamustine has demonstrated improved safety and activity 
over RCHOP, additionally sparing exposure in the elderly to an anthracycline. Ofatumumab 
similarly targets CD20, but has improved CDC activity and slower off rates, factors which may 
improve efficacy in MCL. This group of patients will receive the combination of 
ofatumumab+Bendamustine. Additionally, for patients initial treated with monoclonal Ab and 

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either relapsing or having <PR to induction, there is also a clear indication for 
chemoimmunotherapy. These patients similarly will receive the combination regimen, 
 
 
MicroRNAs 
While advances in understanding MCL pathogenesis have afforded new opportunities in the 
design of new drugs targeting these mechanisms, improved methods of prognosticating MCL 
have not emerged. Given the limitations of existing prognostic models, predictive models able to 
combine the quantification of the proliferation activity with other robust molecular profiles may 
improve the estimation of patient prognosis in MCL. 
MiRNA expression profiling plays an important role in the classification and function of 
hematologic malignancies. Deletions in miR-15a and miR-16-1 were found in patients with 
chronic lymphocytic leukemia (CLL) when compared to normal mature CD 5+ lymphocytes from 
healthy donors. Through BCL-2 targeting, this cluster exhibited tumor suppressor activity. 
Overexpression caused apoptosis in leukemic cell lines, supporting a future role for miR-15a/16- 
1 restoration in the treatment of CLL. A putative tumor suppressive role for miR-29b has been 
reported in acute myelogenous leukemia (AML), by targeting DNA methyltransferases, as well 
as CDK6 and MCL-1, causing cell death and inhibition of cell proliferation. In MCL, 
unsupervised hierarchical clustering analysis of highly purified leukemic MCL cells 
demonstrated dysregulated miRNA profiles compared with normal lymphoid cells. Two 
distinctive subsets of tumors were revealed, showing significant differences in the IgVH 
mutational status, proliferation signature, and number of chromosomal alterations. 
Studies in AML and CLL have demonstrated the role for miRNAs as novel biomarkers as well. 
Elevated levels of miR-181 were associated with superior event free survival in patients with 
high risk AML, whereas in CLL, increased expression of miR-155 and 146 were correlated with 
progression of disease. In MCL, miR-16 was found to target the 3’untranslated region of cyclin 
D1, resulting in cyclin D1 overexpression by evading miR-16-1’s regulatory effects. Moreover, a 
miRNA expression signature recently identified five altered miRNAs in over 50% of samples 
evaluated. Specifically, decreased expression of the miR-29 family was associated with shorter 
survival in patients with MCL. MiR-29 caused CDK6 inhibition by direct binding to the 
3’untranslated region. Down-regulation of the miR-29 family resulted in up-regulation of CDK6 in 
MCL, suggesting that miR-29 collaborates with cyclin D1 in MCL pathogenesis. 

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These data support that miRNAs have an important role in the classification, function and 
prognosis of leukemias and lymphomas. They have potential to improve molecular disease 
characterization and establish new biomarkers to improve existing methods of prognosticating 
MCL. Consequently, we hypothesize that a miRNA signature from MCL will enhance existing 
prognostic methods and identify miRNAs relevant to MCL biology. 
While these emerging data suggest that microRNAs may be relevant to MCL pathogenesis, they 
do not address the question of how to they may influence proliferation or chemoresistance. 
SOX11 is a transcription factor specifically expressed in the nucleus of MCL compared with 
other lymphomas and benign lymphoid tissue. Although the role of SOX11 presently is not 
known in lymphocyte ontogeny, it is normally expressed in the developing central nervous 
system in the embryo. SOX11 has recently been shown to be up-regulated in MCL and can 
distinguish it from other B-cell lymphomas. Additionally SOX11 was found to be equally 
expressed in D1-positive and D1-negative MCL. Cyclin D1 overexpression is the hallmark of 
MCL even though approximately 10% of MCLs lack Cyclin D1 expression, and may be 
misdiagnosed by overreliance on Cyclin D1. Prospectively staining for SOX11 expression 
immunohistochemically [through a commercially available polyclonal rabbit antibody (Sigma- 
Aldrich)] may help provide insight into the clinical-pathologic correlates associated with its 
expression (Ek et al, Blood 2008 (111):2; 800-805, Mozoz et al, Haematologica, 2009 (94):11; 
1555-1562). 
 
Please see Appendix III for details regarding experimental design, methods and 
specimen handling. 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
4.1 
Design 
The proposed study is a Simon 2 stage optimal study design investigating the activity of 
ofatumumab alone or in conjunction with Bendamustine for patients with MCL who are either not 
candidates for ASCT or aged 65 or older. The study design will allow for an estimation of the 
single agent response of ofatumumab in patients at low biologic risk for immediate disease 
progression, as defined in this protocol, based on absent NCCN/GELF criteria for treatment 
(see appendix V), low risk bMIPI, absent blastic morphology, and Ki-67 <30%. The combined 
regimen will assess the response rates of the combined chemo-immunotherapy program in 

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patients with need for cytoreductive therapy, or high risk for disease progression, as defined in 
this protocol by: 1) Any NCCN/GELF criteria for treatment, 2) high risk bMIPI, 3) blastic 
morphology, 4) Ki-67 >30%, or 5) POD on biologic induction). Patients will be stratified based 
on the use of clinical risk factors and the bMIPI. Patients at lower risk for early disease 
progression can be identified and stratified to monoclonal only therapy, while those patients with 
an immediate need for cytoreductive therapy (i.e. symptomatic disease or higher risk) would be 
stratified to the combination regimen. 
Immunotherapy: 
The immunotherapy strata will plan to enroll a total of 38 untreated patients and assess ORR at 
12 weeks post completion of ofatumumab induction. In MCL, single agent rituximab has an 
ORR ranging between 22-37% in patients with relapsed, refractory disease, and previously 
untreated disease 32, 43, 44, 47. Complete responses are between 3 and 14%. In CLL, single agent 
ofatumumab has an ORR of 47-58% 41, while in follicular lymphoma, ofatumumab has an ORR 
between 20-63% 23. A single agent ORR of ≥60% (20% improvement) to ofatumumab in 
this setting would be considered promising. 
 
Chemoimmunotherapy: 
The chemoimmunotherapy strata will plan to enroll a total of 38 untreated patients with 
GELF/NCCN criteria for treatment, high risk bMIPI, or blastic histology. In both first line setting 
and relapsed settings, the combination of rituximab + Bendamustine as a historic comparator 
has demonstrated ORR of 75-92%, with a CR rate of 42-50% 13, 35-36. As this study will stratify 
for patients with a higher initial risk profile and NCCN/GELF criteria for therapy, responses rates 
may be lower. 
 
The efficacy will be measured by the sum of complete response and partial response. Since the 
combination of rituximab-Bendamustine for untreated patients yielded CR rates of 
approximately 40%, this study will be considered successful if the complete response rate 
is at least 60%. 
 
• 
Patients will be stratified by the need for immediate chemoimmunotherapy or 
immunotherapy induction: 
 
o Parameters for Immunotherapy: 

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o No GELF/NCCN criteria for therapy (see appendix V), Biologic MIPI (bMIPI) Low 
or Intermediate, No Blastic MCL features, Ki67<30%. 
▪ 
Blastic features are characterized by a homogeneous population of cells 
displaying lymphoblastic morphology; and are more likely to have 
secondary chromosomal aberrations such as p53 mutations or 
overexpression, del (13q14) or del p16. 
▪ 
GELF Criteria: Involvement of => 3 nodal sites, each with diameter => 3 
cm, any nodal or extranodal tumor => 7 cm, B symptoms, Massive 
Splenomegaly, Pleural effusions or peritoneal ascites, Cytopenias (ANC < 
1.0, Plt<100K), Leukemic phase 
▪ 
bMIPI (age, ECOG, LDH, WBC, MIB-1%) : As per Hoster et al (Hoster E, 
Dreyling M, Klapper W, et al., A new Prognostic index (MIPI) for patients 
with advanced stage mantle cell lymphoma. Blood. 2008 Jan 15; 111 
(2):558-565). 
bMIPI 
calculator 
available 
online 
at 
http://www.qxmd.com/calculate-online/hematology/prognosis-mantle-cell- 
lymphoma-mipi 
 
o Parameters for Chemoimmunotherapy: 
o Patients meeting any GELF/NCCN criteria for therapy, bMIPI high risk, Blastic 
MCL features or Ki-67> 30%. 
 
• 
Note: Patients with a leukemic phase only presentation of mantle cell lymphoma 
generally have clinically low-risk disease, regardless of mantle cell IPI calculations. Upon 
reciew with the principal investigator, these patients may be stratified to the 
immunotherapy only arm if clinically appropriate. 
 
4.2 
Intervention 
Patients will receive either ofatumumab alone (immunotherapy schema below) or in conjunction 
with bendamustine (chemoimmunotherapy schema below) based on their assigned initial risk 
stratification. 
• 
Schema for patients receiving Immunotherapy (N= 38) 
o Ofatumumab Day 1 Week 1: 1000 mg, Day 2 week 1: 1000mg. Patients who 
exhibit a baseline leukocytosis ≥ 20,000 will receive 300 mg of ofatumumab on 
day 1, week 1. Thereafter, they can receive the 1000 mg dose 
o Ofatumumab Day 1, Weeks 2-4: 1000 mg 
o Will reassess 8-10 weeks after conclusion of treatment with CT CAP, and 
following this q 12 wks for 2 yrs, then q 6mo until POD or for a maximum of 5 
years 
▪ 
Patients with PR or CR at week 8-10: continued monitoring q 12 wks for 
2 yrs, then q 6mo until POD or for a maximum of 5 years. At POD 

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crossover to chemoimmunotherapy regimen (within 4 weeks of date of 
progression). 
▪ 
Patients in <PR, i.e. with < 50% reduction in nodal masses, SD or POD: 
proceed to chemoimmunotherapy regimen directly (within 4 wks of 
restaging 
CT 
CAP). 
Subsequent 
follow-up 
will 
be 
as 
per 
chemoimmunotherapy arm 
 
• 
Schema for patients receiving Chemoimmunotherapy (N=38) 
o Ofatumumab day 1 + Bendamustine 90 mg/m2 days 1 & 2 x 6 cycles q 28 days 
▪ 
Cycle 1, day 1: Ofatumumab 1000 mg followed by Bendamustine 90 
mg/m2. Patients who exhibit a leukocytosis > or equal to 20,000 will 
receive 300 mg of ofatumumab on day 1, week 1. Thereafter, they can 
receive the 1000 mg dose. 
▪ 
Cycle 1, day 2: Ofatumumab 1000mg followed by Bendamustine 90 
mg/m2 
▪ 
Cycles 2-6: Ofatumumab 1000 mg day 1, Bendamustine 90 mg/m2 days 1 
and 2 
o  Will reassess 4-6 weeks after conclusion of treatment with CT CAP, and 
following this q 12 wks for 2 yrs, then q 6mo until POD or for a maximum of 5 
years 
We will evaluate data at the conclusion of the first Simon stage. 
 
 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS 
Bendamustine: 
Bendamustine will be prepared and administered as per MSKCC guidelines. Patients will 
receive bendamustine 90mg/m2 administered per institutional guidelines for two consecutive 
days. Cycles will be repeated every four weeks and a total of 6 cycles will be planned. 
 
Identity of Bendamustine medication 
Bendamustine HCL (TreandaTM) is commercially supplied Cephalon, Inc. It is supplied 
as a lyophilized powder for injection with 100mg of drug per vial. 
 
Mechanism of action 
Bendamustine HCl acts as an alkylating agent, causing the formation of intra-strand and 
inter-strand cross-links between DNA bases. This directly inhibits DNA replication, 
repair, and transcription. In addition, bendamustine HCl has potential purine-analog 
activity. 

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Pharmacokinetics and Metabolism 
Following intravenous administration, greater than 95% of bendamustine HCl is protein 
bound. Bendamustine HCl undergoes extensive first-pass metabolism by the liver and is 
rapidly eliminated from plasma via urine. The elimination half life is biphasic with 
respective half lives in plasma of 6-10 minutes and 30 minutes.[7] 
 
Packaging, labeling, and storage 
Formulation: Bendamustine HCl is supplied as a lyophilized powder for injection in 
single-use, amber glass vials containing 100mg bendamustine HCl and 170mg mannitol. 
 
Preparation: Reconstitute each vial with 20mL of sterile water for injection to final 
concentration of 5.0mg/mL. The calculated dose is withdrawn and immediately diluted 
further in 500mL of 0.9% Sodium Chloride for injection. 
 
Storage: Vials should be refrigerated (2˚-8˚C) and protected from light. The admixture is 
stable for 3 days when refrigerated (2˚-8˚C) and for 3 hours at room temperature (15˚- 
30˚C). 
Ofatumumab 
GlaxoSmithKline will supply commercial ofatumumab to the investigator as content-labelled 
Ofatumumab vials presented as either 100 mg – acetate formulation, 20 mg/mL, 5 mL fill vials, 
or 1000 mg – acetate formulation, 20 mg/mL, 50 mL fill vials. 
5.1  Mechanisms: Ofatumumab is a monoclonal antibody which binds specifically the 
extracellular (small) loops of the CD20 molecule (which is expressed on normal B 
lymphocytes and in B-cell CLL) resulting in potent complement-dependent cell lysis and 
antibody-dependent cell-mediated toxicity in cells that overexpress CD20. 
5.2 Preparation: 
Ofatumumab will be prepared as 1000 mL dilution of ofatumumab in sterile, pyrogen-free 
0.9% NaCl. Once diluted into saline, the product is stable for up to 48 hours at ambient 
temperature. However, the product contains no preservative and should be used as 
soon as possible after dilution. 
Preparation of drug solution for intravenous injection by the site pharmacist or designee 
will be done in accordance with the protocol, and in these dilution instructions. 
Ofatumumab intravenous solution will be prepared using standard dilution methods and 
following general aseptic practice standard to preparation of IV medications. Eyes and 
hands should be protected when handling ofatumumab. 

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For intravenous administration, compatibility of the following components for 
ofatumumab in clinical studies (i.e., not for commercial product) has been established: 
 
 
Table 1: Dosing Components for Ofatumumab in Clinical Studies 
 
Dosing component 
Material of construction 
Suggested Vendor 
1L Saline Bags 
Polyvinyl Chloride (PVC) 
Baxter 
Polyolefin [polyethylene* 
(PE)/polypropylene (PP)] 
Baxter, B. Braun 
Administration Set 
PVC 
Baxter 
PVC lined with Polyethylene 
B. Braun 
Filter Extension Set 
Sterilizing-grade (0.22 m) 
hydrophilic filter 
Durapore brand by Millipore 
Lines made of PVC, filter 
membrane material polyether 
sulfone 
Baxter 
Lines made of PVC lined with 
Polyethylene, filter 
membrane material polyether 
sulfone 
Alaris/Cardinal Health 
 
Preparation of the 1000 mL infusion bags should be done on the day of planned infusion. 
* polyethylene (IUPAC name: polyethene) 
 
5.3 Storage: Store intact vials at 2°C to 8°C (36°F to 46°F); do not freeze. Protect from 
light. Solutions diluted for infusion may be stored for up to 24 hours at 2°C to 8°C (36°F 
to 46°F); begin infusion within 12 hours of preparation. 
5.4 Ofatumumab Preparation and Administration : 
Pre-medication before each ofatumumab infusion must be given within 30 minutes to 2 
hours prior to the treatment as per the following table: 

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Table 2: Supplemental Medication 
 
Pre- 
medication 
Requirements 
prior to 
Ofatumumab 
Infusions- 
Infusion # 
Acetaminophen 
(po) 
or equivalent 
(650 mg po x 2) 
Antihistamine (iv 
or po) 
diphenhydramine 
or equivalent 
Glucocorticoid (iv) 
prednisolone 
or equivalent 
1st 
1300 mg 
50 mg 
50 mg 
2nd 
1300 mg 
50 mg 
50 mg 
3rd -Nth 
1300 mg 
50 mg 
0 – 50 mg1 
If the 2nd infusion has been completed without the subject experiencing any grade = 3 AEs, pre- 
medication with glucocorticoid may be reduced or omitted before the 3rd to Nth infusion at the 
discretion of the investigator. 
Materials for Preparation and Administration of Infusion 
The following materials are needed when preparing and administering the infusion: 
• 
1000 mL sterile pyrogen free 0.9% saline (NaCl) infusion bag(s). The solution can be 
kept at ambient temperature for a maximum of 24 hours after preparation; however, the 
product does not contain a preservative and dosing should begin as soon as possible 
after dose preparation. 
• 
Ofatumumab 100 mg and 1000 mg vials (supplied by GSK) 
• 
Needles and syringes (50 mL sterile syringe) not supplied by GSK 
 
Dilution of Ofatumumab 
• 
Ensure the correct container number is used. 
• 
Take a 1000 mL infusion bag (sterile pyrogen free 0.9% saline), remove and dispose of 
the appropriate amount of saline according to Table 2 or Table 3 below 
• 
Draw the required amount of ofatumumab according to Table 2 (100 mg vials) or Table 3 
(1000 mg vials) below 
• 
Inject ofatumumab into the saline bag 
• 
Invert the infusion bag slowly 3 times, avoiding formation of any foam 
• 
Label the infusion bag with the completed label 

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Table 3 
Preparation of Ofatumumab Infusion: 100 mg vials 
 
Dose of 
Ofatumumab 
Infusion bag 
size 
Volume of NaCl to 
be removed from 
infusion bag 
Volume ofatumumab 
(number of ofatumumab 
vials) 
300 mg 
1000 mL 
15 mL 
15 mL 
(3 vials, 5 mL/vial) 
1000 mg 
1000 mL 
50 mL 
50 mL 
(10 vials, 5 mL/vial) 
 
Table 4 
Preparation of Ofatumumab Infusion: 1000 mg vials 
 
Dose of 
Ofatumumab 
Infusion bag 
size 
Volume of NaCl to 
be removed from 
infusion bag 
Volume ofatumumab 
(number of ofatumumab 
vials) 
1000 mg 
1000 mL 
50 mL 
50 mL 
(1 vial, 50 mL/vial) 
 
Ofatumumab Infusion Set up 
Ofatumumab must be administered by i.v. infusion through an in-line filter and through a well- 
functioning i.v. catheter (i.v. cannula) into a vein in the arm (or other venous access) by an 
infusion pump. 
Please Note: It is mandatory to use an in-line low protein binding 0.2 micron polyether 
sulfone filter for all IV dosing of ofatumumab drug product. 
DO NOT ADMINISTER AS AN INTRAVENOUS PUSH OR BOLUS. 
Ofatumumab should not be mixed with any other medication. If ofatumumab is to be 
dosed through an in-dwelling catheter, then, any previous medication should be removed 
by flushing with normal saline prior to dosing with ofatumumab. 
Please note that the infusion site can be used for blood sampling only if there is no risk 
of contamination of the infusion needle with the saline, infusion solutions, or any other 
fluid(s). Only a newly inserted needle can be used for the predose blood samples. 
• 
Check subject ID against the label on the infusion bag and ensure the expiry of the 
solution. The solution must be administered in its entirety to the subject within 48 hours 
from time of preparation. 
• 
Attach the 1000mL infusion bag to the infusion set (if not done at the pharmacy). 
• 
Attach the in-line filter to the infusion set (closest to the subject). Note: The in-line filter 
must be used during the entire infusion. 

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• 
Prime the infusion set and filter with ofatumumab (if not done at the pharmacy). 
• 
In case of a problem with the filter (i.e. clogging/blockage), please change, re-prime the 
new filter, and continue the infusion. 
• 
In case of problem with infusion set, follow local procedures. 
• 
Collect the pre-dose blood samples, if required. 
• 
Check the backflow from the i.v. cannula according to routine practice at site 
• 
Set the pump at the initial infusion rate 12mL/hr for the first infusion and 25mL/hr for the 
subsequent infusions (if no grade ≥ 3 infusion-associated AEs were observed in the 
previous infusion) 
• 
Start the infusion using the following infusion rates (as study applicable). 
 
 
Immunotherapy: 
 
The first cycle of ofatumumab monotherapy will consist of an infusion of 1000 mg on Day 1 and 
an infusion of 1000 mg on Day 2 of Cycle 1. For subsequent cycles, a dose of 1000 mg will be 
infused on Day 1 of weeks 2, 3 and 4; a single cycle will be administered. Patients who exhibit a 
leukocytosis > or equal to 20,000 will receive 300 mg of ofatumumab on day 1, week 1. 
Thereafter, they can receive 1000 mg as noted above. 
Chemoimmunotherapy: 
 
The first cycle of ofatumumab in combination with chemotherapy will consist of an infusion of 
1000 mg on Day 1 and an infusion of 1000 mg on Day 2 of Cycle 1. The cycle length will be 
four weeks as appropriate based on the concomitant chemotherapy regimen. 
For patients who exhibit a leukocytosis > or equal to 20,000: First Infusion of 300mg 
Ofatumumab 
The first dose administered of ofatumumab should be 300 mg to minimize infusion reactions. 
The initial rate of the first infusion of 300mg ofatumumab (0.3mg/ml) should be 12ml/h. If no 
infusion reactions occur the infusion rate should be increased every 30 minutes, to a maximum 
of 400 ml/h, according to Table 2. If this schedule is followed, the infusion duration will be 
approximately 4.5 hours. 

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Table 5 
Infusion rate at 1st Ofatumumab infusion 
 
Time 
mL/hour 
0 – 30 minutes 
12 
31 – 60 minutes 
25 
61 – 90 minutes 
50 
91 – 120 minutes 
100 
121 - 150 minutes 
200 
151 - 180 minutes 
300 
181+ minutes 
400 
 
If an infusion reaction develops, the infusion should be temporarily slowed or interrupted. Upon 
restart, the infusion rate should be half of the infusion rate at the time the infusion was paused. 
If, however, the infusion rate was 12 mL/hour before the pause, the infusion should be restarted 
at 12 mL/hour. Hereafter, the infusion rate may be increased according to the judgment of the 
investigator, in the manner described in this section. 
Subsequent infusion of full dose Ofatumumab 
 
If the previous infusion has been completed without grade ≥ 3 infusion-associated AEs, the 
subsequent infusion of the first full dose of ofatumumab can start at a rate of 25 mL/hour and 
should be doubled every 30 minutes up to a maximum of 400 ml/h, according to Table 3. 
Duration of the infusion will be approximately 4 hours if this schedule is followed. If the previous 
infusion has been completed with grade ≥ 3 infusion associated AEs, the subsequent infusion 
should start at a rate of 12 mL/hour according to Table 3. 
Table 6 
Infusion rate at subsequent Ofatumumab infusion 
 
Time 
mL/hour 
0 – 30 minutes 
25 
31 – 60 minutes 
50 
61 – 90 minutes 
100 
91 – 120 minutes 
200 
121+ minutes 
400 
 
During infusion the patient should be monitored closely and appropriate measurements should 
be performed whenever judged necessary. 

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6.0 
CRITERIA FOR SUBJECT ELIGIBILITY 
6.1 
Subject Inclusion Criteria 
• 
Untreated, non-transplant eligible, newly diagnosed mantle cell lymphoma with 
measurable disease as determined by CT, and bone marrow biopsy. 
• 
Age > 65 years or >18 year and ineligible for HDT/ASCT 
• 
Subjects must not be candidates for intensive high-dose chemotherapy, with or without 
an autologous stem cell transplant (ASCT), due to one or more of the following factors: 
o Age ≥ 65 years 
▪ 
Patients <65 years of age must be ineligible for HDT/ASCT on the basis 
of comorbidity, organ dysfunction or patient refusal for HDT/ASCT 
o Comorbid disease, such as CAD, CHF, pulmonary dysfunction, liver or kidney 
dysfunction, precluding high dose therapy secondary to expected increased 
morbidity and mortality. 
▪ 
poor performance status (KPS 70% or less) 
▪ 
Ejection fraction <45% 
▪ 
Impaired pulmonary function test with DLCO <50% expected 
o Patient refusal 
o Medical conditions which in the opinion of the treating physician and DMT 
preclude HDT/ASCT. 
• 
Patients must have a serum creatinine clearance ≥ 40 mL/min as per the Jelliffe method 
or by 12-hour or 24-hour urine creatinine clearance. 
• 
Patients must have ANC>1,000/mcl and Platelets>100,000/mcl (unless secondary to 
MCL). 
• 
Patients must have a bilirubin level of < 2.0 mg/dl in the absence of a history of Gilbert's 
disease (or pattern consistent with Gilbert’s). 
• 
Negative serologies for Hepatitis B (HB) defined as a negative test for HBsAg. In 
addition, if negative for HBsAg but HBcAb positive (regardless of HBsAb status), a HB 
DNA test will be performed and if negative, patient may be included but must undergo 
HBV DNA PCR testing at the beginning of treatment and throughout treatment duration, 
at least every 2 months. In addition patients will require treatment with Entacavir .5mg po 
qday per MSKCC institutional guidelines (see Appendix III of protocol). 
• 
No active co-morbid cardiac condition such as active CHF or CAD. 
• 
KPS performance ≥ 70% 
• 
Histologically confirmed mantle cell lymphoma classified according to WHO criteria 
confirmed at MSKCC. 
• 
No prior treatment for mantle cell lymphoma with the exception of corticosteroids for 7 
days or less, or 1 course of involved-field radiation. 
• 
No prior malignancies within 5 yrs, unless treated early stage breast cancer, treated 
carcinoma in situ of the cervix, resected skin malignancies, or treated prostate cancer. 
• 
Women who are pre-menopausal must have a negative serum pregnancy test. Subjects 
must agree to use appropriate contraception until 4 weeks after the completion of 
chemotherapy. 

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• 
Patients must be HIV negative, and have negative serologies for Hepatitis C. 
 
 
6.2 
Subject Exclusion Criteria 
• 
Subjects who have current active hepatic or biliary disease (with exception of patients 
with Gilbert's syndrome, asymptomatic gallstones, hepatic involvement by MCL, or 
stable chronic liver disease per investigator assessment). 
• 
Known pregnancy or breast-feeding. 
• 
Medical illness unrelated to MCL within the prior one month that will preclude 
administration of chemotherapy safely. This includes patients with uncontrolled infection, 
chronic renal insufficiency, myocardial infarction within the past 6 months, unstable 
angina, active congestive heart failure, cardiac arrhythmias other than chronic atrial 
fibrillation and chronic active or persistent hepatitis. 
7.0 
RECRUITMENT PLAN 
Patients with MCL will be recruited from MSKCC. Patients seen in the inpatient or outpatient 
setting at MSKCC with histologically confirmed mantle cell lymphoma will be evaluated for 
this study. An attending physician of the Lymphoma or Hematology service will evaluate all 
patients to determine their eligibility. If their physician considers them eligible, they will be 
provided with information regarding the clinical trial and asked to participate. We will enroll 38 
patients the single agent Ofatumumab arm, and 38 additional patients for the 
chemoimmunotherapy arm with Ofatumumab and Bendamustine. We intend to accrue 1-2 
patients per month. 
 
8.0 
PRETREATMENT EVALUATION 
• 
Consent to utilize tumor sample and/or peripheral blood sample for research (perform 
clinical correlates). 
• 
Tissue block preferred or at least 10 unstained slides, if available, for confirmation of 
diagnosis: 
o Immunohistochemistry staining for Ki-67, p53, CD20, CD5, CD23, CD10, cyclin 
D1. (Cyclin D2, D3 will be obtained as needed, if Cyclin D1 negative) 
o Ki-67 will be determined by optical image assessment whenever technically 
feasible; standard visual assessment will otherwise be utilized. 
• 
Within 2 weeks prior to initiating treatment: 
o History and physical including height, weight, and vital signs 
o Karnofsky performance status 
o Complete blood count with differential 
o Comprehensive metabolic panel (includes liver function testing, serum LDH) 
o Creatinine clearance evaluation per the Jelliffe method or 12-hour or 24-hour 
urine creatinine clearance 
o Quantitative serum immunoglobulin levels 
o Serum lactate dehydrogenase 

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o Pregnancy test in pre-menopausal women 
o Modified Comprehensive Geriatric Assessment (CGA) & comorbidity *This can 
be completed either at baseline or cycle 1 day 1 of therapy. It does not need to 
be completed twice prior to therapy. 
▪ 
Non-English speaking patients are not required to participate in the CGA 
o NIA/NCI Co-morbidity Scale (baseline only) 
• 
Within 6 weeks prior to initiating treatment: 
o CT scans of chest, abdomen, and pelvis with contrast for pretreatment staging. 
o CT of neck may be obtained as clinically indicated 
▪ 
MRIs may be used instead of CT scans in patients for whom CT scans 
are contraindicated. 
o Colonoscopy with blind biopsy is advisable when clinically indicated and 
acceptable from a risk:benefit standpoint as GI tract involvement is common, but 
this study is not a mandatory per protocol and left to the discretion of the treating 
physician. 
o Appropriate bone marrow biopsy and aspirate for detection of involvement 
o Electrocardiogram 
o Hepatitis B surface antigen and antibody, core antibody 
o Hepatitis C serology 
o HIV 1/2 antibodies 
o CMV PCR for patients enrolling onto chemoimmunotherapy arm 
9.0 
TREATMENT/INTERVENTION PLAN 
Immunotherapy alone: 
• 
Patients receiving immunotherapy alone will receive ofatumumab every week ± 1 day for 
4 weeks. 
• 
During the first week only, there are 2 days of treatment. Thereafter, there is only 1 day 
of treatment. 
• 
On the first week, ofatumumab will be given on two consecutive days at the same doses: 
Week 1, day 1: 1000 mg, Week 1, day 2: 1000mg. Patients who exhibit a leukocytosis > 
or equal to 20,000 will receive 300 mg of ofatumumab on day 1, week 1. Thereafter, they 
can receive 1000 mg as noted above. 
• 
During weeks 2, 3, and 4, patients will only receive ofatumumab on one day: Day 1, 
1000 mg. 
• 
8-10 weeks after completion of ofatumumab, patients will be restaged with CT scans of 
chest, abdomen and pelvis. 
• 
If a CR or PR is documented, patients will be restaged every 24 weeks for a total of 2 
years, and then every 12 months until disease progression, or for a maximum of five 
years. 
o If restaging documents less than PR, SD, or progression of disease (POD), 
patients will proceed to the chemoimmunotherapy arm within the next 4 weeks, 
and receive ofatumumab combined with bendamustine. Patients crossing over to 
the chemoimmunotherapy induction should complete the pre-treatment 
investigations in section 8.0 prior to starting chemoimmunotherapy; A repeat 
bone marrow biopsy can be deferred at this time, but must be repeated to 
confirm CR post chemoimmunotherapy if appropriate. 

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Chemoimmunotherapy: 
• 
Patients will receive treatment with both ofatumumab and bendamustine every 4 weeks 
± 3 day (every month) for a total of 6 months (cycles). Here, one cycle is one month of 
treatment. 
• 
As above, on the first cycle of treatment only, ofatumumab will be given on two 
consecutive days at the same doses: Cycle 1, day 1: 1000 mg, Cycle 1, day 2: 1000mg. 
Patients who exhibit a leukocytosis ≥20,000 will receive 300 mg of ofatumumab on day 
1, cycle 1. Thereafter, they can receive 1000 mg as noted above. 
• 
For the first cycle, Bendamustine will be administered together with ofatumumab on day 
1 and 2 at 90 mg/m2. 
• 
For cycles 2 through 6, Ofatumumab will be given with Bendamustine on day 1, and 
Bendamustine will be given alone on day 2. 
• 
Patients will receive a total of 6 cycles of both ofatumumab and bendamustine (one 
cycle every 28 days ± 3 days; or approximately 6 months of therapy). 
• 
After 4-6 weeks, patients will undergo restaging with CT of chest, abdomen and pelvis 
(and neck, as clinically indicated), and subsequently every 24 weeks for a total of 2 
years, and then every 12 months until disease progression, or for a maximum of five 
years. 
• 
CMV PCR will be drawn 4-6 weeks after cycle 6 
Dose Adjustments: 
 
Dose Adjustments for Bendamustine: Patients may be delayed up to 17 days for cytopenias or 
toxicity prior to removal from study. Treatment will be delayed until the absolute neutrophil count 
is >1000/mcl and the platelet count is >75,000/mcl. A lower threshold is allowed for patients that 
have a baseline platelet count ≤100,000/mcl secondary to MCL: their platelet count must be 
>50,000/mcl prior to treatment. Delays for neutropenia at the time of next cycle, or grade 3-4 
neutropenia lasting >7 days during a cycle, will result in Bendamustine dose reduction to 70 
mg/m2 days 1 and 2; Pegylated GCSF or GCSF should be utilized for all subsequent cycles for 
patients delayed for neutropenia. If cytopenia resolve with G-CSF/Peg-GCSF support, the 
bendamustine dose may be re-escalated to 90 mg/m2. 
Dose Adjustments for ofatumumab: 
Immunotherapy Alone: Ofatumumab weekly dosing may be delayed up to 17 days for 
cytopenias or toxicity; Treatment will be delayed until the absolute neutrophil count is > 
1000/mcl; If cycle 1 day 2 ofatumumab therapy is delayed for toxicity this dose will be omitted, 
recommencing with weekly dosing; the dose of ofatumumab will not be decreased. 

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Chemoimmunotherapy: Patients may be delayed up to 17 days for cytopenias or toxicity prior 
to removal from study. Treatment will be delayed until the absolute neutrophil count is > 
1000/mcl and the platelet count is > 75,000/mcl Delays for neutropenia at the time of next 
cycle, or grade 3-4 neutropenia lasting >7 days during a cycle, with Bendamustine dose 
reduction as above; The dose of ofatumumab will not be decreased on study. Pegylated GCSF 
or GCSF should be utilized for all subsequent cycles for patients delayed for neutropenia. If 
cytopenia resolve with G-CSF/Peg-GCSF support, the bendamustine dose may be re- 
escalated to 90 mg/m2. 
The most common adverse event resulting from ofatumumab use is infusion reactions. We will 
interrupt infusion for infusion reactions of any severity. 
• 
For grade 4 infusion reactions, do not resume the infusion. 
• 
For grade 1, 2, or 3 infusion reaction, if the infusion reaction resolves or remains less 
than or equal to grade 2, resume infusion with the following modifications according to 
the initial grade of the infusion reaction: 
o For grade 1 or 2: Infuse at one-half of the previous infusion rate. 
o For grade 3: Infuse at a rate of 12 mL/hour. 
After resuming the infusion, the infusion rate may be increased according to the following table 
or based on patient tolerance. 
 
 
Ofatumumab doses that cannot be completed secondary to infusion reactions will not be made 
up: 
Table 7 
 
Time 
mL/hour 
0 – 30 minutes 
25 
31 – 60 minutes 
50 
61 – 90 minutes 
100 
91 – 120 minutes 
200 
121+ minutes 
400 
 
 
Supportive care: Antiemetics will be provided per institution protocol. Growth factor support with 
Pegylated GCSF or GCSF will be provided as clinically indicated. 
 
 
10.0 EVALUATION DURING TREATMENT/INTERVENTION 

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Assessments prior to each cycle of immunotherapy or chemoimmunotherapy: 
• 
Physical exam 
• 
Karnofsky Performance Status 
• 
Assessment for toxicity will be performed prior to each cycle of chemotherapy. 
• 
Modified Comprehensive Geriatric Assessment (CGA) comorbidity will be done prior to 
cycle 1 and restaging for the immunotherapy arm. For the chemoimmunotherapy arm, 
the CGA will be performed before each cycle and at restaging. For cycle 1 day 1 only, if 
the CGA is completed at screening it does not need to be completed on cycle 1 day 1. 
o Non-English speaking patients are not required to complete the CGA. 
• 
CBC (Patients must have ANC>1000/mcl and Platelets>75,000/mcl) 
o Treatment will be delayed until the absolute neutrophil count is > 1000/mcl and 
the platelet count is > 75,000/mcl. 
• 
Quantitative serum immunoglobulin levels once every other cycle beginning cycle 1 and 
subsequently at each physician visit after conclusion of treatment for 2 years. 
• 
Comprehensive metabolic panel, including serum LDH: 
o For both immunotherapy and chemoimmunotherapy arms: prior to each cycle 
and at restaging. 
 
Interim restaging: 
• 
Interim CT scan of chest, abdomen, and pelvis after 3 cycles of chemoimmunotherapy 
for interim staging per institutional guidelines. 
• 
CT of neck may be obtained as clinically indicated 
• 
MRIs may be used instead of CT scans in patients for whom CT scans are 
contraindicated. 
• 
CMV PCR post cycle 3 of chemoimmunotherapy 
 
Liver monitoring on Ofatumumab: 
• 
If ALT > 3xULN and bilirubin  2xULN (>35% direct bilirubin), ALT > 8xULN, or ALT  
5xULN for more than 2 weeks, ofatumumab will be stopped and patient will be 
withdrawn from study. 
 
o 
Patients with ALT >3xULN and bilirubin >2xULN, must return to clinic and repeat 
liver chemistries in 24 hours, and then twice weekly until liver chemistries (ALT, 
AST, alkaline phosphatase, bilirubin) resolve, stabilize or return to within baseline 
values. 
 
▪ 
A specialist or hepatology consultation is recommended 
▪ 
Liver follow up assessment as per appendix IV 
 
o Patients with ALT > 8xULN, or ALT  5xULN for more than 2 weeks, must return 
to clinic within 24-72 hrs for repeat liver chemistries and then weekly until liver 
chemistries (ALT, AST, alkaline phosphatase, bilirubin) resolve, stabilize or 
return to within baseline values. 
▪ 
Liver follow up assessment as per appendix IV 
 
o Patients with ALT 5xULN who exhibit a decrease to ALT x3xULN, but <5xULN 
and bilirubin <2xULN without hepatitis symptoms or rash, and who can be 
monitored weekly for 4 weeks can continue ofatumumab. 

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▪ 
Patients must return weekly for repeat liver chemistries until they resolve, 
stabilize or return to within baseline. 
• 
If, after 4 weeks of monitoring, ALT <3xULN and bilirubin <2xULN, 
monitor patients twice monthly until liver chemistries normalize or return 
to within baseline values. 
• 
Liver follow up assessment as per appendix IV 
 
Progressive Multifocal Leukoencephalopathy (PML) monitoring while on Ofatumumab: 
• 
Patient will be monitored for signs and symptoms of PML, such as visual disturbances, 
ocular movements, ataxia, and changes in mental status such as disorientation or 
confusion, or any other symptom that may be suggestive of PML in the judgment of the 
investigator. 
 
Table 8: Testing During and After Immunotherapy (Ofatumumab alone) 
 
Immunotherapy (Ofatumumab alone) 
Baseline 
(pretreatment) 
Week 1 
(+/-24hr) 
Week 2 
(+/-24hr) 
Week 3 
(+/-24hr) 
Week 4 
(+/-24hr) 
Restaging 
History, Physical, 
KPS 
X 
X 
X 
X 
X 
X 
Comprehensive 
Geriatric 
Assessment 
X* 
X* 
X 
NIA/NCI 
Comorbidity 
scale 
X 
CBC with diff. § 
X 
X 
X 
X 
X 
X 
Comp§, LDH§ 
X 
X 
X 
X 
X 
X 
Creatinine 
Clearance per 
the Jelliffe 
method or by 12 
or 24 hour urine 
creatinine 
clearance 
X 
X 
HIV 1 and 2 
antibodies 
X 
Pregnancy test 
in pre- 
menopausal 
women 
X 
Serum 
Immunoglobulins 
X 
X 
X 
X 
CT CAP (or MRI 
as clinically 
X 
X 

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indicated) 
Colonoscopy 
with blind biopsy 
if clinically 
indicated and at 
the discretion of 
the investigator 
discretion of 
investigator 
Bone marrow 
Biopsy and 
aspirate with one 
aspirate sample 
for research 
X 
EKG 
X 
Peripheral Blood 
for research 
X 
Hepatitis B 
surface antigen 
and antibody, 
core antibody 
X 
Hepatitis C 
Serology 
X 
*The Comprehensive Geriatric Assessment can either be completed at baseline or week 1 day 1. It does 
not need to be completed at both time points. 
 
Table 9: Testing During and After Chemoimmunotherapy (Ofatumumab and 
Bendamustine) 
Chemoimmunotherapy (Ofatumumab + Bendamustine) 
Baseline 
(pretreatment) 
Cycle 
1 
Cycle 
2 
Cycle 
3 
Cycle 
4 
Cycle 
5 
Cycle 
6 
Restaging 
Window for Tx 
+/- 72 
hr 
+/- 72 
hr 
+/- 72 
hr 
+/- 72 
hr 
+/- 72 
hr 
+/- 72 
hr 
+/- 72 hr 
History, Physical, 
KPS 
X 
X 
X 
X 
X 
X 
X 
X 
Comprehensive 
Geriatric 
Assessment 
X** 
X** 
X 
X 
X 
X 
X 
X 
NIA/NCI 
Comorbidity 
scale 
X 
CBC with diff. § 
X 
X 
X 
X 
X 
X 
X 
X 
Comp§, LDH§ 
X 
X 
X 
X 
X 
X 
X 
X 
Creatinine 
Clearance per 
the Jelliffe 
method or by 12 
or 24 hour urine 
creatinine 
clearance 
X 

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HIV 1 and 2 
antibodies 
X 
Pregnancy test 
in pre- 
menopausal 
women 
X 
Serum 
Immunoglobulins 
X 
X 
X 
X 
X 
Interim restaging 
CT CAP (or MRI 
as clinically 
indicated) 
X 
X 
(prior 
to 
cycle 
4) 
X 
Colonoscopy 
with blind biopsy 
if clinically 
indicated and at 
the discretion of 
the investigator 
discretion of 
investigator 
Bone marrow 
Biopsy and 
aspirate with one 
aspirate sample 
for research 
X 
*X 
EKG 
X 
Peripheral Blood 
for research 
X 
Hepatitis B 
surface antigen 
and antibody, 
core antibody 
X 
Hepatitis C 
Serology 
X 
CMV PCR 
X 
X 
X 
*Bone marrow biopsy to confirm CR if appropriate 
**The Comprehensive Geriatric Assessment can either be completed at baseline or cycle 1 day 1. It 
does not need to be completed at both time points. 
§ Pretreatment Comp, CBC and LDH may be obtained up to 72 hours prior to treatment to allow for 
chemotherapy preparation process 
 
• 
Patients who show a partial or complete response at restaging 8-10 weeks after 
Ofatumumab alone will continue to be restaged with CT CAP every 24 weeks (+/- 2 
weeks) for two years, then every12 months thereafter until disease progresses, or for a 
maximum of 5 years. Also during follow up, a CBC, comprehensive metabolic panel, 
serum LDH, quantitative immunoglobulins, and physical exam will be performed at every 
12 weeks (+/- 2 weeks), for 2 years, then q 6 months (+/- 2 weeks) thereafter until 
disease progresses, or for a maximum of 5 years. 

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• 
Patients who show less than partial response, stable disease, or progression of disease 
at restaging 8-10 weeks after Ofatumumab alone will begin the combination of 
Ofatumumab + Bendamustine within 4 weeks of restaging. 
 
o Schedule of tests and evaluation follows the same schedule as patients originally 
stratified to this treatment arm (See table 9), with the exception that HIV and viral 
Hepatitis serologies, which do not require repeating as repeat baseline testing if 
crossing over to the chemoimmunotherapy arm within 6 months of last screening 
 
• 
Patients who show a partial or complete response at restaging 4-6 weeks after 
Ofatumumab + Bendamustine will continue to be restaged with CT CAP every 24 weeks 
(+/- 2 weeks) for two years, then every 12 months thereafter until disease progresses, or 
for a maximum of 5 years. Also during follow up, a CBC, comprehensive metabolic 
panel, serum LDH, quantitative immunoglobulins, and a physical exam will be performed 
every 12 weeks (+/- 2 weeks), for 2 years, then q 6 months (+/- 2 weeks) thereafter until 
disease progresses, or for a maximum of 5 years. 
 
Response Criteria as per Cheson et al, JCO 1999, Response criteria for malignant lymphoma 
(see section 12.0). 
 
 
11.0 TOXICITIES/SIDE EFFECTS 
Bendamustine 
• 
Myelosuppression 
Patients treated with Bendamustine are likely to experience myelosuppression. In 
the two NHL studies, 98% of patients had Grade 3-4 myelosuppression. Three 
patients (2%) died from myelosuppression-related adverse reactions; one each 
from 
neutropenic 
sepsis, 
diffuse 
alveolar 
hemorrhage 
with 
Grade 
3 
thrombocytopenia, and pneumonia from an opportunistic infection (CMV). 
Hematologic nadirs can be observed predominantly in the third week of therapy. 
Hematologic nadirs may require dose delays if recovery to the recommended 
values have not occurred by the first day of the next scheduled cycle. 
• 
Infections 
Infection, including pneumonia and sepsis, has been reported in patients in 
clinical trials and in post-marketing reports. Infection has been associated with 
hospitalization, septic shock and death. Patients with myelosuppression following 
treatment with Bendamustine are more susceptible to infections. 
• 
Infusion Reactions and Anaphylaxis 
Infusion reactions to Bendamustine have occurred commonly in clinical trials. 
Symptoms include fever, chills, pruritus and rash. In rare instances severe 
anaphylactic and anaphylactoid reactions have occurred, particularly in the 
second and subsequent cycles of therapy. 
• 
Tumor Lysis Syndrome 
Tumor lysis syndrome associated with Bendamustine treatment has been 
reported in patients in clinical trials and in post-marketing reports. The onset 
tends to be within the first treatment cycle of Bendamustine and, without 
intervention, may lead to acute renal failure and death. Preventive measures 

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include maintaining adequate volume status, and close monitoring of blood 
chemistry, particularly potassium and uric acid levels. Allopurinol has also been 
used during the beginning of Bendamustine therapy. However, there may be an 
increased risk of severe skin toxicity when Bendamustine and 
allopurinol are administered concomitantly 
• 
Skin Reactions 
A number of skin reactions have been reported in clinical trials and post- 
marketing safety reports. These events have included rash, toxic skin reactions 
and bullous exanthema. Some events occurred when Bendamustine was given 
in combination with other anticancer agents, so the precise relationship to 
Bendamustine is uncertain. In a study of Bendamustine (90 mg/m2) in 
combination with rituximab, one case of toxic epidermal necrolysis (TEN) 
occurred. TEN has been reported for rituximab Cases of Stevens-Johnson 
syndrome (SJS) and TEN, some fatal, have been reported when Bendamustine 
was administered concomitantly with allopurinol and other medications known to 
cause these syndromes. The relationship to Bendamustine cannot be 
determined. Where skin reactions occur, they may be progressive and increase 
in severity with further treatment. Therefore, patients with skin reactions should 
be monitored closely. If skin reactions are severe or progressive, Bendamustine 
should be withheld or discontinued. 
• 
Other Malignancies 
There are reports of pre-malignant and malignant diseases that have developed 
in patients who have been treated with Bendamustine, including myelodysplastic 
syndrome, myeloproliferative disorders, acute myeloid leukemia and bronchial 
carcinoma. The association with Bendamustine therapy has not been 
determined. 
• 
Extravasation 
There are postmarketing reports of bendamustine extravasations resulting in 
hospitalizations from erythema, marked swelling, and pain. Precautions should 
be taken to avoid extravasation, including monitoring of the intravenous infusion 
site for redness, swelling, pain, infection, and necrosis during and after 
administration of Bendamustine. 
• 
Gastrointestinal Side effects 
Nausea and vomiting, constipation, diarrhea, stomatitis, decreased appetite. In 
very rare cases, alopecia. 
• 
Metabolic Side Effects 
Hypercalcemia, renal insufficiency, and adrenal hemorrhage, though rare. 
• 
Fluid Overload 
Non cardiogenic pulmonary edema may occur, though rare. 
 
Ofatumumab 
• 
Infusion Reactions 
Ofatumumab 
can 
cause 
serious 
infusion 
reactions 
manifesting 
as 
bronchospasm, dyspnea, laryngeal edema, pulmonary edema, flushing, 
hypertension, hypotension, syncope, cardiac ischemia/infarction, back pain, 
abdominal pain, pyrexia, rash, urticaria, and angioedema. Infusion reactions 
occur more frequently with the first 2 infusions. In a study of patients with 
moderate to severe chronic obstructive pulmonary disease, an indication for 

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which Ofatumumab is not approved, 2 of 5 patients developed Grade 3 
bronchospasm during infusion. 
• 
Cytopenias 
Prolonged (≥1 week) severe neutropenia and thrombocytopenia can occur with 
Ofatumumab. 
• 
Progressive Multifocal Leukoencephalopathy 
Progressive multifocal leukoencephalopathy (PML), including fatal PML, can 
occur with Ofatumumab. Consider PML in any patient with new onset of or 
changes 
in 
pre-existing 
neurological 
signs 
or 
symptoms. 
Discontinue 
Ofatumumab if PML is suspected, and initiate evaluation for PML including 
consultation with a neurologist, brain MRI, and lumbar puncture. 
• 
Hepatitis B Reactivation 
Hepatitis B reactivation, including fulminant hepatitis and death, occurs with other 
monoclonal antibodies directed against CD20. Hepatitis B virus (HBV) infection, 
including fatal infection, can occur in patients taking ofatumumab. 
• 
Intestinal Obstruction 
Obstruction of the small intestine can occur in patients receiving Ofatumumab. 
• 
Immunizations 
The safety of immunization with live viral vaccines during or following 
administration of Ofatumumab has not been studied. Live viral vaccines should 
not be administered to patients who have recently received Ofatumumab since 
the ability to generate an immune response to any vaccine following 
administration of Ofatumumab has not been studied. 
• 
Gastrointestinal Side Effects 
Diarrhea 
• 
Other side effects 
Chills, fever, fatigue. 
12.0 CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
From Cheson et al JCO 1999, Response criteria for malignant lymphoma. 
Measurable disease 
Measurable lesions are defined as those that can be accurately measured in at least one 
dimension (longest diameter to be recorded) as >20 mm with conventional CT scan. All tumor 
measurements must be recorded in millimeters (or decimal fractions of centimeters). 
Non-measurable disease 
 
All other lesions (or sites of disease), including small lesions (longest diameter <20 mm with 
conventional techniques or <10 mm using spiral CT scan), are considered non-measurable 
disease. Bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, 
lymphangitis cutis/pulmonis, inflammatory breast disease, abdominal masses (not followed by 
CT or MRI), and cystic lesions are all non-measurable. 

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CR requires the following: 
 
1. Complete disappearance of all detectable clinical and radiographic evidence of 
disease and disappearance of all disease-related symptoms if present before 
therapy, and normalization of those biochemical abnormalities (eg, lactate 
dehydrogenase [LDH]) definitely assignable to NHL. 
2. All lymph nodes and nodal masses must have regressed to normal size (≤ 1.5 cm in 
their greatest transverse diameter for nodes > 1.5 cm before therapy). Previously 
involved nodes that were 1.1 to 1.5 cm in their greatest transverse diameter before 
treatment must have decreased to ≤ 1 cm in their greatest transverse diameter after 
treatment, or by more than 75% in the sum of the products of the greatest diameters 
(SPD). 
3. The spleen, if considered to be enlarged before therapy on the basis of a CT scan, 
must have regressed in size and must not be palpable on physical examination. 
However, no normal size can be specified because of the difficulties in accurately 
evaluating splenic and hepatic size. For instance, spleens thought to be of normal 
size may contain lymphoma, whereas an enlarged spleen may not necessarily reflect 
the presence of lymphoma but variations in anatomy, blood volume, the use of 
hematopoietic growth factors, or other causes. The determination of splenic volume 
or splenic index by CT scan is cumbersome and not widely used.35,36 Any 
macroscopic nodules in any organs detectable on imaging techniques should no 
longer be present. Similarly, other organs considered to be enlarged before therapy 
due to involvement by lymphoma, such as liver and kidneys, must have decreased in 
size. 
4. If the bone marrow was involved by lymphoma before treatment, the infiltrate must 
be cleared on repeat bone marrow aspirate and biopsy of the same site. The sample 
on which this determination is made must be adequate (≥ 20 mm biopsy core). Flow 
cytometric, molecular, or cytogenetic studies are not considered part of routine 
assessment to document persistent disease at the present time. These studies 
should only be incorporated into trials examining important research questions. 
CR/unconfirmed (CRu) includes those patients who fulfill criteria 1 and 3 above, but with 
one or more of the following features: 
1. A residual lymph node mass greater than 1.5 cm in greatest transverse diameter that 
has regressed by more than 75% in the SPD. Individual nodes that were previously 
confluent must have regressed by more than 75% in their SPD compared with the 
size of the original mass. 
2. Indeterminate bone marrow (increased number or size of aggregates without 
cytologic or architectural atypia). 
PR requires the following: 

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1. ≥ 50% decrease in SPD of the six largest dominant nodes or nodal masses. These 
nodes or masses should be selected according to the following features: (a) they 
should be clearly measurable in at least two perpendicular dimensions, (b) they 
should be from as disparate regions of the body as possible, and (c) they should 
include mediastinal and retroperitoneal areas of disease whenever these sites are 
involved. 
2. No increase in the size of the other nodes, liver, or spleen. 
3. Splenic and hepatic nodules must regress by at least 50% in the SPD. 
4. With the exception of splenic and hepatic nodules, involvement of other organs is 
considered assessable and not measurable disease. 
5. Bone marrow assessment is irrelevant for determination of a PR because it is 
assessable and not measurable disease; however, if positive, the cell type should be 
specified in the report, eg, large-cell lymphoma or low-grade lymphoma (ie, small, 
lymphocytic small cleaved, or mixed small and large cells). 
6. No new sites of disease. 
 
Stable disease is defined as less than a PR (see above) but is not progressive disease 
(see below). 
Relapsed disease (CR, CRu) requires the following: 
 
1. Appearance of any new lesion or increase by ≥ 50% in the size of previously 
involved sites. 
2.  ≥ 50% increase in greatest diameter of any previously identified node greater than 1 
cm in its short axis or in the SPD of more than one node. 
Progressive disease (PR, nonresponders) requires the following: 
 
1. ≥ 50% increase from nadir in the SPD of any previously identified abnormal node for 
PRs or nonresponders. 
2. Appearance of any new lesion during or at the end of therapy. 
 
Response Assessment 
Response is currently assessed on the basis of clinical, radiologic, and pathologic (ie, bone 
marrow) criteria. 
1. CT scans remain the standard for evaluation of nodal disease. Thoracic, abdominal, 
and pelvic CT scans are recommended even if those areas were not initially involved 
because of the unpredictable pattern of recurrence in NHL. Studies should be 
performed no later than 2 months after treatment has been completed to assess 
response. This interval may vary with the type of treatment, eg, a longer period may 
be more appropriate for biologic agents where the anticipated time to response may 
be greater. 

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2. A bone marrow aspirate and biopsy should only be performed to confirm a CR if they 
were initially positive or if it is clinically indicated by new abnormalities in the 
peripheral blood counts or blood smear. 
 
 
 
 
 
 
 
 
Table 10 
 
Response 
Category 
Physical 
Examination 
Lymph 
Nodes 
Lymph Node 
Masses 
Bone Marrow 
CR 
Normal 
Normal 
Normal 
Normal 
CRu 
Normal 
Normal 
Normal 
Indeterminate 
Normal 
Normal 
> 75% 
decrease 
Normal or 
indeterminate 
PR 
Normal 
Normal 
Normal 
Positive 
Normal 
50% 
decrease 
50% 
decrease 
Irrelevant 
Decrease in 
liver/spleen 
50% 
decrease 
50% 
decrease 
Irrelevant 
Relapse/progression Enlarging 
liver/spleen; new 
sites 
New or 
increased 
New or 
increased 
Reappearance 
Definition of end points: 
 
Overall Survival 
Overall survival is the least ambiguous end point, although it usually is not optimal to use for a 
lymphoma clinical trial. Overall survival is defined as the time from entry onto the clinical trial 
(random assignment in a phase III study) until death as a result of any cause. Survival, as well 
as other time-dependent variables (PFS, event-free survival) should be measured in a 
randomized trial because data derived from historical controls are unreliable and subject to bias. 

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Survival should be measured in the intent-to-treat population, including all patients even if they 
did not fulfill the eligibility criteria. A per-protocol analysis includes all patients who received the 
treatment to which they were assigned. A treatment-given analysis includes all patients who 
received a particular treatment. Both of these types of analyses should be interpreted with 
caution because they are subject to considerable bias. 
PFS 
PFS is defined as the time from entry onto a study until lymphoma progression or death as a 
result of any cause. PFS is often considered the preferred end point in lymphoma clinical trials, 
especially those involving incurable histologic subtypes (eg, follicular, other low-grade 
lymphoma, or mantle cell lymphoma). PFS reflects tumor growth, and therefore is interpretable 
earlier than the end point of overall survival. In addition, PFS is not confounded by the 
administration of subsequent therapy. However, in studies in which failure to respond without 
progression is considered an indication for another therapy, such patients should be censored 
at that point for the progression analysis. Whether a prolongation of PFS represents direct 
clinical benefit or is an acceptable surrogate for clinical benefit depends on the magnitude of the 
effect and the risk-benefit ratio of the therapy under investigation. Unlike survival, the precise 
date of progression is generally unknown. It may be defined as the first date of documentation 
of a new lesion or enlargement of a previous lesion, or the date of the scheduled clinic visit 
immediately after radiologic assessment has been completed. When there is missing 
information, censoring of the data may be defined as the last date at which progression status 
was assessed adequately or the first date of unscheduled new antilymphoma treatment. 
Response Duration 
Response duration is from the time when criteria for response (i.e., CR or PR) are met, for 
which the event is the first documentation of relapse or progression. 
 
13.0 
CRITERIA FOR REMOVAL FROM STUDY 
• 
Patients found at any time to be ineligible as designated in section 6.0. 
• 
Patients who request to be removed from the study. This will not compromise the 
care they receive at this institution. 
• 
Patients who are non-compliant with treatment or follow-up. 
• 
Patients who develop unacceptable toxicity 
• 
Patients that develop progression of disease after 4 cycles of the combination of 
ofatumumab and bendamustine. These patients may be offered alternate treatments 
or similar treatment off protocol. 

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14.0 
BIOSTATISTICS 
This is a Simon 2-stage study investigating the activity of ofatumumab alone or in conjunction 
with bendamustine for non-transplant eligible untreated mantle cell lymphoma patients. The 
study design will allow for an estimation of the single agent response in patients at low biologic 
risk for immediate progression. The combined regimen will assess the efficacy of a chemo- 
immunotherapy program in patients with need for cytoreductive therapy (high risk). 
Immunotherapy alone: 
For the low risk arm, it is expected that the new regimen will improve the overall response rate 
(ORR) from 40% to 60%. To this end, an optimal Simon 2-stage design will be used. In stage 1, 
12 patients will enter the study. If 5 or less patients respond, then the study will be terminated 
early and declared to have a negative result. If 6 or more patients respond, enrollment will be 
extended to 38 patients. This is, at stage 2, an additional 26 patients will be enrolled. The 
treatment will be declared effective and worthy of further testing if 19 or more patients respond 
among the total 38 patients entered. This optimal Simon 2-stage design has a type I error rate 
of 0.10 and type II error rate at 0.20. The probability of early stopping under the null hypothesis 
is 67%. The probability of early stopping under the alternative hypothesis is 16%. 
Chemoimmunotherapy: 
 
For the high risk arm, it is expected that the new regimen will improve the complete response 
(CR) rate from 40% to 60%. Therefore the same design as above will be used. The decision to 
utilize complete remission rate rather than ORR is based on previous research which showed 
that better quality remissions (eg. Increased CR) are correlated with improved duration of 
benefit. Furthermore, the ORR with chemoimmunotherapy are generally high (>90%), requiring 
large numbers of patients to assess for small difference with less clear clinical benefit. 
Patients will be followed per every 3 months with imaging (CT CAP) every 3 months for the first 
2 years; subsequently, patients will be seen every 3 months with CT CAP every 6 months until 
progression of disease or a maximum of five years. 
We anticipate accrual in 24-36 months. 
The secondary objectives contain analysis of the following four survival endpoints: Overall 
survival (calculated from registration to death); Progression free survival (calculated from 
registration until progression or death); Remission duration (calculated from confirmation of CR 

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to progression); Response duration (calculated from confirmation of response (CR/PR) to 
progression. The first two endpoints will be analyzed using Kaplan-Meier estimation, and log- 
rank tests or Cox regression models when covariates are involved. The last two endpoints will 
be analyzed using competing risks tools (with death as a competing risk for progression), and 
will be done on the subsets of patients who have CR or CR/PR. 
As part of an exploratory analysis, patients who initially received immunotherapy induction and 
crossed over to chemoimmunotherapy at progression will be analyzed from the time of initial 
enrollment until progression or death. This will allow for assessment of the duration of benefit for 
sequential immunotherapy -> immunochemotherapy program in elderly patients as a strategy to 
delay exposure to chemotherapy. Additionally, exploratory analysis of chemoimmunotherapy 
patients treated previously with immunotherapy induction vs. those directly enrolled onto 
chemoimmunotherapy will be assessed for toxicity, response rate and efficacy outcomes. 
Toxicities (number of occurrences and grades) will be summarized and tabulated. Additionally, 
the CGA will be assessed as a tool to predict toxicity on study in an exploratory analysis. 
The measurement of miRNA expression is dichotomized as either over-expressed or under- 
expressed, and proliferation is dichotomized as either ≥30% or <30%. Thus a contingency table 
will be constructed and a Fisher’s exact test will be used to examine the correlation. 
The standard response criteria for Malignant Lymphoma (Cheson et. Al JCO 25 (5) 2007) 
currently do not recommend PET imaging for incurable routinely FDG avid lymphomas, 
including follicular lymphoma and mantle-cell lymphoma. As such, PET imaging is not a 
protocol defined pre-treatment evaluation. Furthermore, PET imaging post-treatment for 
confirmation of response is not a standard of care based on these same criteria (Cheson 2007) 
for Mantle cell lymphoma. Routine surveillance PET imaging is also not supported by current 
data. Consequently, the clinical trial relies on CT scans to determine baseline pretreatment 
disease state and response and has no protocol specified PET imaging. 
Nevertheless, PET scanning is frequently employed in the clinical management of mantle cell 
lymphoma patients and may convey important information about disease burden and response 
to therapy. In instances where a PET scan has been obtained at the discretion of the treating 
physician, we will prospectively collect this data. This information will not be utilized to 
determine protocol response, but may be used in a purely exploratory analysis post hoc. 

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Primary Endpoints: 
 
• 
Immunotherapy induction (low risk patients) the ORR (CR+PR) rate to ofatumumab 
• 
Chemoimmunotherapy induction (High Risk patients) the CR to ofatumumab + 
Bendamustine 
Secondary Endpoints: 
 
• 
OS, PFS, DFS, DR 
• 
ORR for chemoimmunotherapy induction 
• 
Safety and toxicity profile according to Common Terminology Criteria for Adverse 
Events, version 4.0 (CTCAE v4.0). The ability for the CGA to predict toxicity will be 
explored. 
These outcome parameters will be assessed for each cohort independently. 
 
 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION 
PROCEDURES 
15.1 
Research Participant Registration 
 
 
Confirm eligibility as defined in the section entitled Criteria for Patient/Subject Eligibility. 
Obtain informed consent, by following procedures defined in section entitled Informed 
Consent Procedures. 
During the registration process registering individuals will be required to complete a 
protocol specific Eligibility Checklist. 
All participants must be registered through the Protocol Participant Registration (PPR) 
Office at Memorial Sloan-Kettering Cancer Center. PPR is available Monday through 
Friday from 8:30am – 5:30pm at 646-735-8000. Registrations must be submitted via the 
PPR Electronic Registration System (http://ppr/).The completed signature page of the 
written consent/RA or verbal script/RA, a completed Eligibility Checklist and other 
relevant documents must be uploaded via the PPR Electronic Registration System. 
15.2 
Randomization 
No randomization is to take place. 

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16.0 
DATA MANAGEMENT ISSUES 
A Research Study Assistant (RSA) will be assigned to the study. The responsibilities of the 
RSA include project compliance, data collection, abstraction and entry, data reporting, 
regulatory monitoring, problem resolution and prioritization, and coordination of the activities 
of the protocol study team. The data collected for this study will be entered into a secure 
database. Source documentation will be available to support the computerized patient 
record. 
16.1 
Quality Assurance 
Registration reports will be generated to monitor patient accruals and completeness of 
registration data. Routine data quality reports will be generated to assess missing data 
and inconsistencies. Accrual rates and extent and accuracy of evaluations and follow-up 
will be monitored periodically throughout the study period and potential problems will be 
brought to the attention of the study team for discussion and action. Random-sample 
data quality and protocol compliance audits will be conducted by the study team, at a 
minimum of two times per year, more frequently if indicated. 
 
16.2 
Data and Safety Monitoring 
The Data and Safety Monitoring (DSM) Plans at Memorial Sloan-Kettering Cancer Center were 
approved by the National Cancer Institute in September 2001. The plans address the new 
policies set forth by the NCI in the document entitled “Policy of the National Cancer Institute for 
Data 
and 
Safety 
Monitoring 
of 
Clinical 
Trials” 
which 
can 
be 
found 
at: 
http://cancertrials.nci.nih.gov/researchesr/dsm/index.html. The DSM Plans at MSKCC were 
established and are monitored by the Office of Clinical Research. The MSKCC Data and Safety 
Monitoring 
Plans 
can 
be 
found 
on 
the 
MSKCC 
Intranet 
at: 
http://mskweb2.mskcc.org/irb/index.htm 
There are several different mechanisms by which clinical trials are monitored for data, safety 
and quality. There are institutional processes in place for quality assurance (e.g., protocol 
monitoring, compliance and data verification audits, therapeutic response, and staff education 
on clinical research QA) and departmental procedures for quality control, plus there are two 
institutional committees that are responsible for monitoring the activities of our clinical trials 
programs. The committees: Data and Safety Monitoring Committee (DSMC) for Phase I and II 

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clinical trials, and the Data and Safety Monitoring Board (DSMB) for Phase III clinical trials, 
report to the Center’s Research Council and Institutional Review Board. 
During the protocol development and review process, each protocol will be assessed for its level 
of risk and degree of monitoring required. Every type of protocol (e.g., NIH sponsored, in-house 
sponsored, industrial sponsored, NIC cooperative group, etc.) will be addressed and the 
monitoring procedures will be established at the time of protocol activation. 
 
 
 
 
 
 
 
 
16.3 Safety Monitoring for Ofatumumab: 
Safety Definitions 
Adverse Events: 
Any untoward medical occurrence in a subject or clinical investigation subject, temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product. 
Events meeting the definition of an AE include: 
• 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other 
safety assessments e.g., ECGs, radiological scans, vital signs measurements), including 
those that worsen from baseline, and felt to be clinically significant in the medial and 
scientific judgment of the investigator 
• 
Exacerbation of a chronic or intermittent pre-existing condition including either an increase 
in frequency and/or intensity of the condition 
• 
New conditions detected or diagnosed after investigational product administration even 
though it may have been present prior to the start of the study 
• 
Signs, symptoms, or the clinical sequelae of a suspected interaction 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either investigational 
product or a concomitant medication (overdose per se will not be reported as an AE/SAE) 
“Lack of efficacy” or “failure of expected pharmacological action” per se will not be reported as 
an AE or SAE. However, the signs and symptoms and/or clinical sequelae resulting from lack of 
efficacy will be reported if they fulfill the definition of an AE or SAE. 
Events that do not meet the definition of an AE include: 

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• 
Any clinically significant abnormal laboratory finding or other abnormal safety assessments 
that is associated with the underlying disease, unless judged by the investigator to be more 
severe than expected for the subject’s condition. 
• 
The disease/disorder being studied, or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the subject’s 
condition 
• 
Medical or surgical procedure (e.g., endoscopy, appendectomy); the condition that leads to 
the procedure is an AE 
• 
Situations where an untoward medical occurrence did not occur (social and/or convenience 
admission to a hospital) 
• 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen 
• 
B cell depletion and hypogammaglobulinemia due to ofatumumab treatment 
 
Definition of a SAE 
A serious adverse event is any untoward medical occurrence that, at any dose: 
a. 
Results in death 
b. 
Is life-threatening 
NOTE: The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
subject was at risk of death at the time of the event. It does not refer to an event, which 
hypothetically might have caused death, if it were more severe. 
c. 
Requires hospitalization or prolongation of existing hospitalization 
NOTE: In general, hospitalization signifies that the subject has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
out-patient setting. Complications that occur during hospitalization are AEs. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE 
should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE. 
An overnight hospital stay due to slow infusion rates will not be considered a Serious 
Adverse Event. 
d. 
Results in disability/incapacity, or 
NOTE: The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. This definition is not intended to include experiences of relatively 
minor medical significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (e.g. sprained ankle) which may interfere or prevent 
everyday life functions but do not constitute a substantial disruption. 
e. 
Is a congenital anomaly/birth defect 

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f. 
Medical or scientific judgment should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the 
subject or may require medical or surgical intervention to prevent one of the other outcomes 
listed in the above definition. These should also be considered serious. Examples of such 
events are invasive or malignant cancers, intensive treatment in an emergency room or at 
home for allergic bronchospasm, blood dyscrasias or convulsions that do not result in 
hospitalization, or development of drug dependency or drug abuse. 
Laboratory and Other Safety Assessment Abnormalities Reported as AEs and SAEs 
• 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (e.g., ECGs, radiological scans, vital signs measurements), 
including those that worsen from baseline, and felt to be clinically significant in the 
medical and scientific judgment of the investigator are to be recorded as AEs or SAEs. 
• 
All events meeting liver stopping criteria must be recorded as an SAE. 
• 
However, any clinically significant safety assessments that are associated with the 
underlying disease, unless judged by the investigator to be more severe than expected 
for the subject’s condition, are not to be reported as AEs or SAEs. 
• 
B cell depletion, IgG below LLN, low CD19+ count, and hypogammaglobulinemia due to 
treatment with ofatumumab are not to be reported as AEs or SAEs. 
• 
Infusion related AEs may lead to a prolonged infusion time. Overnight stay at the 
hospital due to slow infusion rate is not to be reported as a SAE. 
 
Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as SAEs 
An event which is part of the natural course of the disease under study (i.e., disease 
progression) does not need to be reported as an SAE. However, if the progression of the 
underlying disease is greater than that which would normally be expected for the subject, or if 
the investigator considers that there was a causal relationship between treatment with 
investigational product or protocol design/procedures and the disease progression, then this 
must be reported as an SAE. 
Time Period and Frequency of Detecting and SAEs 
Once an investigator determines that an event meets the protocol definition of an SAE, the SAE 
will be reported to GSK within 24 hours of being notified of the event. All SAEs regardless of 
relationship to investigational product will be collected from the first dose of investigational 
product to after the last dose of investigational product (minimum of 6 months or until the end of 
the follow-up period whichever is longer). All SAEs regardless of causality will be collected until 
the end of the follow-up period. 
From the time a subject consents to participate in and completes the study all SAEs assessed 
as related to study participation (e.g., protocol-mandated procedures, invasive tests, or 
change in existing therapy) or related Ofatumumab, will be reported promptly to GSK. 
Any SAE brought to the investigator’s attention after the subject has completed the study and 
considered by the investigator as possibly related to investigational product must be reported to 
GSK. 

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Pregnancy 
Any pregnancy that occurs during study participation must be reported to GSK. To ensure 
subject safety, each pregnancy must be reported to GSK within 2 weeks of learning of its 
occurrence. The pregnancy must be followed up to determine outcome (including premature 
termination) and status of mother and child. Pregnancy complications and elective terminations 
for medical reasons must be reported as an AE or SAE. Spontaneous abortions must be 
reported as an SAE. 
Any SAE occurring in association with a pregnancy, brought to the investigator’s attention after 
the subject has completed the study and considered by the investigator as possibly related to 
the investigational product, must be promptly reported to GSK. 
In addition, the investigator must attempt to collect pregnancy information on any female 
partners of male study subjects who become pregnant while the subject is enrolled in the study. 
Pregnancy information must be reported to GSK as described above. 

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17.0 
PROTECTION OF HUMAN SUBJECTS 
Potential risks to human subjects include myelosuppression, infections, infusion related reactions 
to bendamustine and ofatumumab, tumor lysis syndrome, skin reactions, secondary malignancies 
such as myelodysplastic syndrome, myeloproliferative disorders, extravasation, cytopenias, PML, 
Hepatitis B reactivation, and intestinal obstruction. All efforts will be made to avoid any 
complication by completely reviewing patients’ symptoms, providing appropriate management, 
and monitoring blood tests. 
 
Costs to the patient (third party insurer) will include the cost of chemotherapy and hospitalization, 
blood tests and diagnostic studies, office visits, and those admissions which may be required as a 
consequence of treatment-related complications. 
 
17.1 
Privacy 
MSKCC’s Privacy Office may allow the use and disclosure of protected health information 
pursuant to a completed and signed Research Authorization form. The use and disclosure of 
protected health information will be limited to the individuals described in the Research 
Authorization form. A Research Authorization form must be completed by the Principal 
Investigator and approved by the IRB and Privacy Board. 
17.2 
Serious Adverse Event (SAE) Reporting 
 
 
 
 
An adverse event is considered serious if it results in ANY of the following outcomes: 
• 
Death 
• 
A life-threatening adverse event 
• 
An adverse event that results in inpatient hospitalization or prolongation of existing 
hospitalization 
• 
A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
• 
A congenital anomaly/birth defect 
• 
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 
Note: Hospital admission for a planned procedure/disease treatment is not considered an 
SAE. 

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SAE reporting is required as soon as the participant signs consent. SAE reporting is 
required for 30-days after the participant’s last investigational treatment or intervention. Any 
events that occur after the 30-day period and that are at least possibly related to protocol 
treatment must be reported. 
 
If an SAE requires submission to the IRB office per IRB SOP RR-408 ‘Reporting of Serious 
Adverse Events’, the SAE report must be sent to the IRB within 5 calendar days of the event. 
The IRB requires a Clinical Research Database (CRDB) SAE report be submitted 
electronically to the SAE Office as follows: 
For IND/IDE trials: Reports that include a Grade 5 SAE should be sent to 
saegrade5@mskcc.org. All other reports should be sent to saemskind@mskcc.org. 
 
The report should contain the following information: 
Fields populated from CRDB: 
• 
Subject’s initials 
• 
Medical record number 
• 
Disease/histology (if applicable) 
• 
Protocol number and title 
Data needing to be entered: 
• 
The date the adverse event occurred 
• 
The adverse event 
• 
The grade of the event 
• 
Relationship of the adverse event to the treatment (drug, device, or intervention) 
• 
If the AE was expected 
• 
The severity of the AE 
• 
The intervention 
• 
Detailed text that includes the following 
o A explanation of how the AE was handled 
o A description of the subject’s condition 
o Indication if the subject remains on the study 
• 
If an amendment will need to be made to the protocol and/or consent form 
• 
If the SAE is an Unanticipated Problem 
The PI’s signature and the date it was signed are required on the completed report. 
For IND/IDE protocols: 
The CRDB SAE report should be completed as per above instructions. If appropriate, the 
report will be forwarded to the FDA by the SAE staff through the IND Office 
 
17.2.1 Reporting Serious Adverse Events to GSK: 

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All Serious Adverse Events including life-threatening events resulting in required 
hospitalization, disability, congenital anomaly, death, or progression of the disease being 
greater than expected. In the event that the investigator identifies an SAE according to 
protocol definitions, the SAE will be reported to GSK within 24 hours of identification of the 
SAE after reporting to the IRB. 
Send to: GlaxoSmithKline 
Attn: Gaetano Bonifacio, MD 
Medical Director, Clinical Development, R&D/Medical Affairs, North America 
GlaxoSmithKline Oncology, 1250 S. Collegeville Road, Collegeville, PA 19426 
Phone number: (610) 917-5239 
Fax Number: 1.484.902.3041 
Email: Gaetano.a.bonifacio@gsk.com 
 
18.0 
INFORMED CONSENT PROCEDURES 
Before protocol-specified procedures are carried out, consenting professionals will explain 
full details of the protocol and study procedures as well as the risks involved to participants 
prior to their inclusion in the study. Participants will also be informed that they are free to 
withdraw from the study at any time. All participants must sign an IRB/PB-approved consent 
form indicating their consent to participate. This consent form meets the requirements of the 
Code of Federal Regulations and the Institutional Review Board/Privacy Board of this Center. 
The consent form will include the following: 
1. The nature and objectives, potential risks and benefits of the intended study. 
2. The length of study and the likely follow-up required. 
3. Alternatives to the proposed study. (This will include available standard and 
investigational therapies. In addition, patients will be offered an option of supportive 
care for therapeutic studies.) 
4. The name of the investigator(s) responsible for the protocol. 
5. The right of the participant to accept or refuse study interventions/interactions and to 
withdraw from participation at any time. 
Before any protocol-specific procedures can be carried out, the consenting professional will 
fully explain the aspects of patient privacy concerning research specific information. In 
addition to signing the IRB Informed Consent, all patients must agree to the Research 
Authorization component of the informed consent form. 
Each participant and consenting professional will sign the consent form. The participant must 
receive a copy of the signed informed consent form. 
 
Participation is voluntary. The consenting physician will inform patients of their diagnosis, current 
treatment options, including standard treatment, and the risks, benefits and experimental nature 
of this treatment program. All patients will be required to sign a statement of informed consent 

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that conforms to FDA and IRB guidelines. Written consent will be obtained by individuals 
specified in this protocol. Registration of patients is described in section 15.0. All patients will be 
asked to sign a research authorization form. 
 
 
19.0 
REFERENCES 
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23. Hagenbeek et al First clinical use of ofatumumab a novel full human anti CD 20 monoclonal 
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33. Romaguera, J. High Rate of Durable Remissions After Treatment of Newly Diagnosed 
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34. Romaguera, J et al. Untreated aggressive mantle cell lymphoma: results with intensive 
chemotherapy without stem cell transplant in elderly patients. Leuk Lymphoma. 2000 
Sep;39(1-2):77-85. 
 
35. Rummel M., et al. Bendamustine Plus Rituximab Is Effective and Has a 
Favorable Toxicity Profile in the Treatment of Mantle Cell and Low-Grade Non-Hodgkin’s 
Lymphoma. JCO 2005; 23: 3383-3389 
36. Robinson K., et al. Phase II Multicenter Study of Bendamustine Plus Rituximab in Patients 
With Relapsed Indolent B-Cell and Mantle Cell Non-Hodgkin’s Lymphoma. JCO 2008; 26: 
4473-4479. 
 
37. Rummel M., et al. Bendamustine Plus Rituximab Is Superior in Respect of Progression Free 
Survival and CR Rate When Compared to CHOP Plus Rituximab as First-Line Treatment of 
Patients with Advanced Follicular, Indolent, and Mantle Cell Lymphomas: Final Results of a 
Randomized Phase III Study of the StiL (Study Group Indolent Lymphomas, Germany). 
Blood (ASH Annual Meeting Abstracts) 2009, Abstract 405. 
 
38. Teeling J., et al. Characterization of new human CD 20 monoclonal abs with potent cytolytic 
activity against NHL. Blood 2004; 104, 1793-1800. 
 
39. Coiffier B., et al. Safety and efficacy of ofatumumab, a fully humanized monoclonal anti CD 
20 antibody in patients with relapsed or refractory B cell chronic lymphocytic leukemia: A 
Phase 1-2 Study. Blood 2008; 111, 1094-1100. 
 
40. Osterborg A., et al Ofatumumab (HuMax-CD20), a Novel CD20 Monoclonal Antibody, Is An 
Active Treatment for Patients with CLL Refractory to Both Fludarabine and Alemtuzumab or 
Bulky Fludarabine-Refractory Disease: Results from the Planned Interim Analysis of An 
International Pivotal Trial. Blood (ASH Annual Meeting Abstracts) 2008, Abstract 328. 
 
41. Wierda W., et al. Ofatumumab As Single-Agent CD20 Immunotherapy in Fludarabine- 
Refractory Chronic Lymphocytic Leukemia. JCO 2010; 28: 1749-1755. 

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42. Lim S., et al. Anti-CD20 monoclonal antibodies: historical and future perspectives. 
Haematologica. 2010; 95:135-143 
43. Ghielmin et al. The effect of Rituximab on patients with follicular and mantle cell lymphoma. 
Ann Onc 2000; 11: S123-126. 
 
44. Foran et al. Treatment of mantel cell lymphoma with Rituximab (chimeric monoclonal anti- 
CD20 antibody): Analysis of factors associated with response. Ann Onc 2000; 11: @117- 
121. 
 
45. Friedberg et al. Bendamustine in Patients With Rituximab-Refractory Indolent and 
Transformed Non-Hodgkin's Lymphoma: Results From a Phase II Multicenter, Single-Agent 
Study. JCO 2008; 10: 204-210 
 
46. Czuczman et al. Ofatumumab combined with CHOP in previously untreated patients with 
follicular lymphoma (FL). JCO 28:15s, 2010 (suppl; abstr 8042) 
 
47. Nguyen et al. IDEC-C2B8 anti-CD20 (Rituximab) immunotherapy in patients with low-grade 
non-Hodgkin’s lymphoma and lymphoproliferative disorders: evaluation of response on 48 
patients. Eur J Hem 1999; 62: 76-82. 
 
48. Solal-Celigny et al. Doxorubicin containing regimen with or without interferon alpha 2b for 
advanced follicular lymphomas: final analysis of survival and toxicity in the Groupe d’Etude 
des Lymphomes Folliculaire 86 trial. JCO 1998; 16(7):2332-2338. 
 
49. Martin et al. Outcome of Deferred Initial Therapy in Mantle-Cell Lymphoma. JCO 2009; 
27(8):1209-1213. 
 
50. Hoster et al. A new prognostic index (MIPI) for patients with advanced-stage mantle cell 
lymphoma. Blood 2008; 111(2): 558-565. 
 
20.0 
APPENDICES 
III. MSKK Standard for Screening and Treatment of HBV: 
http://mskweb5.mskcc.org/inside_mskcc/html/95104.cfm 
IV. GlaxoSmithKline Liver Chemistry Follow-up Assessments for Ofatumumab: 
Viral hepatitis serology including: 
• 
Hepatitis A IgM antibody; 
• 
Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); 
• 
Hepatitis C RNA; 
• 
Cytomegalovirus IgM antibody; 

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• 
Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain heterophile antibody 
or monospot testing); 
• 
Hepatitis E IgM antibody (if subject resides outside the US or Canada, or has traveled 
outside US or Canada in past 3 months); 
• 
Serum creatine phosphokinase (CPK) and lactate dehydrogenase (LDH). 
• 
Fractionate bilirubin, if total bilirubin 2xULN 
• 
Obtain complete blood count with differential to assess eosinophilia 
• 
Record the appearance or worsening of clinical symptoms of hepatitis or hypersensitivity, such 
as fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever rash or eosinophilia 
as relevant on the AE report form 
• 
Record use of concomitant medications, acetaminophen, herbal remedies, other over the 
counter medications, or putative hepatotoxins, on the concomitant medications report form. 
• 
Record alcohol use on the liver event alcohol intake case report form 
• 
PK is part of the standard follow-up if a liver event occurs. In the event that there is a liver event 
a blood sample would need to be drawn for PK. This is only in the event that a liver event 
occurs, not for all subjects. Blood sample for pharmacokinetic (PK) analysis, obtained within 5 
months of last dose. Record the date/time of the PK blood sample draw and the date/time of 
the last dose of investigational product prior to blood sample draw on the CRF. If the date or 
time of the last dose is unclear, provide the subject’s best approximation. If the date/time of the 
last dose cannot be approximated OR a PK sample cannot be collected in the time period 
indicated above, do not obtain a PK sample. Instructions for sample handling and shipping are 
in the SPM. 
 
The following are required for subjects with ALT 3xULN and bilirubin 2xULN (>35% direct) but are 
optional for other abnormal liver chemistries: 
• 
Anti-nuclear antibody, anti-smooth muscle antibody, and Type 1 anti-liver kidney microsomal 
antibodies. 
• 
Liver imaging (ultrasound, magnetic resonance, or computerized tomography) to evaluate liver 
disease. 
 
 
V. NCCN/GELF Criteria 48: 
NCCN version 1.2011/GELF Criteria for the initiation of therapy: 
• 
Involvement of ≥3 nodal sites, each with a diameter of ≥3 cm 
• 
Any nodal or extranodal mass with a diameter of ≥7 cm 
• 
B symptoms, defined as weight loss >10% body weight, fevers >38.6 degrees, 
night sweats 
• 
Splenomegaly associated with cytopenias or symptoms 
• 
Pleural effusions or peritoneal ascites 
• 
Cytopenias (leukocytes < 1.0 x 10e9/L and/or platelets <100 x 10e9/L) 
• 
Leukemic phase (>5 x 10e9/L malignant cells) 

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Note: The presence of any of these factors is an indication for chemoimmunotherapy 
induction. 
Reference: 
Doxorubicin-containing regimen with or without interferon alfa-2b for advanced follicular lymphomas: 
final analysis of survival and toxicity in the Groupe d'Etude des Lymphomes Folliculaires 86 Trial. 
Solal-Céligny P, Lepage E, Brousse N, Tendler CL, Brice P, Haïoun C, Gabarre J, Pignon B, Tertian 
G, Bouabdallah R, Rossi JF, Doyen C, Coiffier B. 
J Clin Oncol. 1998 Jul;16(7):2332-8. 
 
VI. Correlative Science: MicroRNA Determinants of Clinical Outcomes in Mantle Cell 
Lymphoma: 
This protocol, through obtaining tissue specimens, will also be used to evaluate the relevance of 
miRNAs in MCL. Recent studies of miRNA expression in MCL have revealed several dysregulated 
miRNAs and suggested potential roles for several miRNAs, including miR-16 and miR-29, in MCL 
pathogenesis and clinical outcomes19 20. The implication of these studies is that miRNAs may 
mediate the inherent chemoresistance of MCL cells. In addition, these studies did not consider the 
proliferation status of the MCL samples tested, suggesting that prognostication of MCL clinical 
outcomes may be improved by taking both miRNA determinants of MCL chemoresponses and 
proliferation index/gene signatures into account. We hypothesize that miRNAs may regulate MCL 
patient outcomes by modulating chemoresponsive pathways, and their expression profiles can be 
utilized to enhance existing prognostic methods. We aim to identify candidate miRNAs in MCL that 
mediate chemoresistance, to evaluate the role of miRNAs in MCL chemoresistance and biology, and 
to identify miRNAs that provide enhanced prognostic information in MCL. 
 
Patients with MCL will be enrolled in this clinical trial and all patients will be asked to consent to 
provide a sample of bone marrow and/or one tube of peripheral blood in order to characterize 
miRNAs. If a patient has completed a bone marrow biopsy/aspirate as part of staging outside of 
MSKCC, they will not be asked to repeat this procedure for correlative purposes. Instead these 
patients will be asked for a peripheral blood specimen (5 cc of blood in a purple top tube). For 
patients in whom a bone marrow biopsy/aspirate is required at MSKCC for staging purposes, a bone 
marrow aspirate specimen will be obtained, as well as one sample of peripheral blood for research 
purposes will be obtained following informed consent. 
 
Handling of Research Specimens: 

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Once samples of bone marrow aspirate and peripheral blood are obtained, they will be placed in a 
biohazard specimen storage bag. The consenting physician will page the lymphoma clinic RSA (pg. 
x6265) who will arrange for the delivery of the specimens from 205 E. 64th St to the laboratory of Dr. 
Christopher Y. Park in the Human Oncology and Pathogenesis Program at Memorial Sloan- 
Kettering Cancer Center in the Zuckerman Research Building, 410 East 69th Street Room 502. The 
delivery will be arranged by the same mechanisms as all HOTB samples that are sent from 205 E 
64th St. Kristina Knapp, the HOTB coordinator can be contacted at 646-888-3227. If the RSA is not 
immediately available, or the specimen is collected after-hours the bone marrow specimen may be 
refrigerated temporarily) until they can be delivered the following day. 
 
miRNA Analysis 
For the purposes of miRNA analysis, the Park lab will first begin identifying candidate miRNAs in 
MCL that mediate chemoresistance in cell lines. Utilizing near-diploid MCL cell lines harboring the 
pathognomonic MCL t(11:14) translocation (e.g. REC-1, MAVER-1), we will identify miRNAs 
potentially regulating chemoresistance. MCL cell lines will be treated with CHOP chemotherapy in 
vitro. After establishing doses of CHOP that induce >95% cell death, miRNAs will be measured 
using TaqMan based RT-PCR in emerging/residual chemoresistant cells and mock treated control 
cells, similar to that recently described for non-small cell lung cancer cell lines 27. miRNAs will be 
measured at two time points following initiation of therapy: 1) at the nadir of cell survival following 
CHOP (reflecting early responses to CHOP); and 2) after continued maintenance of resistant cells 
grown in the presence of CHOP, which would represent changes associated with long-term 
maintenance therapy. 
 
Subsequently, we will then evaluate the role of miRNAs in MCL chemoresistance and biology. Once 
candidate miRNA mediators of chemoresistance are identified in cell lines, it will be necessary to 
characterize the functional role of such miRNAs in multiple aspects of MCL biology. We will test 
candidate miRNAs identified in AIM 1 for their effects on cellular growth, apoptosis, and 
chemoresistance using MCL cell lines stably expressing miRNAs or their “antagomirs” after 
transduction with lentiviral vectors. Cell counts will be taken and apoptosis measured by flow 
cytometry by staining for annexin V at predetermined time points. Similar measurements will be 
taken following CHOP as well, both in acutely treated cells as well as chemoresistant clones. 
 
Lastly we will identify miRNAs that provide enhanced prognostic information in MCL. As previously 
noted, the most robust predictor of clinical outcomes in MCL is the PI. However, even within groups 
of patients stratified on this basis, individual outcomes are difficult to predict. Thus, it is important to 

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identify additional molecular markers that can be measured to better prognosticate clinical 
outcomes. We will initially characterize miRNA expression profiles in MCL samples drawn from 
formalin fixed, paraffin embedded tissue (FFPE) previously characterized at MSKCC with respect to 
PI and clinical outcomes 16. miRNA profiles will be generated using our TaqMan based human 
miRNA RT-PCR platform, which can generate robust miRNA profiles from as few as 500 cells. 
These results will allow us to generate a predictive algorithm for MCL outcomes (e.g. OS, EFS). 
Following the identification of miRNAs that further stratify MCL patients after taking PI into account, 
we will evaluate a validation set of MCL cases collected prospectively from patients enrolled on this 
clinical trial. miRNA expression profiles will be determined in at least 30 MCL samples using our 
TaqMan RT-PCR method, and the prognostic utility of the miRNAs evaluated will be assessed by 
correlation with the PI as measured by Ki-67. 
SOX11 analysis: 
 
Immunohistochemical staining for SOX11 would be performed at MSKCC by the Department of 
Pathology, Dr Julie-Teruya Feldstein. Patients would be requested to donate 2 unstained slides from 
the subset of diagnostic slides made available to MSKCC for confirmation of diagnosis. For biopsies 
performed at MSKCC, we would request 2 unstained slides from the tissue block for SOX11 
staining. SOX11 analysis will be performed following validation/QA of the immunohistochemistry 
test at MSKCC.