Clinical trial NCT01458366
Conditions: Non-Hodgkin's Lymphoma
Keywords: Non-Hodgkin's Lymphoma Lymphoma B-Cell Lymphoma
Sponsor: Sidney Kimmel Cancer Center at Thomas Jefferson University
Start date: 2011-11-09; Completion date: 2020-07-23
Enrollment: 38 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The Phase I part of the study will apply to identify dose-limiting toxicities (DLT) and to define maximum-tolerated dose (MTD) for a new chemoimmunotherapy combination of bendamustine, ofatumumab, carboplatin, and etoposide in patients with Non Hodgkin's lymphoma whose disease has progressed or has recurred after prior chemotherapy.

The Phase II part of the study will be a single-arm, open-label study in which all patients will receive combination bendamustine, ofatumumab, carboplatin and etoposide at the MTD dose defined in phase I.

This study hopes to identify a life-prolonging therapy for patients with Non-Hodgkin's Lymphoma whose disease has progressed or has recurred after prior chemotherapy. The hypothesis is that the proposed combination of chemotherapy is well-tolerated and is efficacious for the treatment of relapsed/refractory aggressive B cell lymphomas.

Detailed description:
Fifty percent of patients with aggressive B cell non-Hodgkin lymphomas are expected to relapse after initial standard chemotherapy. There is no standard salvage regimen for patients with relapsed or refractory disease and at least 75% of patients are expected to succumb to their condition with the commonly used therapy. The recent CORAL study was evaluating the most frequently used rescue regimens R-ICE (rituximab, ifosfamide, carboplatin, etoposide) vs. R-DHAP (rituximab, dexamethasone, high-dose cytarabine and cisplatin) for relapsed aggressive lymphomas, the overall response (OR) was 83% and 3 year event-free survival (EFS) was 47% for "rituximab naïve" patients. In contrast, OR was 51% and 3 year EFS was only 21% in patients who had relapsed after a rituximab containing regimen. There was no significant difference between R-ICE and R-DHAP (in 3-year EFS or overall survival). This study confirmed that rituximab containing rescue was less effective in those patients who had received prior rituximab. Currently, there is virtually no relapsed B-cell lymphoma patients who had not received a rituximab containing induction; therefore, novel strategies are needed to overcome rituximab resistance and to improve overall poor outcome in the relapsed setting. Ofatumumab is a human IgG1 monoclonal anti-CD20 antibody which binds to different CD20 epitopes and is presumed to destroy B cells that are insensitive to rituximab due to their low CD20-expression due to its higher binding avidity and higher antibody and complement dependent cytotoxicity. It was approved by FDA for the treatment of patients with refractory Chronic Lymphocytic Leukemia (CLL). It is being actively studied in low grade and aggressive CD20 positive lymphomas. Bendamustine is an alkylator/purine analogue hybrid cytotoxic compound that has demonstrated single agent activity in lymphomas refractory to other alkylating agents, such as cyclophosphamide. Weidmann et al (2002) demonstrated single agent activity and safety of bendamustine at the dose of 120mg/m2 (day 1, 2) in relapse/refractory aggressive lymphomas. This study had an ORR of 44% in 18 patients. Non-hematological toxicity was mild (13% grade 3 and 0 grade 4). Bendamustine has shown impressive activity and a favorable safety profile when used in combination with rituximab and other cytotoxic drugs: Weide R et al (2007) studied bendamustine (90 mg/m2 day 1, 2) in combination with rituximab and mitoxantrone in 57 patients' with indolent lymphomas and mantle cell lymphoma (MCL). ORR was 92% in follicular and 78% in MCL Vacirca et al presented interim safety analysis of bendamustine (120mg/m2, day 1, 2) and rituximab combination in aggressive B cell lymphomas at 2010 ASCO meeting (in 76 cycles 1 grade 4 neutropenia and 9 additional grade 3 events). Thus, bendamustine combinations are effective and can be given safely in patients with relapsed lymphomas.

The investigators propose a novel R-ICE-like salvage combination regimen in which rituximab is substituted with ofatumumab and ifosfamide with bendamustine in combination with carboplatin and etoposide for refractory or relapsed aggressive B cell lymphomas. The investigators hope to avoid the substantial ifosfamide mediated urinary bladder toxicity (incidence of grade 3 and 4 hemorrhagic cystitis 8-12%) and neurologic toxicity (10-30%: somnolence, confusion, psychosis and seizure) by substituting ifosfamide for bendamustine. The proposed regimen is convenient and can be administered on the outpatient basis which presents an additional benefit to the patients and to the providers. The investigators propose a phase I/II clinical trial and will first determine safety and toxicity of escalating dose bendamustine in combination with fixed doses of ofatumumab, carboplatin and etoposide. The investigators recognize that the commonly used doses of bendamustine in lymphoid malignancies range from 70-120 mg/m2. The investigators will determine maximum-tolerated dose (MTD) and dose-limiting toxicity (DLT) of the combination by using dose escalation of bendamustine from 70mg/m2 in a standard 3 by 3 design. The investigators will then assess efficacy of the combination regimen in relapsed and refractory aggressive B-cell lymphomas.

Arms: arm 1: Level 1: Bendamustine 70mg/m\^2 Ofatumumab, Carboplatin, and Etoposide arm 2: Level -1: Bendamustine 50mg/m\^2 Ofatumumab, Carboplatin, and Etoposide arm 3: Level 2: Bendamustine 90mg/m\^2 Ofatumumab, Carboplatin, and Etoposide arm 4: Level 3: Bendamustine 120mg/m\^2 Ofatumumab, Carboplatin, and Etoposide arm 5: Phase II: Bendamustine at MTD from Phase I, Ofatumumab, Carboplatin, and Etoposide
Interventions: intervention 1: Bendamustine intervention 2: Ofatumumab intervention 3: Carboplatin intervention 4: Etoposide intervention 5: CT Scan intervention 6: PET Scan intervention 7: Stem Cell Transplant (STC)
Intervention descriptions: intervention 1: Phase 1: Given via IV at the following dose levels:

* Level 1: 70 mg/m2
* Level -1: 50 mg/m2
* Level 2: 90 mg/m2
* Level 3: 120 mg/m2

Phase II: Given via IV on Days 1 and 2 of each cycle at the maximum-tolerated dose level found in the Phase I portion of the study. intervention 2: Phase II

* Cycle 1: 300 mg via IV on Day 1 and 1000 mg via IV on Day 3
* Cycles 2 and 3: 1000 mg via IV on Day 1 intervention 3: Phase II: AUC 5 via IV on Day 2 of each cycle intervention 4: Phase II: 100 mg/m2 via IV on Days 1, 2, and 3 of each cycle intervention 5: CT Scan to assess disease after Cycle 2 (approximately 25 days) and 3-8 weeks post-treatment intervention 6: PET Scan to assess disease after Cycle 2 (approximately 25 days) and 3-8 weeks post-treatment intervention 7: For potential transplant candidates:

* Autologous STC: after 2 cycles of BOCE upon discretion of Thomas Jefferson University hematopoietic stem cell transplant group and in agreement with the study PI or her designee
* Allogeneic STC: after 2 cycles of BOCE upon discretion of Thomas Jefferson University hematopoietic stem cell transplant group and in agreement with the study PI or her designee

Protocol documents:
Prot_SAP_000.pdf: 
 
Protocol Version 6.3 
1
  Phase I/II Study of Bendamustine in Combination with Ofatumumab, Carboplatin 
and Etoposide for Refractory or Relapsed Aggressive B-cell Lymphomas. 
 
AUTHORS 
 
Principal Investigator 
Joanne Filicko-O’Hara, MD 
 
Co-Investigators 
S. Onder Alpdogan, MD 
Matthew Carabasi, MD 
Jerald Gong, MD 
Margaret Kasner, MD 
Neal Flomenberg, MD 
Ubaldo Martinez, MD 
John L.Wagner, MD 
Dolores Grosso, DNP, CRNP 
Avnish Bhatia, MD 
Andrew Chapman, DO 
Michael Ramirez, MD 
Lewis Rose, MD 
Atrayee Basu-Mallick, MD 
Allison Zibelli, MD 
Christina Brus, MD 
Sameh Gaballa, MD 
Pierluigi Porcu, MD 
Neil Palmisiano, MD 
Lindsay Wilde, MD 
 
Biostatistician 
Inna Chervoneva, PhD 
 
 
Division of Hematologic Malignancies and  
Hematopoietic Stem Cell Transplantation 
Department of Medical Oncology 
Kimmel Cancer Center 
Thomas Jefferson University 
834 Chestnut Street, Suite # 320, 
Philadelphia, Pa 19107 
Phone (215) 503-5894 
 
Original Date: 
7.19.11 (Version 1.0) 
Updated Protocol 
Versions 
1.12.12 (Version 1.2) 
7.31.12 (Version 1.3) 
10.4.11 (Version 1.1) 


 
Protocol Version 6.3 
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1.7.13 (Version 2.0) 
4.2.13 (Version 2.1) 
6.5.13 (Version 2.2) 
3.12.14 (Version 3.0) 
12.31.14 (Version 3.1) 
2.4.15 (Version 3.2) 
8.12.15 (Version 4.0) 
9.10.15 (Version 5.0) 
11.13.15 (Version 5.1) 
02.11.16 (Version 5.2) 
05.27.16 (Version 6.0) 
03.10.17 (Version 6.1) 
11.16.17 (Version 6.2) 
09.17.18 (Version 6.3) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Protocol Version 6.3 
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INDEX 
STUDY SUMMARY 
1 
INTRODUCTION ……………………………………………………………………………………………………………..11 
1.1      BACKGROUND    …………………………………………………………………………………………………………………..11   
1.2     INVESTIGATIONAL AGENT-OFATUMUMAB………………………………………………………………………………….13 
1.2.1Preclinical Data………………………………………………………………………………………………………...13 
1.2.2 Clinical Data…………………………………………………………………………………………………………….14 
     1.2.3   Adverse Events noted in Follicular Lymphoma Subjects………………………………………………14 
     1.2.4   Ofatumumab Combination Therapy…………………………………………………………………………..14    
     1.3         INVESTIGATIONAL AGENT-BENDAMUSTINE……………………………………………………………….15 
      1.4        OFATUMUMAB AND BENDAMUSTINE COMBINATION………………………………………………….16 
      1.5        STUDY RATIONALE …………………………………………………………………………………………………….17 
      1.6        RATIONALE FOR CORRELATIVE STUDIES…………………………………………………………………….17 
  1.6.1    Analysis of the surface expression og CD20 on malignant cells in relapsed aggressive B cell    
lymphoma…………………………………………………………………………………………………………………………17 
  1.6.2    Biologic profile of relapsed and refractory aggressive B cell    lymphoma……………………18 
  1.6.3   Validation of oligo nucleotide based microarray platform for NHL risk stratification…..19 
2 
STUDY OBJECTIVES………………………………………………………………………………………………………….19 
2.1 
PRIMARY OBJECTIVE FOR PHASE I PART OF STUDY………………………………………………………19 
2.2 
SECONDARY OBJECTIVE FOR PHASE I……………………………………………………………………………20 
2.3 
PRIMARY OBJECTIVE FOR PHASE II STUDY……………………………………………………………………20 
2.4 
SECONDARY OBJECTIVES FOR PHASE II STUDY……………………………………………………………..20 
3 
STUDY DESIGN………………………………………………………………………………………………………………….20 
3.1 
GENERAL DESIGN PHASE I……………………………………………………………………………………………..20 
3.2           GENERAL DESIGN PHASE II……………………………………………………………………………………………22 
3.3 
PRIMARY STUDY ENDOPINT PHASE I……………………………………………………………………………..22 
3.4 
SECONDARY STUDY ENDPOINTS PHASE 1………………………………………………………………………22 
3.5 
PRIMARY STUDY ENDPOINTS PHASE II…………………………………………………………………………22 
3.6 
SECONDARY STUDY ENDPOINTS PHASE II………………………………………………………………………22 
3.7 
PRIMARY SAFETY ENDPOINTS ………………………………………………………………………………………23 
4 
SUBJECT SELECTION AND WITHDRAWAL…………………………………………………………………………23 
4.1 
INCLUSION CRITERIA………………………………………………………………………………………………………..23 
4.2 
EXCLUSION CRITERIA……………………………………………………………………………………………………….24 
4.3 
SUBJECT RECRUITMENT AND SCREENING………………………………………………………………………………25 
4.4 
EARLY WITHDRAWAL OF SUBJECTS……………………………………………………………………………………...26 
4.4.1 
When and How to Withdraw Subjects…………………………………………………………………………26 
4.4.2 
Data Collection and Follow-up for Withdrawn Subjects……………………………………………….26 
5 
STUDY DRUGS……………………………………………………………………………………………………………….........26 


 
Protocol Version 6.3 
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   5.1        OFATUMUMAB………………………………………………………………………………………………………………..26 
   5.2        BENDAMUSTINE……………………………………………………………………………………………………………...29 
   5.3        ETOPOSIDE……………………………………………………………………………………………………………………...31 
   5.4        CARBOPLATIN………………………………………………………………………………………………………………....33 
   5.5        TREATMENT REGIMEN…………………………………………………………………………………………………….34 
       5.5.1        Chemotherapy Regimen………………………………………………………………………………………………..34 
       5.5.2        Supportive Care……………………………………………………………………………………………………………34 
          5.5.2.1 Pre-medication……………………………………………………………………………………………………………..34 
          5.5.2.2 Ofatumumab infusion……………………………………………………………………………………………………35 
          5.5.2.3 Tumor Lysis prophylaxis………………………………………………………………………………………………..36 
          5.5.2.3 Tumor Lysis Prophylaxis……………………………………………………………………………………………………35 
5.5.2.4 Growth factor support……………………………………………………………………………………………………35 
          5.5.2.5 Prophylaxis of Pneumocystis jirovecii………………………………………………………………………………35 
          5.5.2.6 Anti fungal Prophylaxis…………………………………………………………………………………………………..35 
          5.5.2.7 Anti viral prophylaxis……………………………………………………………………………………………………..35 
5.5.2.8  Prophylaxis of CNS Disease..……………………………………………………………………………………………..35 
   5.6 
Method for Assigning Subjects to Treatment Group……………………………..………………………….……35 
     5.7 
PREPARATION AND ADMINISTRATION OF STUDY DRUG……………………………..………………………………..35 
     5.8 
SUBJECT COMPLIANCE MONITORING……………………………..……………………………………………………….36 
     5.9 
PRIOR AND CONCOMITANT THERAPY……………………………..……………………………………………………….36 
     5.10 
RECEIVING, STORAGE, DISPENSING AND RETURN……………………………..……………………………………..…36 
5.10.1 
Receipt of Drug Supplies……………………………..……………………………………………………………….36 
5.10.2 
Storage……………………………..……………………………………………………………………………………….36 
5.10.3 
Dispensing of Study Drug……………………………………………………………………...……..………………36 
5.10.4 
Return or Destruction of Study Drug……………………………..………………………………………………36 
6 
STUDY PROCEDURES……………………………………………………………………………….37 
      6.1       SCHEMA……………………………………………………………………………………………………………………………37 
      6.2       STEM CELL MOBILIZATION AND STEM CELL TRANSPLANT……………………………………………….37 
      6.3       DOSE DELAYS AND DOSE REDUCTIONS……………………………………………………………………………..38 
            6.3.1 Cycle Delays ……………………………………………………………………………………………………………………..38 
           6.3.2 Dose Reduction of Bendamustine …………..…………………………………………………………………………...38 
           6.3.3 Dose Modifications of Carboplatin, Etoposide and Ofatumumab …………………………………………..38 
      6.4       DISEASE RESPONSE…………………………………………………………………………………………………………..39 
      6.5       CORRELATIVE STUDIES………………………………………………………………………………………………...….40 
            6.5.1 Flow Cytometry for CD20 Expression………………………………………………………………………………....40 
            6.5.2 Immunohistochemistry Studies…………………………………………………………………………………………..40 
           6.5.3 FISH Studies……………………………………………………………………………………………………………………...40 
           6.5.4 Analysis of EBER………………………………………………………………………………………………………………..40 
            
          6.5.5 Submission of Blood and Bone Marrow Samples……………………………………………………………………41 
          6.5.6 Freezing and Storage………………………………………………………………………………………………………….41 
      6.6 DURATION OF THERAPY ………………………………………………………………………………………………………...41 
      6.7 DURATION OF FOLLOW UP …………………………………………………………………………………………………….41 
6.8 FOLLOW UP/MONITORING …………………………………………………………………………………………………….41 
7 
STATISTICAL PLAN……………………………………………………………………………………………………………….41 
7.1 
SAMPLE SIZE DETERMINATION…………………………………………………………………………………………………41 
7.2 
STATISTICAL METHODS…………………………………………………………………………………………………………..42 
7.3 
SUBJECT POPULATION(S) FOR ANALYSIS……………………………………………………………………………………..44 
7.4             ANALYSIS OF MISSING DATA……………………………………………………………………………………………...44 
8 
SAFETY AND ADVERSE EVENTS…………………………………………………………………….44 
8.1 
DEFINITIONS…………………………………………………………………………………………………………………………44 
8.2 
RECORDING OF ADVERSE EVENTS…………………………………………………………………………………………….…47 


 
Protocol Version 6.3 
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8.3 
STOPPING RULES……………………………………………………………………………………………………………………47 
8.4             LIVER CHEMISTRY STOPPING AND FOLLOW UP CRITERIA…………………………………………………..47 
8.5 
DATA AND SAFETY MONITORING PLAN………………………………………………………………………………………..50 
8.5.1 
Medical Monitoring and AE/SAE Reporting………………………………………………………………….……50 
8.5.2 
Data and Safety Monitoring Committee……………………………………………………………………….……51 
 
9 
DATA HANDLING AND RECORD KEEPING……………………………………………………………………….……………52 
9.1 
CONFIDENTIALITY…………………………………………………………………………………………………….……………..52 
9.2 
SOURCE DOCUMENTS………………………………………………………………………………………………….……………52 
9.3 
CASE REPORT FORMS………………………………………………………………………………………………………………52 
9.4 
RECORDS RETENTION………………………………………………………………………………………………………………53 
10 
STUDY MONITORING, AUDITING, AND INSPECTING………………………………….…………50 
10.1 
STUDY MONITORING PLAN…………………………………………………………………………………………………………50 
10.2 
AUDITING AND INSPECTING…………………………………………………………………………………………………………54 
         10.2.1 Independent External and Internal Audits…………..…………………………………………………………………54 
11 
ETHICAL CONSIDERATIONS…………………………………………………………………………..55 
12 
STUDY FINANCES………………………………………………………………………………………55 
12.1 
FUNDING SOURCE…………………………………………………………………………………………………………………..55 
12.2 
CONFLICT OF INTEREST……………………………………………………………………………………………………………55 
13 
PUBLICATION PLAN……………………………………………………………………………………55 
14 
REFERENCES…………………………………………………………………………………………….56 
15 
APPENDICES…………………………………………………………………………………………58 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Protocol Version 6.3 
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List of Abbreviations  
ABC 
AE 
ANC 
Activated B-cell–Type 
Adverse Event 
Absolute Neutrophil Count 
ASCO 
American Society of clinical Oncology 
ASCT 
AUC 
Autologous Stem Cell Transplant 
Area Under the Curve 
BOCE 
Bendamustine, Ofatumumab, Carboplatin and Etoposide 
BUN 
Blood Urea Nitrogen 
CBC 
CCRRC 
CDC 
Complete Blood Count 
Clinical Cancer Research Review Committee 
Complement Dependent Cytotoxicity 
CD 
Cluster of Differentiation 
CHOP 
Cyclophosphamide, Doxorubicin, Vincristine and Prednisone 
CLL 
Chronic Lymphocytic Leukemia 
CMP 
Comprehensive Metabolic Panel   
CR 
Complete Response 
CRMO 
Clinical Research and Management Office 
DLBCL 
Diffuse Large B cell Lymphoma 
D5W 
5% Dextrose in Water 
DLT 
DSMC 
Dose Limiting Toxicity 
Data and Safety Monitoring Committee 
EFS 
EBER 
Event Free Survival 
Epstein Barr Encoded RNA 
FDA 
FDG 
FISH 
Food and Drug Administration 
Fludeoxyglucose 
Fluorescence In Situ Hybridization 
FLIPI 
Follicular Lymphoma IPI score 
GCB 
GFR 
Germinal-Center B-cell–like 
Glomerular Filtration Rate 
HAART 
HB 
HC 
HIPAA 
HIV 
Highly active Antiretroviral Therapy 
Hepatitis B 
Hepatitis C  
Health Insurance Portability and Accountability Act 
Human Immunodeficiency Virus  


 
Protocol Version 6.3 
7
ICE 
Ifosfamide, Carboplatin, Etoposide 
IHC 
Immunohistochemistry 
IRB 
IWG 
Institutional Review Board 
International Working Group 
FC 
Fludarabine, Cyclophosphamide 
IgG 1k 
IWG 
KCC 
Immunoglobulin G1 kappa 
International Working Group 
Kimmel Cancer Center 
KPS 
Karnofsky Performance Status 
LDH  
M-BACOD 
 
MACOP-B 
Lactate Dehydrogenase 
Methotrexate with Leucovorin, Bleomycin, Doxorubicin, 
Cyclophosphamide, Vincristine, and Dexamethasone 
Methotrexate with Leucovorin, Doxorubicin, Cyclophosphamide, 
Vincristine, Prednisone, and Bleomycin 
MCL 
Mantle Cell Lymphoma 
MTD 
Maximum Tolerated Dose 
NCCN 
National Comprehensive Cancer Network 
NCI 
NHL 
NIH 
NS 
National Cancer Institute 
Non Hodgkin Lymphoma 
National Institute of Health 
Normal Saline 
OPRR 
OS 
US Dept of Health & Human Serv./Office for Protection from Research Risk 
Overall survival 
ORR 
Overall Response Rate 
ProMACE-
CytaBOM 
 Prednisone, Methotrexate, Doxorubicin,  Cyclophosphamide, Etoposide-
CytaBOM: Cytarabine, Bleomycin, Vincristine, Methotrexate 
PD 
PET 
Progressive Disease 
Positron Emission Tomography 
PFS 
Progression Free Survival 
PHI 
PML 
PR 
Protected Health Information 
Progressive Multifocal Leukoencephalopathy 
Partial Response 
PS 
Performance Status 
RICE 
Rituximab, Ifosfamide, Carboplatin, Etoposide 
RT 
SAAIPI 
Radiotherapy 
Second line Age Adjusted International Prognostic Index 
SAE 
Serious Adverse Event  
SEER 
Surveillance Epidemiology and End Results 
SLL 
Small Lymphocytic Lymphoma  
SWOG 
South Western Oncology Group 
ULN 
Upper Limit of Normal 


 
Protocol Version 6.3 
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Title 
Phase I/II Study of Bendamustine in Combination with 
Ofatumumab, Carboplatin and Etoposide for Refractory or 
Relapsed Aggressive B-cell Lymphomas. 
Short Title 
BOCE in Relapsed/Refractory Aggressive Lymphomas 
Protocol Number 
11D.404 
Phase 
Phase I/II 
Methodology 
Phase I – 3x3 design, open label. Phase II - Single arm, open label. 
Study Duration 
2 years 
Study Center(s) 
Single center 
Objectives 
Primary objective for Phase I part of the study: 
Safety and toxicity profile of bendamustine in combination with 
ofatumumab, carboplatin and etoposide for refractory or relapsed 
aggressive B cell lymphomas. 
Secondary objective for Phase 1: 
To determine the Overall Frequency of Response with combination 
bendamustine, ofatumumab, carboplatin and etoposide for refractory or 
relapsed aggressive B cell lymphomas. 
Primary objective for Phase II study: 
Determine the Overall Frequency of Response with combination 
bendamustine, ofatumumab, carboplatin and etoposide for refractory or 
relapsed aggressive B cell lymphomas. 
Secondary objectives for Phase II study: 
 To determine CR rate  
 To determine 1 and 2 year progression free survival. 
 To determine 1 and 2 year overall survival. 
 To define safety and toxicity of the combination of ofatumumab, 
bendamustine, carboplatin and etoposide for refractory or relapsed 
aggressive B cell lymphomas. 
 To evaluate the level of CD20 expression in the various biologic 
types of relapsed aggressive B cell lymphomas and to correlate that 
with response to the study regimen.  
Number of Subjects 
(max) 
36 
Diagnosis and Main 
Inclusion Criteria 
Relapsed/refractory aggressive B cell Non-Hodgkin’s lymphoma 
 


 
Protocol Version 6.3 
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Study Product, Dose, 
Route, Regimen 
In the Phase I part of the study a standard 3+3 design will apply to identify 
dose limiting toxicities (DLT) and to define maximum tolerated dose 
(MTD) of combination bendamustine, ofatumumab, carboplatin, and 
etoposide in refractory and relapsed aggressive B cell lymphomas. 
The Phase II part of the study will be a single-arm, open-label study in 
which all patients will receive combination bendamustine, ofatumumab, 
carboplatin and etoposide at the MTD dose defined in phase I 
Patients will be followed on the study until disease progression, 
unacceptable toxicity, or withdrawal of consent or for total of 2 years post 
completion of therapy (whichever is earlier). 
 
Agent 
Dose 
Route 
Schedule 
Ofatumumab 
Cycle 1: 300 mg on 
day 1 (or up to 3 
days prior to day 1), 
1000 mg on day 3.  
Cycles 2 and 3: 
1000 mg on day 1.  
IV  
Cycle 1: days 1 (or up 
to 3 days prior to day 1) 
and day 3. 
Cycle 2 and 3: day 1 
Bendamustine Phase I: as per 
escalating dose 
protocol. 
Phase II: MTD 
achieved in Phase I 
IV  
Day 1 and 2 
Carboplatin 
AUC 5 
IV 
Day 2 
Etoposide 
100 mg/m² 
IV 
Day 1, 2 and 3 
Duration of 
administration 
3 cycles approximately every 3 weeks or upon blood cell recovery, 
whichever is later  
Reference therapy 
RICE (rituximab, ifosfamide, carboplatin, etoposide).  
Statistical Methodology 
A total of 9 to a maximum of 18 patients will be enrolled in Phase I part of 
the trial. Twenty four patients will be enrolled in Phase II part of the trial. 
This is based on the Simon Optimal Two-Stage Design with the 
assumption that an ORR rate of 25% indicates that the treatment is not 
effective and an ORR rate of 50% indicates that the treatment is effective 
with alpha (type I error) 0.05 and 80% power. The last 6 patients enrolled 
at the MTD level in Phase I will be included in the Phase II part of the 
study. Thus the estimated maximum sample size will be 36 patients. 
 
 
 
 
 
 
 
 
 


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Protocol Version 6.3 
11 
1. INTRODUCTION 
1.1 Background: 
Epidemiology 
According to the Surveillance, Epidemiology and End Results (SEER) data, around 65,540 
people in the United States will be diagnosed with and 20,210 will die of non-Hodgkin 
lymphomas (NHL) in 2010. Aggressive B cell lymphomas consist of diffuse large B cell 
lymphoma (DLBCL), the single largest category of all lymphomas, primary mediastinal large B 
cell lymphoma, T cell rich B cell lymphoma, transformed low grade B cell lymphomas and a 
variant of mantle cell lymphoma (MCL). All the above lymphomas are unified by their B cell 
origin, aggressive behavior and similar standard treatment approach. Burkitt lymphoma has a 
highly aggressive clinical course and is thus treated with different, more aggressive regimens and 
will not be discussed here. 
 
First Line Treatment 
In the early 1970’s Levitt and DeVita initially described potentially curative combination 
chemotherapy for large cell lymphomas (1, 2). Since then, CHOP (cyclophosphamide, 
doxorubicin, vincristine and prednisone) has been widely used in the treatment of aggressive 
NHL. Its superiority over other second and third generation combination chemotherapy (m-
BACOD, ProMACE-CytaBOM, and MACOP-B) was established by the historic Phase III 
SWOG trial (Fisher RI et al 1993) which showed equal efficacy and superior safety profile of 
CHOP with an overall survival of 54% at three years (3). 
 
The addition of Rituximab to chemotherapy for patients with aggressive B cell lymphoma has 
significantly improved outcome. The use of rituximab in combination with CHOP (RCHOP) vs. 
CHOP in young patients with good prognosis DLBCL has resulted in better PFS and OS. 
Pfreundschuh et al evaluated RCHOP vs. CHOP in young patients (age 18-60) with good 
prognosis DLBCL (4). The 3 year event free survival was 79% in the RCHOP arm vs. 59% in 
the CHOP arm. Similar improved results were seen in the elderly population. A 10 year follow 
up study of elderly (age 60-80) patients with DLBCL showed that, 10 year PFS was 36.5% in 
RCHOP arm vs. 20% in the CHOP alone arm (5). Ten year OS was 43.5% in RCHOP compared 
to 26.7 % in CHOP arm. 
 
Relapsed/Refractory Aggressive B cell NHL 
Up to 50% of patients with aggressive B cell lymphomas will relapse after CHOP-like 
chemotherapy with rituximab. There is no standard salvage regimen for patients with relapsed or 
refractory disease and at least 75% of patients are expected to succumb to their condition with 
the commonly used rescue regiments.  
 
Prognostic Factors for Relapsed/Refractory NHL: 
There are various factors that predict outcome in relapsed/refractory lymphomas. These include 
Second Line Age Adjusted International Prognostic Index (sAAIPI), (see Table 1 and Appendix 
1), initial remission lasting more than 12 months and use of Rituximab in initial therapy. 
Prognostic factors are useful to assess the efficacy of new treatment regimens compared to 
previous approaches. They are also helpful in identifying groups which have a poor prognosis 
with existing regimens and may benefit from alternative therapies. sAAIPI assessed at the 


 
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initiation of second line therapy, predicts the outcome after Autologous Stem Cell Transplant 
(AutoSCT) in patients with relapsed/refractory lymphomas (6).  
 
Table 1-sAAIPI assessed at the time of second line therapy 
Risk factors: 
Score 
LDH >ULN 
1 
Stage III or IV 
1 
KPS <80% 
1 
 
Low risk (L) with 0 factors, low intermediate (LI) risk with 1 factor, high-intermediate risk (HI) 
with 2 factors, and high risk (H) with all 3 factors present. 
 
Treatment of Relapsed/Refractory NHL 
For patients with relapsed/refractory disease, there is no standard salvage regimen. For patients 
that are eligible for transplant the National Comprehensive Cancer Network (NCCN) 
recommends a rescue regimen followed by high dose therapy and AutoSCT or high dose therapy 
followed by AlloSCT in selected patients.  
 
Salvage Regimens: 
There are a number of regimens that have been described for relapsed/refractory aggressive 
lymphomas in the era of monoclonal antibodies. No regimen has shown clear superiority to the 
other and response rates have ranged between 35-78% depending on prior rituximab use in 
frontline setting; uniformly there were inferior outcomes among patients who had relapsed after 
a rituximab containing frontline therapy. See table 2. These inferior clinical outcomes apply to 
our current relapsed patient population who overwhelmingly had previously been treated with 
rituximab containing frontline regiments.  
 
Table 2 
Regimen  Previous 
rituximab 
use 
sAAIPI>2 CR/Cru ORR 
OS 
Author 
R-ICE 
0% 
47.2% 
53% 
78% 
N/A 
Kewalramani , 
2004 (7) 
 
62% 
37.1% 
36%* 
63.5%*,  47% *(at 3 
years) 
Gisselbrecht, 
2010 (8) 
DHAP 
0% 
N/A 
31% 
55% 
25% at 2 years 
Velasquez, 
1988 (9) 
R-DHAP 
62% 
38.1% 
40%* 
62.8%* 
51%* (at 3 
years) 
Gisselbrecht, 
2010 (8) 
R-
ESHAP 
56% 
35% 
45% 
73% 
55.8% at 29 
months 
Martin, 2008 
(10) 
R-
EPOCH 
16% 
58% 
28% 
68% 
35%projected 
OS at 3 yrs 
Jermann M, 
2004 (11) 
GEMOX-
R 
N/A 
69% 
34% 
43% 
41% at 1 yr 
Lopez A, 2008 
(12) 
*CR, ORR and OS Significantly lower in patients who had prior rituximab 


 
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RICE (Rituximab, Ifosfamide, carboplatin and Etoposide) is the most frequently used salvage 
regiment in the United States and DHAP is widely used in Europe. RICE has been developed 
and investigated at the Memorial Sloan-Kettering Cancer center. Kewalramani et al investigated 
the RICE regimen in 36 patients with aggressive lymphomas that had relapsed after or were 
refractory to single standard anthracycline based chemotherapy (7). The ORR was 78% and CR 
was 53%.  Among 25 patients who underwent transplantation after RICE 2 year progression free 
survival was 54%.  
 
DHAP (high dose cytarabine with cisplatin and dexamethasone) was studied by Velasquez et al 
in 90 patients with relapsed/refractory lymphomas (9). The ORR was 55% and the CR was 31%. 
Both these regimens were also investigated in a randomized Phase III trial (CORAL study) 
comparing RICE vs. RDHAP followed by high dose therapy and autologous transplant in 
patients with relapsed/refractory DLBCL (8). The ORR of 63% and 62% with RICE and 
RDHAP, respectively, and the 3 year event free survival was 26% and 35%, respectively 
(p=0.6). Three-year EFS was affected by prior rituximab treatment versus no prior rituximab 
(21% v 47%, respectively).  
 
R-ESHAP (rituximab with etoposide, cytarabine, cisplatin and methylprednisolone) is another 
salvage regimen in relapsed/refractory aggressive lymphomas. Martine et al retrospectively 
evaluated the efficacy of R-ESHAP in 163 patients as a salvage regimen (10). In the rituximab 
naïve group the CR and ORR was 56% and 81% respectively. In comparison, the 94 patients 
who had been treated with rituximab earlier the CR and ORR was 37% and 67%. These data 
strongly indicated that rituximab containing salvage regimens were less effective in the patients 
who were previously treated with a rituximab containing frontline therapy. 
R-EPOCH (rituximab with doxorubicin, etoposide, vincristine, cyclophosphamide and 
prednisone) was evaluated by Jermann et al in 50 patients with relapsed/refractory large B cell 
lymphomas and mantle cell lymphomas (11). The ORR was 68% and CR was 28%.  
GEMOX-R (rituximab with gemcitabine and oxaliplatin) when studies in 32 patients with 
relapsed/refractory lymphomas had a ORR of 43% and a Cr of 34% (12). 
 
1.2 Investigational Agent- Ofatumumab: 
Ofatumumab is a fully human IgG1κ monoclonal anti-CD20 antibody. It recognizes a distinct 
epitope encompassing both the large and the small extracellular loops on the human CD20 
molecule expressed on B cells. Binding of ofatumumab causes clustering of CD20 on the cell 
surface and promotes cell death through the induction of complement mediated cytotoxicity 
(CDC) and antibody dependent cell mediated cytotoxicity (ADCC). It has been approved by 
FDA for use in relapsed/refractory CLL and has been extensively investigated in indolent and 
aggressive B cell NHLs. 
 
1.2.1. Preclinical Data 
In in-vitro studies, Ofatumumab has shown more complement dependent cytotoxicity (CDC) 
than rituximab (13). It has similar binding to CD20 as rituximab, but has a slower off rate which 
contributes to increased CDC (13). Ofatumumab targets an epitope on the small extracellular 
loop of CD20 in contrast to rituximab which targets only the large extracellular loop of CD20 


 
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(14). This proximity of target may also contribute to increased CDC. Importantly, Ofatumumab 
is able to lyse cells that are insensitive to rituximab due to their low CD20-expression (13). 
 
1.2.2. Clinical Data 
Coiffier et al demonstrated the safety and efficacy of ofatumumab in 33 patients with 
relapsed/refractory B cell CLL (15). They dose escalated ofatumumab to initial 500 mg infusion 
followed by three 2000 mg infusions. The response rate was 50%. The majority of adverse 
effects occurred at the time of first infusion and decreased with subsequent infusions. 51% of 
patient’s experienced infectious complication and majority (88%) were Grade 1 or 2.  
Hagenbeek et al reported use of ofatumumab in 40 patients with relapsed/refractory low grade 
(Grade 1 or 2) follicular lymphoma (16). They escalated the dose to 4 weekly infusions of 1000 
mg. As seen by Coiffier et al, the majority of adverse effects occurred on the first infusion day 
and declined with subsequent infusions, which was similar to the infusion reactions observed 
with rituximab. Twenty infectious adverse effects were noted and 2 were Grade 3.The clinical 
response ranged from 20%-63%. Based on these studies, it has been established that ofatumumab 
is safe to give as a single agent in B cell lymphomas. 
 
1.2.3. Adverse Events Noted in Follicular Lymphoma Subjects: 
Gastrointestinal: nausea, vomiting, abdominal pain.CGM2008/00147/04 
Respiratory: pharyngolaryngeal pain, dyspnoea, cough, bronchospasm. 
Skin: rash, pruritus, urticaria, flushing. 
General and Administration Site Conditions: hypotension, influenza-like illness, fatigue, fever, 
chills, headache, dizziness, hyperhidrosis, cytokine release syndrome, infusion-related reaction. 
Musculoskeletal: arthralgia, myalgia. 
Immune System: hypersensitivity. 
 
1.2.4. Ofatumumab Combination Therapy 
Ofatumumab has been evaluated in combination with chemotherapy for treatment of chronic 
lymphocytic leukemia (CLL) and other lymphoid malignancies. Czuczman et al presented 
(ASCO 2010 Abstract No 8042) clinical data of combination ofatumumab with CHOP 
(cyclophosphamide, doxorubicin, vincristine and prednisolone) chemotherapy in previously 
untreated 59 patients with follicular lymphoma (17). Patients were randomized to 2 groups: 
Ofatumumab dose 500 mg (Group A) or 1,000 mg (Group B). The combination was well 
tolerated and had a CR/CR unconfirmed of 76% in patients with FLIPI (Follicular lymphoma IPI 
score) of 3-5 at a median follow up of 9.7 months. Ofatumumab infusion-related reactions were 
primarily Grade 1-2; 2 patients had Grade 3 reactions during first dose, but were able to receive 
subsequent doses. The most common Grade 3-4 adverse events were leukopenia and neutropenia 
(31 and 28%, Group A; 28 and 17%, Group B). Incidences of Grade 3-4 leukopenia and 
neutropenia were 83 and 90% in Group A and 72 and 90% in Group B, respectively. Grade 3-4 
infections occurred in 10% of pts in Group A and 3% in Group B, with febrile neutropenia in 7 
and 3% of pts, respectively. No deaths have been reported. 
 
Wierda et al (ASCO 2010, abstract 6520) reported preliminary results of a phase II trial 
investigating the efficacy and safety of two dose levels of Ofatumumab-FC (fludarabine, 
cyclophosphamide) in previously untreated patients with CLL (18). Sixty one patients were 
randomized to ofatumumab 500 mg (Group A) or 1,000 mg (Group B) Day 1, with FC 


 
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chemotherapy. Due to the short follow up (8 months) at the time of presentation, response rates 
were not reported. The same group published preliminary results in 2011 (19).  A total of 61 
patients were treated in the study. Treatment response was assessed using the 1996 NCI 
Guidelines. The CR rate was 32% in patients who received 500 mg of ofatumumab (n=31) and 
50% in patients who received 1000 mg of ofatumumab (n=30). The overall response rate was 
77% in the 500 mg treatment group and 73% in the 1000 mg treatment group. There were no 
unexpected safety findings reported during treatment and within 30 days after last infusion. The 
most common adverse event reported was neutropenia at 48%. Other common adverse events 
(greater that 15 percent) were nausea, leukopenia, rash, vomiting, pyrexia, headache and 
thrombocytopenia. The number of patients, who experienced adverse events, including serious 
adverse events, was similar between the two dose groups. One death was reported and was 
judged by the investigator as unrelated to ofatumumab. 
 
The safety of ofatumumab combinations has been addressed in multiple studies. 
There are several ongoing trials that are registered on the clinicaltrials.gov website looking at the 
safety and efficacy of ofatumumab in combination with chemotherapy in patients with 
lymphoma. NCT01014208 is a randomized trial ‘Ofatumumab Versus Rituximab Salvage 
Chemoimmunotherapy Followed by ASCT in Relapsed or Refractory DLBCL”. This study plans 
to enroll 380 patients with relapsed/refractory DLBCL and has been enrolling since March 2010. 
Patients are randomized to ofatumumab plus chemotherapy- DHAP (cisplatin, cytarabine and 
dexamethasone) or DVD (DHAP Cycle 1 and 3, VIM-etoposide, ifosfamide and methotrexate 
Cycle 2) or rituximab plus chemotherapy-DHAP or DVD. The primary endpoint of this trial is 
PFS. Another Phase II trial is “A Single Arm, Safety and Efficacy Study of Ofatumumab in 
Combination With ICE or DHAP Chemotherapy in Relapsed or Refractory Aggressive 
Lymphoma Prior to Autologous Stem Cell Transplantation” NCT00823719. In this Phase II 
trial, patients with relapsed/refractory DLBCL, transformed follicular lymphoma or Grade 3b 
follicular lymphoma will be treated with ofatumumab in combination with ICE chemotherapy or 
DHAP chemotherapy prior to autologous stem cell transplantation. The primary endpoint of this 
study is ORR. This study has been opened and accruing since May 2009 and is expected to be 
completed by December 2011. The Ofatumumab-ICE arm in this trial is comparable to our 
proposed study, except for a novel alkylating agent bendamustine which in our trial will 
substitute ifosfamide.  
 
1.3 Bendamustine 
On October 31, 2008, the U.S. Food and Drug Administration (FDA) approved bendamustine 
hydrochloride (TREANDA®, Cephalon, Inc.), an intravenously administered alkylating agent, 
for the treatment of patients with indolent B-cell NHL that progressed during or within six 
months of treatment with rituximab or a rituximab-containing regimen. The recommended dose 
for NHL is 120 mg/m2 on day 1 and 2 of each cycle. Bendamustine is an alkylator/purine 
analogue hybrid cytotoxic drug with a distinct pattern of activity, different from other alkylators 
(20).Bendamustine has demonstrated single agent activity in lymphomas refractory to other 
alkylating agents, such as cyclophosphamide. Friedberg et al showed the safety and efficacy of 
single agent Bendamustine in 76 patients with indolent or transformed NHL that was refractory 
to rituximab (21). Patients were treated with bendamustine 120 mg/m2 on day 1 and 2 every 3 
weeks for 6 cycles as long as they had a response or stable disease. Fifteen patients required dose 
reduction to 90 mg/m2 and 4 needed reduction to 60 mg/m2. The most common adverse effects 


 
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were hematological. Grade 3 or 4 neutropenia occurred in 54%, thrombocytopenia in 25% and 
anemia in 12%. The overall response rate was 77% in this study. In another multicenter study, 
Kahl et al evaluated the response to a single agent Bendamustine in 100 patients with rituximab 
refractory indolent B cell lymphoma (22). Treatment consisted of bendamustine 120 mg/m2 on 
day 1 and 2 every 3 weeks for 6-8 cycles as long as response or stable disease occurred. Twenty 
four patients had dose reductions, 20 patients to 90 mg/m2 and 4 to 60 mg/m2. They achieved a 
similar overall response rate of 75%. Grade 3 or 4 hematological toxicities included neutropenia 
(61%), thrombocytopenia (25%) and anemia (10%). 
 
In in vitro studies, rituximab has shown chemosensitizing effect when used in combination with 
bendamustine in lymphoma cell lines (23). Based on this, Robinson et al investigated the 
efficacy of combination of Bendamustine and Rituximab in 67 patients with relapsed indolent 
lymphoma and mantle cell lymphoma (24). In this study patients received rituximab 375 mg/m2 
on day 1 and bendamustine 90 mg/m2 days 2 and 3 of a 28-day cycle for 4-6 cycles. An 
additional dose of rituximab was administered 1 week before the first cycle and 4 weeks after the 
last cycle. The combination was well tolerated and the primary toxicity was hematological; 
Grade 3 or 4 neutropenia (36%), Grade 3 or thrombocytopenia (9%) and anemia (2%). Ten 
episodes of Grade 3 or 4 infections occurred. Overall response rate was 93% in indolent 
lymphomas and 92% in mantle cell lymphomas.  
 
Bendamustine has also been used in combination with mitoxantrone and rituximab. Weide et al 
from the German Lymphoma study group used this combination in 57 patients with relapsed and 
refractory indolent lymphomas and mantle cell lymphomas (25). Treatment consisted of 
bendamustine 90 mg/m2 on days 1 and 2, mitoxantrone 10 mg/m2 on day 1 rituximab 375mg/m2 
on day 8; repeated every 4weeks for four cycles. Grade 3 or 4 adverse events included anemia 
(10%), thrombocytopenia (16%), and neutropenia (46%). ORR was 89%, 92% in follicular 
lymphoma and 78% in mantle cell lymphoma. Vacirca et al presented preliminary data of 
bendamustine and rituximab combination in aggressive B cell lymphomas at 2010 ASCO 
meeting (26). Bendamustine was given at 120 mg/m2 on day 1 and 2 and rituximab 375mg/m2 
on day 1 of a 28 day cycle for 6 cycles. Efficacy data showed ORR of 53% in 17 evaluable 
patients. The combination was safe, in 76 cycles 1 Grade 4 neutropenia and 9 additional Grade 3 
events. Thus, bendamustine combinations have shown to be effective and can be given safely in 
patients with relapsed lymphomas.  
 
1.4 Ofatumumab and Bendamustine Combinations 
A total of 10 phase I/II and phase III studies of ofatumumab and bendamustine combination 
regiments have been registered to date on the ‘clinicaltrials.gov’ site and at least 5 of them have 
been actively recruiting patients with NHL and CLL. Among them are the following trials: 
 A Phase II study of Ofatumumab and Bendamustine for Previously Treated CLL and 
small lymphocytic lymphoma (SLL) has been accruing patients since 2009. Ofatumumab 
is given at 300-mg IV on Day 1 of week -1 and then 1000 mg on Day 1 of each cycle for 
6 cycles and Bendamustine is given at 70 mg/m2 IV on days 1 and 2 of each cycle for 6 
cycles. The primary outcome of the study is the overall response rate. Clinical trial 
identifier: NCT01010568. 
 A Phase I/II Trial of Dexamethasone, Ofatumumab and Bendamustine as first-line 
treatment of Mantle-cell Lymphoma (MCL) in the elderly has been recruiting patients 


 
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since 2010.The starting dose of the 2 main component drugs is the MTD of each drug as 
single agent. Ofatumumab infused iv on day 1 at 300 mg during the first cycle, followed 
by infusions of 1000 mg on day 1 of each subsequent cycle Bendamustine infused iv at 
the dose of 120 mg/m2 (days 2, 3 every 21 days) or 120 mg/m2 (days 2, 3 every 28) or 90 
mg/m2 (days 2, 3 every 28 days) depending on toxicity Dexamethasone administered i.v. 
at 40 mg (days 1, 2, 3, 4). The primary endpoint of the phase II part of the study is the 
complete remission rate. Clinical trial identifier: NCT 01221103. 
 A Phase III study of ofatumumab plus bendamustine versus bendamustine alone has been 
opened for patients with indolent B-cell NHL who did not respond to rituximab or 
progressed on a rituximab-containing regimen during or within six months of the last 
rituximab treatment. A total of 338 patients in this open label study will be randomized to 
receive either ofatumumab in addition to bendamustine or bendamustine alone.  Each 
group will receive up to eight cycles of bendamustine while the combination group will 
be given ofatumumab on day one of each cycle.  Once patients in the combination group 
have completed bendamustine therapy, they will continue to receive ofatumumab 
monthly until 12 doses have been given.  The primary endpoint of the study is 
progression free survival. Clinical trial identifier: NCT01077518. 
1.5. Study Rationale: 
Bendamustine in combination with ofatumumab containing therapy may present a novel 
attractive salvage regimen for relapsed aggressive B cell lymphomas. We propose a novel RICE-
like salvage combination regimen in which rituximab is substituted with ofatumumab and 
ifosfamide with bendamustine in combination with carboplatin and etoposide for refractory or 
relapsed aggressive B cell lymphomas. We hope to avoid the substantial well recognized 
ifosfamide mediated bladder toxicity (incidence of Grade 3 and 4 hemorrhagic cystitis in 8-12%) 
and neurologic toxicity (incidence 10-30%; namely, somnolence, confusion, psychosis and 
seizure) by substituting ifosfamide for bendamustine. Bendamustine has a single agent activity in 
relapsed aggressive lymphomas, including those refractory to other alkylating agents, and has 
shown a favorable safety profile in combination with other chemotherapeutic agents, as noted 
above. The proposed regimen is convenient and, unlike RICE, can be administered on the 
outpatient basis which presents an additional benefit to the patients and to the providers.  
 
We will first determine safety and toxicity of escalating dose bendamustine in combination with 
fixed doses of ofatumumab, carboplatin and etoposide. We recognize that the commonly used 
doses of bendamustine in lymphoid malignancies range from 70-120 mg/m2. The recommended 
dose of bendamustine in NHL is 120 mg/m2 and a dose of 90 mg/m2 has been commonly used 
in combination regimens. Thus, we propose to initiate bendamustine in combination at a dose of 
70mg/m2 and escalate to a dose of 120 mg/m2. 
 
We will determine maximum-tolerated dose (MTD) and dose-limiting toxicity (DLT) of the 
combination by using dose escalation of bendamustine from 70mg/m2 in a standard 3 by 3 
design. We will then assess efficacy of the combination regiment at MTD in relapsed and 
refractory aggressive B-cell lymphomas. 
 
1.6 Rationale for the Correlative Studies: 
1.6.1. Analysis of the Surface Expression of CD20 on Malignant Cells in Relapsed 


 
Protocol Version 6.3 
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Aggressive B-cell Lymphomas    
 CD20 is a mature B cell marker and is present on the surface of most B cell lymphomas with 
variable level of expression. Rituximab which is a human/mouse chimeric monoclonal antibody 
is widely used in the treatment of B cell neoplasms. In-vitro studies have shown a transient 
decrease in CD20 expression after treatment with rituximab (27). When B cell lymphomas 
relapse, the CD20 expression may be decreased, thus making rituximab less effective in the 
relapsed setting. In in-vitro studies, Ofatumumab has shown more complement dependent 
cytotoxicity (CDC) than rituximab (12). Importantly, Ofatumumab is able to lyse cells that are 
insensitive to rituximab due to their low CD20-expression (see section 1.2). Based on these data 
ofatumumab may be more effective at targeting B cells in the relapsed setting. The level of CD 
20 expression on malignant B cells is variable and we will assess the level of CD20 expression in 
patients with relapsed B cell lymphomas. In addition, we will prospectively evaluate if the level 
of CD20 expression correlates with the response to the Ofatumumab based combination 
chemotherapy. To assess the level of CD20 expression we will use IHC based scoring system in 
all studied paraffin tissues. In addition, flow cytometry analysis for CD20 expression distribution 
will be performed in all available fresh tissue samples.  
 
1.6.2. Biologic Profile of Relapsed and Refractory Aggressive B-cell Lymphomas 
DLBCL is a group of aggressive B cell lymphomas which encompass a variety of biologic 
entities with variable clinical and prognostic features. Based on cDNA microarray analysis 
(Rosenwald 2002), DLBCL have been subdivided into two large prognostic subgroups that 
include germinal-center B-cell– (GCB) and activated B-cell–type (ABC) DLBCL (28). When 
treated with standard chemotherapeutic regiments, the GCB group has significantly better 
prognosis as compared to the ABC.  Hans et al used immunohistochemistry techniques to further 
characterize the above two prognostic categories (29). They identified GCB type as CD10 
positive, Bcl-6 positive and MUM-1 negative or as CD10 negative, Bcl-6 positive and MUM-1 
negative and non-GCB type as CD10 negative, Bcl-6 negative and MUM-1 positive or CD10 
negative, Bcl-6 postive and MUM-1 positive. In concert with the data presented by Rosenwald et 
al, the GCB type had an improved overall survival as compared to non-GCB type. In addition, 
Hans et al. assessed Bcl-2 expression in studied samples and Bcl-2 positive subjects had a 
significantly shorter overall survival as compared to Bcl-2 negative. We will evaluate the rate of 
ABC and GCB type among the accrued patients with relapsed or primary refractory lymphomas 
and will follow them for responses to the investigational regimen.   
 
Novel prognostic subcategories have recently been identified among aggressive B cell 
lymphomas. Among them EBV positive B cell lymphoma of the elderly is an increasingly 
recognized biologic entity. Based on morphology and immunophenotype these cases 
overwhelmingly fall into DLBCL category, however, they have distinct clinical presentation and 
tend to relapse or show resistance to R-CHOP-like therapy. It is seen in immunocompetent 
elderly subjects and is associated with a worse clinical outcome (30). In our study, we will assess 
the rate of EBV positive cases among the studied patients with relapsed and refractory aggressive 
B cell lymphomas. We will evaluate EBER expression in tumor tissue using in-situ hybridization 
technique and will evaluate response rate to the investigational rescue therapy in this poor 
prognostic group. 
 


 
Protocol Version 6.3 
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‘Double hit' lymphomas (DH) is a subset of DLBCL with chromosomal breakpoint in cMYC 
locus in combination with another breakpoint, usually Bcl-2, but also BCL-6 (31). These 
lymphomas were recognized in the 2008 WHO classification as a provisional entity entitled “B 
cell lymphoma unclassifiable with features intermediate between DLBCL and BL.” They have 
an adverse prognosis when treated with RCHOP based chemotherapy (31). Cyclin D1+/MYC+ 
represents a variant of mantle cell lymphoma also with a very poor response to standard 
chemotherapy and dismal outcome.   
 
We hypothesize that a high prevalence of the above newly recognized biologic entities will be 
identified in the studied group of patients. We propose to evaluate the rate of the above biologic 
markers in this unfavorable group of patients who have presented with relapsed or primary 
refractory disease. We will assess all available tissue samples for CD10, Bcl 6 and MUM1, 
expression by immunohistochemistry; EBER expression by in-situ hybridization and Bcl-2, Bcl-
6+, Cyclin D1 and cMYC by FISH analysis. We will prospectively assess patients’ clinical 
characteristics and objective responses to the investigational chemotherapy in these biologically 
determined subgroups. 
 
1.6.3. Validation of Oligonucleotide-based Microarray Platform for NHL Risk 
Stratification 
The combination of karyotype analysis and fluorescence in situ hybridization (FISH) has 
revealed key chromosomal abnormalities in various hematologic malignancies, such as acute 
myelogenous and acute lymphocytic leukemias, chronic lymphocytic leukemias, myelodysplastic 
syndrome and multiple myeloma. In contrast, NHL is associated with only a few unique 
chromosomal abnormalities, such as c-Myc, t(11;14), t(14;18) and little is known yet if other key 
aberrations may be identified and used to risk-stratify large NHL groups, such as DLBCL. A 
novel genome-wide microarray technology reveals submicroscopic chromosome aberrations, 
which can’t be picked by conventional cytogenetic analysis and FISH studies (32). We propose 
to identify submicroscopic chromosome aberrations in patients with well-defined diagnoses of 
the selected clinically unfavorable group of B cell NHL. We will perform a comprehensive 
biologic profiling of the biopsy samples of the study group as described above and will use 
OncoChip cytogenetcs platform to determine if there are identifiable unique biologic and 
cytogenetic features upon which risk-group stratification may develop. The Cancer Microarrays 
Signature OncoChip technology (Signature Genomic Laboratories) has the ability to detect 
clinically relevant copy-number imbalances as well as submicroscopic gains and losses not seen 
by conventional cytogenetics. By using microarray platform the OncoChip™ can simultaneously 
identify balanced translocations as well as the translocation breakpoints and their partners. We 
will use this comprehensive system to analyze DNA from cryopreserved or fresh diagnostic 
NHL samples. We will assess these submicroscopic chromosomal aberrations in parallel with the 
conventional karyotype and FISH studies. We will determine the feasibility of incorporating a 
newly developed oligonucleotide-based microarray platform into NHL risk stratification 
analysis.  
 
2 STUDY OBJECTIVES  
2.1 Primary Objective for Phase I Part of the Study: 
To determine the safety and toxicity profile of bendamustine in combination with ofatumumab, 
carboplatin and etoposide for patients with refractory or relapsed aggressive B cell lymphomas. 


 
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2.2 Secondary Objective for Phase 1: 
To determine the overall frequency of response; overall response will include all subjects with 
complete response (CR) and partial response (PR).   
 
2.3 Primary Objective for Phase II Study: 
To determine the overall frequency of response with combination bendamustine, ofatumumab, 
carboplatin and etoposide for refractory or relapsed aggressive B cell lymphomas. 
 
2.4 Secondary Objectives for Phase II Study: 
 To determine CR and PR rate  
 To determine 1 and 2 year progression free survival. 
 To determine 1 and 2 year overall survival. 
 Among transplant eligible patients to determine the proportion of patients who are able to 
undergo stem cell transplant. 
 To define safety and toxicity of the combination of ofatumumab, bendamustine, 
carboplatin and etoposide for refractory or relapsed aggressive B cell lymphomas. 
 To evaluate the level of CD20 expression in the various biologic types of relapsed 
aggressive B cell lymphomas and to correlate that with response to the study regimen.  
 
3 STUDY DESIGN 
Figure 1
 
 
3.1 General Design Phase 1 
The Phase I study is designed to identify dose limiting toxicities (DLT) and to define maximum 
tolerated dose (MTD) of bendamustine in combination with ofatumumab, carboplatin and 
etoposide in refractory and relapsed aggressive B cell lymphomas. Dose escalation will allow the 
identification of maximum-tolerated dose (MTD) and dose-limiting toxicity (DLT) for 
bendamustine given i.v. on day 1, 2 schedule in combination with fixed doses of ofatumumab, 


 
Protocol Version 6.3 
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carboplatin and etoposide. At each dose level DLT will be assessed during a minimum of one 
cycle period.  
 
Schema for Phase 1 
Number of Patients with 
DLT at a Given Dose Level Escalation Decision Rule 
0 out of 3 
Enter 3 patients at the next dose level. 
>2 
Dose escalation will be stopped.  This 
dose level will be declared the 
maximally administered dose (highest 
dose administered).  Three (3) 
additional patients will be entered at the 
next lowest dose level if only 3 patients 
were treated previously at that dose. If 
>2 DLT at (-1) dose level, the study 
will be terminated. 
1 out of 3 
Enter at least 3 more patients at this 
dose level. 
 If 0 of these 3 additional patients 
experience DLT, proceed to the next 
dose level. 
 If 1 or more of the 3 additional 
patients suffer DLT, then dose 
escalation is stopped, and this dose is 
declared the maximally administered 
dose.  Three (3) additional patients 
will be entered at the next lowest 
dose level if only 3 patients were 
treated previously at that dose. 
<1 out of 6 at highest dose 
level below the maximally 
administered dose 
This will be the recommended phase 2 
dose. At least 6 patients must be 
entered at the recommended phase 2 
dose. 
 
Dose Escalation Schedule: 
 
 
 
 
 
 
 
 
Dose level 
Dose of Bendamustine 
Level 1 
70 mg/m² 
Level 2 
90 mg/m² 
Level 3 
120 mg/m² 
Level -1 
50 mg/m² 


 
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3.2 General Design for Phase II 
After MTD of the combination is established from the Phase 1 part of the study, patients with 
relapsed/refractory aggressive B cell-NHL will be enrolled in the Phase II study to determine the 
efficacy of the combination regimen. The Phase II study will be a single-arm, open-label study in 
which all patients will receive combination bendamustine, ofatumumab, carboplatin and 
etoposide (at the MTD dose  defined in phase I) for a maximum of 3 cycles. 
Patients will be followed on the study until disease progression, unacceptable toxicity, or 
withdrawal of consent or for total of 2 years post completion of therapy (whichever is earlier). 
 
3.3 Primary Study End Point for Phase I 
Maximum tolerated dose which is determined using a dose escalation protocol for bendamustine 
in combination with fixed doses of ofatumumab, carboplatin and etoposide. 
 
3.4. Secondary Study End Point for Phase I 
Overall response frequency which is determined as cumulative complete response (CR) and 
partial response (PR) in the studied group 
 
3.5 Primary Study End Point for Phase II 
Overall Response which is determined as cumulative CR and PR in the studied group. The 2007 
Revised Cheson Criteria for NHL will be used to assess response (33); see appendix 5. 
 
CR will be determined if meets all of the following requirements:  
 PET positive prior to therapy: mass of any size permitted if PET negative. Variably FDG-
avid or PET negative prior to therapy: regression to normal size on CT (≤ 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). 
 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. 
 If bone marrow is known to be involved before treatment, then repeat biopsy documents 
clearance 
 
PR will be determined if meets the following requirements: 
1. ≥ 50% decrease in SPD of up to 6 largest dominant masses  
a. FDG-avid or PET positive prior to therapy: one or more PET positive at  previously 
involved site 
b. Variably FDG-avid or PET negative: regression on CT 
2. No new sites of disease or 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. 
 
3.6. Secondary Study End Points for Phase II 
1. CR and PR, assessed per the 2007 Revised Cheson Criteria for NHL (33) 
2. 1 and 2 year progression free and overall survival 
3. Safety and toxicity of the combination of bendamustine, ofatumumab, carboplatin and 
etoposide for refractory or relapsed aggressive B cell lymphoma. Toxicity will be 


 
Protocol Version 6.3 
23 
assessed 
according 
to 
the 
NIH 
CTCAE 
version 
4.0 
(http://ctep.cancer.gov/reporting/ctc.html). Toxicity refers to toxic events during the full 
course of treatment that are attributed as possibly, probably or definitely due to treatment. 
For details of toxicity assessment see Section 8.0. 
4. Tolerability of the combination of bendamustine, ofatumumab, carboplatin and etoposide 
for refractory or relapsed aggressive B cell lymphomas. 
o Tolerability of this regime will be compared to historical controls who received 
RICE protocol 
o Subjects who discontinue therapy prior to Cycle 3 in order to undergo stem cell 
collection and transplant are considered to have successfully completed therapy. 
5. Among transplant eligible patients, the frequency of subjects who undergo autologous or 
allogeneic stem cell transplant. 
 
3.7 Primary Safety End Points    
Toxicities will be graded according to the National Cancer Institute Common Terminology 
Criteria (CTCAE version 4.0). DLT will be defined as any Grade 4 infection, or Grade >/= 3 
non-hematologic toxicity that persists for 7 days or more 
 
4. Subject Selection and Withdrawal 
4.1 Inclusion Criteria: 
1. Age 18 and above 
2. Patients with histologically confirmed aggressive B cell lymphoid malignancy, such as 
DLBCL, including primary mediastinal large B cell lymphoma, T cell rich B cell 
lymphoma, “double hit” DLBCL, mantle cell lymphoma, any transformed low grade B 
cell lymphomas or Grade 3 follicular lymphoma (Grade 3a or 3b) who were refractory to 
RCHOP-like or any anthracycline based chemotherapy or relapsed after at least one prior 
combination chemotherapeutic regimen and who are deemed candidates for a salvage 
type chemotherapy. 
Relapsed disease:  
 Progressive disease after a CR for at least 28 days. Progression will be defined 
according to the Revised Response Criteria for Malignant Lymphoma (Cheson 
2007 (33). 
 
             Refractory disease: 
 Subjects must meet one of the following criteria: 
 Persistent or progressive lymphoma with a CR of <28 days duration or with a PR 
of any duration.  Subjects must have received at least 3 cycles of RCHOP-like or 
any anthracycline base chemotherapy or at least 2 full cycles of HyperCVAD – 
like chemotherapy.             
 Persistent lymphoma and stable disease after at least 2 cycles of RCHOP-like or 
any anthracycline base chemotherapy or at least 1 full cycle of HyperCVAD – 
like chemotherapy (part A and B). 
 Progressive disease despite at least 1 cycle of RCHOP-like or any anthracycline 
base chemotherapy or at least 1 cycle (part A or A and B) of HyperCVAD – like 
chemotherapy 
3. Measurable disease, defined by the revised lymphoma criteria (Cheson 2007). 


 
Protocol Version 6.3 
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4. Absolute neutrophil count ≥1,500 and platelet count ≥ 75,000, unless due to underlying  
lymphoma. 
5. Left ventricular ejection fraction estimated by MUGA scan or 2D-echocardiogram of at 
least 45% Cardiology consult is recommended prior to enrolment if a history of coronary 
artery disease, CHF with estimated LVEF of <50% or clinically significant arrhythmia.   
6. Estimated glomerular filtration rate (GFR) must be ≥ 50 mL/min  
7. Serum bilirubin ≤ 1.5 × upper limit of normal (ULN) unless deemed elevated secondary 
to lymphoma involvement of the liver or known Gilbert’s syndrome.  
8. Aspartate transaminase (AST)/alanine transaminase (ALT)  2.5 × ULN; unless elevated 
secondary to lymphoma involvement of the liver 
9. Alkaline phosphatase  2.5 × ULN; unless elevated secondary to lymphoma involvement 
of the liver. 
10. Performance status of ECOG 0-2.  
11. Both potentially AutoSCT or AlloSCT candidates and those who are not transplant 
candidates are eligible for the study. 
12. Capable of understanding the investigational nature, potential risks and benefits of the 
study, and able to provide valid informed consent and HIPAA consent. 
13. Female patients of childbearing potential must have a negative serum pregnancy test 
within 3 days prior to enrollment.   
14. Male and female patients of reproductive potential must use an effective contraceptive 
method during the study and for a minimum of 1 year after the after study treatment. 
15. Must be able to comply with study and follow up requirements 
 
4.2 Exclusion Criteria: 
1. Current concomitant chemotherapy, radiation therapy, or immunotherapy other than as 
specified in the protocol.  Concomitant use of corticosteroids is permitted as clinically 
indicated.   
2.  Use of investigational agents within 4 weeks prior to enrollment.  
3. Any anticancer therapy within 3 weeks before study entry. This exclusion does not apply 
to corticosteroid therapy. The patient must have recovered from all acute toxicities from 
any previous therapy. 
4. Radioimmunotherapy (i.e. Zevalin) within 8 weeks of enrollment. 
5. Prior treatment with anti-CD20 monoclonal antibody or alemtuzumab within 4 weeks 
prior to start of therapy. 
6. Autologous stem cell rescue within 12 weeks before study enrollment or those who 
underwent allogeneic stem cell transplant within one year of enrollment. 
7. Known leptomeningeal or parenchymal brain involvement with lymphoma unless in 
complete remission after treatment for at least 12 weeks with negative CSF cytology 
within 2 weeks. Prophylaxis of CNS disease using intrathecal or intraventricular dosing 
of cytotoxic regimens is permitted and should be performed according to the discretion of 
the treating physician. 
8. History of serious organ dysfunction or disease involving the heart, kidney, liver or other 
organ system that may place the patient at undue risk to undergo treatment. 
9. Systemic fungal, bacterial, viral, or other infection if not controlled.  Defined as 
exhibiting ongoing signs/symptoms related to the infection and without improvement, 
despite appropriate antibiotics or other treatment.  (May be enrolled if controlled on 


 
Protocol Version 6.3 
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treatment). 
10. Significant concurrent disease, illness, or psychiatric disorder that would compromise 
patient safety or compliance, interfere with consent, study participation, follow up, or 
interpretation of study results. 
11. Subjects who have current active hepatic or biliary disease (with exception of patients 
with Gilbert's syndrome, asymptomatic gallstones, liver metastases or stable chronic liver 
disease per investigator assessment) 
12. History of significant cerebrovascular disease in the past 6 months or ongoing event with 
active symptoms. 
13. Clinically significant cardiac disease including unstable angina, acute myocardial 
infarction within six months prior to randomization, congestive heart failure (NYHA III-
IV), and arrhythmia unless controlled by therapy, with the exception of extrasystoles or 
minor conduction abnormalities. 
14. Other malignancy, unless the patient has been disease-free for at least 3 years following 
the completion of curative intent therapy, with the following exceptions: treated non-
melanoma skin cancer, any in situ carcinoma, or cervical intraepithelial neoplasia, 
regardless of the disease-free duration, are eligible for this study if definitive treatment 
for the condition has been completed. Organ-confined prostate cancer with no evidence 
of recurrent or progressive disease based on prostate-specific antigen (PSA) values are 
also eligible for this study if hormonal therapy has been initiated, or radical 
prostatectomy or definitive prostate irradiation has been performed. 
15. Positive test for the Human Immunodeficiency Virus (HIV), unless undetectable viral 
load within 3 months of enrollment (HIV RNA less than 48 copies/mL) on HAART 
therapy. 
16. Positive serology for Hepatitis B (HB) defined as a positive test for HBsAg. . Patients 
with prior history of Hepatitis B infection, but immune, with only IgG Hepatitis core 
antibody + (HBcAb +) must be checked for hepatitis B virus titers by PCR and if the viral 
load is undetectable may be enrolled. These patients must receive anti-viral prophylaxis, 
such as lamivudine 100 mg po daily (or an equivalent) starting at least one week prior to 
cycle 1 and continued through the completion of treatment and for 9 months after the last 
dose of ofatumumab. Hepatitis B virus titers by quantitative PCR and HBsAg should be 
checked every month (+/- 1 week) while on therapy and every 3 months (+/- 1 month) 
thereafter for 9 months after the last ofatumumab dose. In the event of an early 
termination of the clinical trial for any reason, a treating physician will be determining 
the frequency and the length of follow up studies of hepatitis B virus titers and HBsAg 
status. It is recommended that the patient remains on prophylactic lamivudine or an 
equivalent, as above, regardless of whether the study was continued or terminated. In 
addition, if appropriate consultation with a hepatologist should be obtained. 
17. Positive serology for hepatitis C (HC) defined as a positive test for HCAb if confirmed 
by HC RIBA immunoblot assay (for positive HCAb reflexively perform a HC RIBA 
immunoblot assay on the same sample) 
18. Pregnant or lactating women. 
 
Inclusion of Women and Minorities 
Both men and women of all races and ethnic groups are eligible for this trial.   
 


 
Protocol Version 6.3 
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4.3 Subject Recruitment and Screening 
Subjects will be recruited from the practices of the Department of Medical Oncology, Thomas 
Jefferson University. Patients who meet eligibility criteria will be invited by their physician to 
participate in the study. All therapeutic options will be discussed with the patient and the 
patient’s questions will be answered to the patient’s satisfaction. Patients will be asked to read, 
comment/ask questions about the study and then sign the informed consent form before study 
procedures are to take place. 
 
Subjects will be screened based on review of previous diagnostic workup including diagnostic 
tissue biopsy and other laboratory parameters. Another tissue biopsy will be obtained to confirm 
the relapse, if possible and if patient is agreeable. The diagnosis will be confirmed on the basis of 
review of initial diagnostic pathology by our institutional hemato-pathologist. Screening 
laboratory work to be performed will include blood chemistries, viral serologies (for HIV, 
Hepatitis B and Hepatitis C), pregnancy testing (if applicable), physical assessment and other 
tests as per section 6. 
4.4 Early Withdrawal of Subjects 
4.4.1 When and How to Withdraw Subjects 
Patients will be withdrawn from the study if any of the following occurs: 
 Disease progression, 
 Intercurrent illness that prevents further administration of treatment, 
 Unacceptable adverse event(s), 
 Patient noncompliance. 
 Patient decides to withdraw from the study 
 General or specific changes in the patient's condition that render the patient unacceptable 
for further treatment in the judgment of the investigator. 
 Initiation of alternative therapy by the treating physician  
 Stem cell transplant prior to completion of 3 cycles of treatment. Of note, stem cell 
collection is allowed after 2 or 3 cycles upon discretion of TJU bone marrow transplant 
group and study PI or her designee and patients will continue on the trial until initiation 
of a conditioning regimen and SCT, unless excluded due to other conditions as listed 
above. 
 
After withdrawal from the study further treatment for the subject will be per the discretion of the 
treating physician. 
 
4.4.2 Data Collection and Follow-up for Withdrawn Subjects 
In case of early withdrawal of study, attempts will be made to collect data on subjects who have 
received at least 1 cycle of treatment. Survival data will be gathered from the treating physician 
of the subject. If a subject withdrew consent to participate, but allow survival and disease status 
follow up, attempts will be made to record the data up to the protocol-described end of follow-up 
period. Patients will be followed for disease status and survival at Months 3, 6, 9, 12, 18 and 24 
months post treatment or post ASCT with a window of ± 1 month. 
 
5 
Study Drug 
5.1 Ofatumumab 


 
Protocol Version 6.3 
27 
Other Names : Arzerra™ 
Classification : Antineoplastic Agent, Monoclonal Antibody 
Mode of Action: Ofatumumab is an anti-CD20 monoclonal antibody and binds specifically to 
both the small and large extracellular loops of the CD20 molecule. The Fab domain of 
ofatumumab binds to the CD20 molecule and the Fc domain mediates immune effector functions 
to result in B-cell lysis in vitro. Data suggest that possible mechanisms of cell lysis include 
complement-dependent cytotoxicity and antibody-dependent, cell-mediated cytotoxicity. 
 
Incompatibilities: Do not mix drug with or administer as an infusion with other medicinal 
products. 
 
Availability: Novartis will provide Ofatumumab vials presented as either 100mg – acetate 
formulation, 20mg/mL, 5mL fill vials or 1000mg – acetate formulation 20mg/mL, 50mL fill 
vials.  
 
Storage: Refrigerate between 2° to 8°C (36° to 46°F). Do not freeze. Vials will be protected from 
light. Start infusion within 12 hours of preparation. Discard prepared solution after 24 hours.  
 
Preparation: Prepare all doses in 1,000 mL of 0.9% Sodium Chloride Injection, USP. The solution 
will be a colorless and may contain a small amount of visible translucent-to-white, amorphous, 
ofatumumab particles.  
 
Route of Administration: iv infusion 
 
Pre-medications 
Antiemetics (ondansetron 24 mg IV or equivalent) will be administered prior to chemotherapy. 
Acetaminophen 650  mg po, diphenhydramine 50 mg po/iv and dexamethasone 20 mg iv (or 
equivalent) will be given within 30 minutes to 2 hours prior to ofatumumab treatment. If the 2nd 
infusion has been completed without the subject experiencing any Grade 3/4 adverse events 
(AEs), pre-medication with glucocorticoid may be reduced or omitted before the 3rd infusion at 
the discretion of the investigator. 
 
Ofatumumab Infusion 
 
The first dose of ofatumumab will be 300 mg to minimize infusion reactions. The initial rate of 
the first infusion of 300 mg ofatumumab (0.3 mg/mL) will be 12 mL/h. If no infusion reactions 
occur the infusion rate will be increased every 30 minutes, to a maximum of 400 mL/h, 
according to Table below. If this schedule is followed, the infusion duration will be 
approximately 4.6 hours. 
 
Infusion rate at 1st ofatumumab infusion (300 mg) 
Time 
mL/hour 
0 – 30 minutes 
12 
31 – 60 minutes 
25 


 
Protocol Version 6.3 
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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 will be temporarily slowed or interrupted. Upon 
restart, the infusion rate will 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 will be restarted at 12 
mL/hour. Thereafter, the infusion rate may be increased according to the judgment of the 
investigator, in the manner described. 
 
If the previous infusion has been completed without Grade ≥ 3 infusion-associated AEs, the 
subsequent infusion of the 1000 mg of ofatumumab (1 mg/mL) can start at a rate of 25 mL/hour 
and will be doubled every 30 minutes up to a maximum of 400 mL/h, according to Table 4. 
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 will start at a rate of 12 mL/hour according to Table 2. 
 
Infusion rate at subsequent ofatumumab infusion (1000 mg) 
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 subject will be monitored closely and appropriate measurements should be 
performed whenever judged necessary. 
 
Side Effects of Ofatumumab: 
Hematologic: Neutropenia (≥ Grade 3: 42%; Grade 4: 18%; may be prolonged >2 weeks),  
anemia (16%; Grades 3/4: 5%). Prolonged (≥1 week) severe neutropenia and thrombocytopenia 
can occur with ofatumumab. Complete blood counts (CBC) and platelet counts will be monitored 
at regular intervals as described in section 6 
 
Common: (>10% Frequency): Pneumonia, Upper respiratory tract infection, bronchitis, 
anemia, cough, dyspnea, diarrhea, nausea, rash, pyrexia and fatigue. Infusion Reactions  
Ofatumumab can cause significant infusion reactions, including serious. Please see above section 
regarding premedications and ofatumumab infusion.  
 
Occasional: (5-10% Frequency): sinusitis, sepsis, nasopharyngitis, herpes zoster, insomnia, 
headache, hypertension, hypotension, tachycardia, urticaria, hyperhidrosis, back pain, muscle 
spasms, peripheral edema, chills. 
 
Rare but Serious (<5% frequency): 


 
Protocol Version 6.3 
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Severe Infusion Reactions 
Ofatumumab can cause serious infusion reactions. Please see above section regarding 
premedications and ofatumumab infusion 
 
Progressive Multifocal Leukoencephalopathy  
Progressive multifocal leukoencephalopathy (PML), including fatal PML, can rarely occur with 
ofatumumab. PML diagnosis will be considered in any patient with new onset of changes in pre-
existing neurological signs or symptoms. Ofatumumab will be discontinued if PML is suspected, 
and subject will be evaluated for PML including consultation with a neurologist, brain MRI, and 
lumbar puncture.  
 
Hepatitis B Infection and Reactivation  
Fulminant and fatal hepatitis B virus (HBV) infection can occur in patients newly exposed to 
HBV following treatment with ofatumumab. Subjects will be screened for HBV infection before 
initiation of treatment and if positive will be excluded. If subjects develop Hepatitis B during 
treatment, ofatumumab will be discontinued and subjects will be taken off study. 
 
Intestinal Obstruction  
Obstruction of the small intestine was reported in two patients receiving ofatumumab. Subjects 
will have a diagnostic evaluation if obstruction is suspected.  
 
Nursing/Patient Implications:  
Advise patients to contact a healthcare professional for any of the following:  
 
Signs and symptoms of infusion reactions including fever, chills, rash, or breathing problems 
within 24 hours of infusion  
 
Bleeding, easy bruising, petechiae, pallor, worsening weakness, or fatigue  
 
Signs of infections including fever and cough  
 
New neurological symptoms such as confusion, dizziness or loss of balance, difficulty talking 
or walking, or vision problems  
 
Symptoms of hepatitis including worsening fatigue or yellow discoloration of skin or eyes  
 
New or worsening abdominal pain or nausea  
 
Pregnancy or nursing  
 
Advise patients of the need for:  
 
Periodic monitoring for blood counts  
 
Avoiding vaccination with live viral vaccines.  
 
Immunizations  
The safety of immunization with live viral vaccines during or following administration of 
ofatumumab has not been studied. Live viral vaccines will not be administered to subjects within 1 
month of ofatumumab administration.  
 
5.2 Bendamustine 
Other Names: Treanda® 
Classification : Antineoplastic Agent, Alkylating Agent; (Nitrogen Mustard) 


 
Protocol Version 6.3 
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Mode of Action: Bendamustine is a bifunctional mechlorethamine derivative containing a 
purine-like benzimidazole ring. Mechlorethamine and its derivatives form electrophilic alkyl 
groups. These groups form covalent bonds with electron-rich nucleophilic moieties, resulting in 
interstrand DNA crosslinks. The bifunctional covalent linkage can lead to cell death via several 
pathways. Bendamustine is active against both quiescent and dividing cells. The exact 
mechanism of action of bendamustine remains unknown 
 
Reconstitution: Use appropriate precautions for handling and disposal. Reconstitute 25 mg vial 
with 5 mL and 100 mg vial with 20 mL of sterile water for injection to a concentration of 5 
mg/mL; powder usually dissolves within 5 minutes. Prior to administration, dilute appropriate 
dose in 500 mL NS (or D2.51/2NS) to a final concentration of 0.2-0.6 mg/mL; mix thoroughly. 
 
Storage: 
Bendamustine may be stored up to 25°C (77°F) with excursions permitted up to 30°C (86°F). 
Retain in original package until time of use to protect from light 
 
Preparation: Bendamustine will be aseptically reconstituted with Sterile Water for 
Injection, USP per manufacturer’s guidelines. The volume needed for the required dose (based 
on 5 mg/mL concentration) will aseptically withdrawn from the vial and transferred to a 500 mL 
infusion bagof 0.9% Sodium Chloride Injection, USP (normal saline), or  a 500 mL infusion bag 
of 2.5% Dextrose/0.45% Sodium Chloride Injection, USP. The resulting final concentration of 
bendamustine HCl in the infusion bag should be within 0.2 – 0.6 mg/mL. The reconstituted 
solution must be transferred to the infusion bag within 30 minutes of reconstitution. The 
admixture should be a clear and colorless to slightly yellow solution. Any unused solution should 
be discarded according to institutional procedures for antineoplastics. 
 
Route of Administration: iv 
 
Contraindications: Known hypersensitivity (e.g., anaphylactic and anaphylactoid reactions) to 
bendamustine or mannitol. 
 
Availability: Bendamustine hydrochloride for Injection is available commercially and is supplied 
in individual cartons as follows: 
NDC 63459-390-08 Bendamustine hydrochloride for Injection, 25 mg in 8 mL amber single-use 
vial 
NDC 63459-391-20 Bendamustine hydrochloride for Injection, 100 mg in 20 mL amber single-
use vial 
 
Drug Interactions: Inhibitors of CYP1A2 may increase plasma concentrations of bendamustine 
and decrease plasma concentrations of active metabolites. Inducers of CYP1A2 may decrease 
plasma concentrations of bendamustine and increase plasma concentrations of its active 
metabolites. Caution should be used, if concomitant treatment with CYP1A2 inhibitors or 
inducers is needed. 
 
Side Effects of Bendamustine  
Common (>20% Frequency): Nausea, Vomiting, Diarrhea, constipation, fatigue, fever, 
anorexia, headache, cough. 


 
Protocol Version 6.3 
31 
 
Hematological: leukopenia, neutropenia, lymphopenia, anemia, thrombocytopenia occur in 
majority of patients. 
 
Occasional (5-20% Frequency): Tachycardia, Stomatitis, abdominal pain, dyspepsia, 
gastroesophageal reflux, dry mouth, abdominal distention, chills, edema, asthenia, infusion site 
pain, pain, herpes zoster infection, upper respiratory infection, sinusitis, pneumonia, febrile 
neutropenia, oral candidiasis, nasopharyngitis, weight loss, dehydration, hypokalemia, back pain, 
arthralgia, bone pain, pain in extremities, dizziness, dysgeusia, insomnia, anxiety, depression, 
dyspnoea, pharyngolaryngeal pain, wheezing, nasal congestion, rash, pruritis, dry skin, night 
sweats, hyperhidrosis and  hypotension. 
 
Rare but Serious (< 5% Frequency): hyperglycemia (3%), elevated creatinine (2%0, 
hyponatremia (2%), hypocalcemia (2%). Severe hypersensitivity reactions, including Steven-
Johnson syndrome may occur. 
 
Nursing/Patient Implications:  
1. Allergic (Hypersensitivity) Reactions: Patients will be informed of possibility of severe 
allergic reactions including Steven-Johnson syndrome when the drug is used 
concomitantly with allopurinol and other medications known to cause these syndromes. 
Patients should immediately reports any rash, facial swelling, or difficulty breathing. 
2. Myelosuppression. Monitor CBC. Advice patients of increased risk of infection with 
absolute neutrophil count less than 500 cells/mm³ and increased risk of bleeding with 
platelet counts less than 20,000 cells/ mm³. Advise patients to call the office if they 
develop a fever above 100.4ºF or notice any easy bruising, petechiae (pinpoint red spots 
on skin), or prolonged bleeding. 
3. Pregnancy and nursing. The drug can cause fetal harm. Women who are pregnant or 
become pregnant will be excluded from the study and will be advised to avoid becoming 
pregnant throughout treatment and for 12 months after treatment. Men receiving the drug 
should use reliable contraception for the same time period. Any pregnancy will be 
reported. Nursing mothers will be excluded from study. 
4. Fatigue. Patients will be advised to avoid driving and operating heavy machinery as the 
drug may cause fatigue. 
5. Nausea and Vomiting. Advise patients that the drug may cause nausea and/or vomiting. 
Antiemetics will be administered as indicated. 
6. Diarrhea. Advise patients that the drug may cause diarrhea.  
7. Rash. Advise patients to immediately report severe or worsening rash. 
 
5.3 Etoposide 
Other Names: VP 16  
 
Classification: Podophyllotoxin derivative, topoisomerase II inhibitor 
 
Mode of Action: Two different dose-dependent responses are seen. At high concentrations (10 
mcg/mL or more), lysis of cells entering mitosis is observed. At low concentrations (0.3 to 10 
mcg/mL), cells are inhibited from entering prophase. It does not interfere with microtubular 


 
Protocol Version 6.3 
32 
assembly. The predominant macromolecular effect of etoposide appears to be DNA synthesis 
inhibition. 
 
Storage and Stability: Store at controlled room temperature 15° to 30°C. Unopened vials are 
stable for 24 months at room temperature (25°C). Vials diluted as recommended to a 
concentration of 0.2 to 0.4 mg/mL are stable for 96 and 24 hours, respectively, at room 
temperature (25° C) under normal room fluorescent light in both glass and plastic containers. 
 
Preparation: Etoposide Injection will be diluted with either 5% Dextrose Injection, USP or 0.9% 
Sodium Chloride Injection, USP to give a final concentration of 0.2 to 0.4 mg/mL.  
 
Route of Administration: i.v 
 
Availability: Etoposide is available commercially for intravenous use as a sterile 20 mg/mL 
solution in 5 mL, 25 mL, or 50 mL sterile multiple dose vials. Each mL contains 20 mg 
Etoposide. Etoposide Injection 20 mg/mL is supplied as follows: 
NDC Number Size 
0703-5643-01 100 mg 5 mL Multiple Dose Vials 
0703-5643-03 100 mg 5 mL Multiple Dose Vials 
0703-5646-01 500 mg 25 mL Multiple Dose Vials 
0703-5646-03 500 mg 25 mL Multiple Dose Vials 
Also available as: 
0703-5667-01 1 gram 50 mL Multiple Dose Vials 
5 mL and 25 mL vials are available individually or packaged 10 per shelfpack. 
50 mL vials are individualy packaged. 
 
Side Effects of Etoposide 
Common (>20% frequency): Alopecia (8% to 66%), Nausea/vomiting (31% to 43%), 
Leukopenia (60% to 91%; Grade 4: 3% to 17%; nadir: 7-14 days; recovery: by day 20), 
thrombocytopenia (22% to 41%; Grades 3/4: 1% to 20%; nadir 9-16 days; recovery: by day 20), 
anemia (≤33%). 
 
Occasional (5-20% frequency): anorexia (10% to 13%), diarrhea (1% to 13%) 
 
Rare but Serious (< 5% Frequency): Hypotension (1% to 2%; due to rapid infusion), 
Stomatitis (1% to 6%), abdominal pain (up to 2%), Hepatic toxicity (up to 3%), Peripheral 
neuropathy (1% to 2%), Anaphylactic-like reaction (I.V. infusion 1% to 2%; oral capsules <1%; 
including chills, fever, tachycardia, bronchospasm, dyspnea). 
 
<1% (Limited to important or life-threatening): Amenorrhea, blindness (transient/cortical), 
cyanosis, extravasation (induration/necrosis), facial swelling, hypersensitivity, hypersensitivity-
associated apnea, interstitial pneumonitis, laryngospasm, maculopapular rash, metabolic 
acidosis, MI, mucositis, optic neuritis, perivasculitis, pruritus, pulmonary fibrosis, radiation-
recall dermatitis, rash, seizure, Stevens-Johnson syndrome, tongue swelling, toxic epidermal 
necrolysis weakness.  
 


 
Protocol Version 6.3 
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5.4 Carboplatin 
Classification: Platinum analog 
 
Mode of Action: Produces predominantly interstrand DNA cross-links rather than DNA-protein 
cross-links. 
 
Storage and Stability: Unopened vials of carboplatin injection are stable for the life indicated on 
the package when stored at 20° to 25°C (68° to 77°F).  Protect from light. 
 
Dose Specifics: Doses will be calculated by the target AUC using the Calvert formula, where 
Total dose (mg) = Target AUC x (GFR + 25). If estimating glomerular filtration rate (GFR) 
instead of a measured GFR, the GFR will be capped at a maximum of 125 mL/minute to avoid 
potential toxicity. In this study an AUC of 5 will be used for carboplatin dosing.  
 
Preparation: Carboplatin injection is a premixed aqueous solution of 10 mg/mL. 
Carboplatin injection can be further diluted to concentrations as low as 0.5 mg/mL with 5% 
Dextrose in Water (D5W) or 0.9% Sodium Chloride Injection. When prepared as directed, 
carboplatin injection is stable for 8 hours at room temperature 25°C (77°F). It is recommended 
that carboplatin injection be discarded 8 hours after dilution. 
 
Route of Administration: iv 
 
Compatibility: Stable in D5 1/4NS, D5 1/2NS, D5NS, D5W, NS.  
 
Availability: Carboplatin Injection, 10 mg/mL, is available commercially and is supplied as 
follows: 
NDC 55390-153-01, 50 mg/5 mL aqueous solution in multidose vials, individually boxed. 
NDC 55390-154-01, 150 mg/15 mL aqueous solution in multidose vials, individually boxed. 
NDC 55390-155-01, 450 mg/45 mL aqueous solution in multidose vials, individually boxed. 
 
Side Effects of Carboplatin  
Common (>20% frequency): Pain (23%), Hyponatremia (29% to 47%), hypomagnesemia 
(29% to 43%), hypocalcemia(22% to 31%), hypokalemia (20% to 28%), Vomiting (65% to 
81%), Myelosuppression (dose related and dose limiting; nadir at ~21 days; recovery by ~28 
days), anemia (71% to 90%; Grades 3/4: 21%), leukopenia (85%; Grades 3/4: 15% to 26%), 
neutropenia (67%; Grades 3/4: 16% to 21%), thrombocytopenia (62%; Grades 3/4: 25% to 35%), 
Alkaline phosphatase increased (24% to 37%), AST increased (15% to 19%), Creatinine 
clearance decreased (27%), BUN increased (14% to 22%) 
 
Occasional (5-20% Frequency): abdominal pain (17%), nausea (without vomiting: 10% to 
15%), Weakness (11%), Hypersensitivity/allergic reaction (2% to 16%), Neurotoxicity (5%), 
Constipation (6%), diarrhea (6%), Bleeding (5%), hemorrhagic complications (5%), Bilirubin 
increased (5%), Peripheral neuropathy (4% to 6%), Creatinine increased (6% to 10%), Infection 
(5%). 
Rare but Serious (< 5% Frequency): Alopecia (2% to 3%), stomatitis/mucositis (1%), taste 


 
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dysgeusia (1%), Visual disturbance (1%), Ototoxicity (1%). 
 
<1% (Limited to important or life-threatening): Anaphylactic reaction, bronchospasm, 
cardiac failure, cerebrovascular accident, dehydration, embolism, erythema, hemolytic uremic 
syndrome (HUS), hyper-/hypotension, injection site reactions (pain, redness, swelling), necrosis 
(associated with extravasation), neutropenic fever, pruritus, rash, secondary malignancies, 
urticaria, vision loss.  
 
Contraindications  
History of severe allergic reaction to cisplatin, carboplatin, other platinum-containing 
formulations, mannitol, or any component of the formulation. 
 
5.5 Treatment Regimen 
5.5.1 Chemotherapy Regimen 
Agent 
Dose 
Route 
Infusion 
duration 
Schedule 
Ofatumumab 
Cycle 1: 300 mg on day 
1 (or up to 3 days prior 
to day 1), 1000 mg on 
day 3.  
Cycles 2 and 3: 1000 
mg on day 1.  
IV  
Per section 
5.1 
Cycle 1: 
Days 1 and 
3. Cycle 2 
and 3: Day 1. 
Bendamustine Phase I: per the dose 
level. 
Phase II: MTD 
achieved in Phase I 
IV  
30 minutes 
Days 1and 2 
Carboplatin 
AUC 5 
IV  
1 hour 
Day 2 
Etoposide 
100 mg/m² 
IV 
1 hour 
Day 1-3 
 
Cycles will be repeated approximately every 3 weeks or when counts recover, whichever is later. 
Count recovery is defined as ANC >1000/ μl, Platelets >50,000/ μl. 
 
The patients will be admitted to Thomas Jefferson University (TJU) hospital and treated as 
inpatient for the first cycle. If no unexpected Grade ≥3 toxicities occur during infusion of the 
first cycle all subsequent treatments will be administered in the outpatient infusion center of 
Kimmel Cancer Center of TJU or as inpatient at TJUH, as per discretion of the treating physician  
 
5.5.2 Supportive Care: 
5.5.2.1 Pre-medications 
Antiemetics (ondansetron 24 mg IV or equivalent) will be administered prior to chemotherapy.  
Acetaminophen 650 mg po, diphenhydramine 50 mg po/iv and dexamethasone 20 mg iv (or 
equivalent) will be given within 30 minutes to 2 hours prior to ofatumumab treatment. If the 2nd 
infusion has been completed without the subject experiencing any Grade 3/4 adverse events 
(AEs), pre-medication with glucocorticoid may be reduced or omitted before the 3rd infusion at 
the discretion of the investigator. 
 


 
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5.5.2.2 Ofatumumab Infusion 
Will be infused as per Novartis protocol. See section 5.1. 
 
5.5.2.3 Tumor Lysis Prophylaxis 
All patients will receive allopurinol 300 md PO daily starting at least 24 hours prior to the 
initiation of the first cycle of therapy or the day of therapy and continued for at least the first 
week of the initial cycle of therapy. In case of an allergic reaction to allopurinol tumor lysis 
prophylaxis will include aggressive IV hydration and close monitoring of tumor lysis markers. 
Rasburicase may be administered as per discretion of the treating physician. For all patients 
additional measures will include aggressive IV hydration and rasburicase administration at the 
discretion of the treating physician. Patients will also be assessed for laboratory markers of 
tumor lysis syndrome. 
 
5.5.2.4 Growth Factor Support 
A granulocyte colony stimulating factor (either filgrastim or peg-filgrastim) is mandatory and 
will be administered at least 24 hours but not later than 96 hours after completion of each cycle 
of chemotherapy. 
 
5.5.2.5 Prophylaxis of Pneumocystis jirovecii (previously known as Pneumocystis carinii)  
It is recommended that patients receive prophylaxis for Pneumocystis during chemotherapy of 
Trimethoprim/sulfamethoxazole 1 DS PO daily or 2 DS tablets PO Monday, Wednesday, Friday. 
Patients allergic to the drug may receive Dapsone 100 mg/day or Pentamidine at the discretion of 
the treating physician. 
 
5.5.2.6 Anti-Fungal Prophylaxis  
It is recommended that patients receive anti fungal prophylaxis with fluconazole 400 mg daily or 
per the discretion of the treating physician. 
 
5.5.2.7 Antiviral Prophylaxis 
Patients may be given anti viral prophylaxis with acyclovir 400 mg twice daily or per the 
discretion of the treating physician. 
 
5.5.2.8 Prophylaxis of CNS Disease 
Prophylaxis of CNS disease using intrathecal dosing of cytotoxic regimens is permitted but not 
required by protocol and should be performed according to the discretion of the treating 
physician and/or study PI or her designee. 
 
5.6 Method for Assigning Subjects to Treatment Groups 
This is an open label study of a single therapy regimen. 
 
5.7 Preparation and Administration of Study Drug 
Ofatumumab will be delivered to the Investigational Drug Service at TJUH from Novartis. The 
Investigational Drug Service will then provide the doses in the inpatient and outpatient oncology 
infusion setting per the treatment schedule (Cycle 1:Days 1 and 3. Cycle 2 and 3: Day 1). 
Bendamustine, carboplatin and etoposide will be obtained commercially by the qualified 


 
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personnel who are familiar with procedures that minimize undue exposure to them and to the 
environment should undertake the preparation, handling, and safe disposal of chemotherapeutic 
agents in an appropriate environment. 
Discard unused portions of injectable chemotherapeutic agents that do not contain a 
bacteriostatic agent or are prepared with unpreserved diluents (i.e., Sterile Water for Injection 
USP or 0.9% Sodium Chloride for Injection USP) within eight hours of vial entry to minimize 
the risk of bacterial contamination. 
 
The total administered dose of chemotherapy may be rounded up or down within a range of 5% 
of the actual calculated dose. 
 
5.8 Subject Compliance Monitoring 
Only dose delays or modifications by the investigators or treating physician are permissible. 
 
5.9 Prior and Concomitant Therapy 
1. Information of prior cytotoxic regimens will be collected.   
2. All concomitant medical therapy will be collected as part of the history.   
3. All concomitant medicines/therapies are permitted during the study except for those 
noted in the exclusion criteria in section 4.2. 
  
5.10 Receiving, Storage, Dispensing and Return 
5.10.1 Receipt of Drug Supplies 
Ofatumumab will be supplied by Novartis to the Investigational Drug Service (IDS) at Thomas 
Jefferson University hospital. Upon receipt of the study treatment supplies, an inventory must be 
performed and a drug receipt log filled out and signed by the person accepting the shipment. It is 
important that the designated study staff counts and verifies that the shipment contains all the 
items noted in the shipment inventory. Any damaged or unusable study drug in a given shipment 
(active drug or comparator) will be documented in the study files. The investigator must notify 
study sponsor of any damaged or unusable study treatments that were supplied to the 
investigator’s site. 
 
5.10.2 Storage 
See section 5.1 through 5.4 
 
5.10.3 Dispensing of Study Drug 
Ofatumumab will be dispensed by the IDS pharmacy; all other drugs, pre-meds, etc will come 
from commercial supply from the regular pharmacy. Regular study drug reconciliation will be 
performed to document drug assigned, drug administered, and drug remaining. For ofatumumab, 
this reconciliation will be logged by the Investigational Drug Service on the drug reconciliation 
form. 
 
5.10.4 Return or Destruction of Study Drug 
At the completion of the study, there will be a final reconciliation of drug shipped, drug 
consumed, and drug remaining. This reconciliation will be logged on the drug reconciliation 
form, signed and dated. Any discrepancies noted will be investigated, resolved, and documented 
prior to return or destruction of unused study drug. Drug destroyed on site will be documented in 


 
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the study files. The remaining drug will be shipped back to the supplier. If the supplier requests 
that the drug be destroyed on site, it will be documented in the study files. 
 
6 
Study Procedures 
6.1 Schema 
Prior to enrollment (within 28 days) each eligible subject will have a detailed medical history, 
comprehensive physical examination, vital signs and baseline laboratory parameters (including 
CBC, CMP (including liver function tests, kidney function tests, electrolytes), Uric acid, LDH, 
Hepatitis B&C screen, HIV screen, IgG, IgM and IgA. Based on these and a pathological review 
of initial diagnostic biopsy, subjects will be evaluated for study eligibility. Serum pregnancy test 
will be done if applicable in eligible subjects at the time of study enrollment. We will attempt to 
get a repeat lymph node/mass/bone marrow biopsy of a site involved at the time of relapse to 
confirm the diagnosis and for correlative studies. If another biopsy is unobtainable, either due to 
location of disease, risk of procedure or patient preference, the diagnosis will be confirmed on 
the basis of initial diagnostic pathology. 
 
See Appendix 4 for Study Procedures Schedule. 
 
Pathology Review 
If diagnostic biopsy was performed at another institution it is required that diagnostic material 
from the original tumor biopsy must be submitted to TJU hemato-pathology for review and 
classification.  
 
Protocol Deviations 
Protocol coordinator must be notified of any deviations to protocol.   
Any deviations to protocol or unanticipated problems to be reported to the IRB via an OHR-20. 
 
6.2. Stem Cell Mobilization and Stem Cell Transplant 
This section is relevant to potential transplant candidates.  
 
Mobilization of stem cells will be performed after Cycle 2 or Cycle 3 upon discretion of TJU 
hematopoietic stem cell transplant group and in agreement with the study PI or her designee 
from the key study personnel. Stem cells will be mobilized according to TJU hematopoietic stem 
cell transplant group policy using filgrastim, pegfilgrastim or/and prelixafor (Mozobil). Use of 
other agents for mobilization may be approved following consultation with the study PI or her 
designee.  
 
Restaging CT scan should be performed after Cycle 2 and prior to stem cell mobilization and 
restaging whole body PET/CT scan should be performed after Cycle 3; it should be performed 
after Cycle 2 if patient is proceeding to autologous SCT after 2 cycles of the study regimen (see 
section 6).  
 
A patient may proceed to high dose chemotherapy and autologous SCT after 2 cycles of BOCE 
trial or a third cycle of BOCE regimen may be given after stem cell collection and before 
autologous SCT upon discretion of TJU hematopoietic stem cell transplant group and in 
agreement with the study PI or her designee. Stem cell collection should be completed within 8 


 
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weeks following Cycle 2 in order to proceed to Cycle 3. A whole body PET/CT scan will be 
performed in addition to CT scan or MRI if patient is proceeding to autologous SCT after 2 
cycles. 
 
Allogeneic stem cell transplant will be performed in selected cases upon discretion of TJU 
hematopoietic stem cell transplant group and in agreement with the study PI or her designee.     
 
If restaging studies after 2 cycles and before stem cell mobilization reveal progressive disease the 
patient will be withdrawn from the study and no stem cell collection will be attempted at that 
point.         
 
6.3. Dose Delays and Dose Reductions 
6.3.1 Cycle Delays 
Cycles should typically be administered at 3 week intervals. Minor variations, up to 3 days, are 
permissible for logistical reasons; longer delays, up to 8 weeks are allowed for cytopenias, Grade 
≥3 AEs or for stem cell mobilization. Subjects will be withdrawn if dosing is delayed for more 
than 8 weeks due to an AE. Dose reductions may be approved following consultation with the 
protocol coordinator and study PI or her designee. 
 
Administration of Cycle 2 or 3 of the investigational regimen will be delayed if the absolute 
neutrophil count is <1.0x109/L or the platelet count is <50x109/L. However, for subjects with 
counts below these levels at baseline, the start of Cycles 2 and 3 should be delayed until 
neutrophil and platelet counts have recovered to 80% of the baseline values. A granulocyte 
colony stimulating factor (either filgrastim or pegfilgrastim) is recommended at least 24 hours 
but not later than 96 hours after completion of each cycle of chemotherapy. 
 
It is recognized that occasionally mild neutropenia (ANC 0.5-1,0x 109/L) may persist in some 
responding patients in whom further delay in administering treatment is not medically 
appropriate.  Such patients whose counts do not further improve following a 1-2 week delay may 
receive the next cycle of therapy after conferring with the PI (or her designee). 
 
6.3.2 Dose Reduction of Bendamustine 
In case of Grade 4 infection, or Grade ≥ 3 non-hematologic toxicity that persists for 7 days or 
more, dose of bendamustine should be reduced with the following cycle of chemotherapy 
according to the following schema: 
 
 
 
 
 
 
6.3.3 Dose Modifications of Carboplatin, Etoposide and Ofatumumab 
Dose reductions of carboplatin and etoposide should be avoided but, if medically appropriate, a 
25% dose reduction may be approved following consultation with the PI of the study or with her 
designee.  
 
Initial dose  
Decrease dose to: 
120 mg/m² 
90 mg/m² 
  90 mg/m² 
70 mg/m² 
  70 mg/m² 
50 mg/m² 
  50 mg/m² 
Withdraw from the study 


 
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There is no dose reduction for Ofatumumab, only infusion rate adjustment or discontinuation. 
 
Liver Chemistry Interruption/Stopping Criteria (see section 8.4 for more information). 
The sponsor-investigator is to review all events which meet liver chemistry stopping criteria to 
determine if the event was due to; 
 tumor lysis, disease related liver involvement 
 concomitant chemotherapy  
 other identified cause and to exclude drug induced liver injury (DILI) due to 
Ofatumumab 
 
If the event is determined to be due to causes other than Ofatumumab DILI and improvement is 
observed after withdrawal of Ofatumumab, rechallenge may be attempted if deemed appropriate 
by the sponsor-investigator and in addition to consent of the subject.  
 
6.4. Disease Response 
Response Criteria 
Baseline imaging studies such as CT scans of the thorax, abdomen and pelvis or MRI (may 
include other sites, such as head, neck or extremities, if clinically indicated) and the whole body 
PETCT will be performed prior to the start of study therapy. If at any time point starting from 
month 3 post chemotherapy,  a problem occurs with precertification of a particular PET/CT scan 
(documentation is  required for each time point), a diagnostic quality CT scan (as described 
above) or/and MRI (if done at baseline), are acceptable for restaging purposes. Patients will be 
assessed for response based on the revised response criteria by the Revised Response 
Criteria for Malignant Lymphoma [Cheson, 2007] (see appendix 5) incorporating CT scans of 
the thorax, abdomen and pelvis and whole body PET/CT (33). Response will be first assessed 
after 2 cycles using CT scan or/and MRI (if relapse was confirmed by MRI before treatment). 
Restaging studies will be performed 2-8 weeks after Cycle 2 but before Cycle 3. Restaging 
PET/CT scan will be performed after 3 cycles of treatment (3-8 weeks post treatment but before 
high dose chemotherapy and ASCT, if applicable). Additional studies, such as CT scan of chest, 
abdomen and pelvis (or MRI) will be performed after 3 cycles upon discretion of treating 
physician or study PI. Imaging may be submitted for retrospective review. 
 
Bone marrow biopsies will be repeated after completion of 3 cycles or before stem cell 
mobilization if they were abnormal before treatment. 
 
PET/CT Scans 
The International Working Group (IWG) recommends the use of pretreatment PET with a low 
resolution CT (PETCT) scan in evaluation of patients with DLBCL and other aggressive 
lymphomas when response rate is a major end point (33). Thus in the current study we will 
assess patients with PETCT pretreatment and post treatment if initial PETCT was positive. Post 
treatment PETCT will be performed 3-8 weeks after completion of therapy. Of note, the CT 
portion of PET/CT should not be counted as diagnostic CT scan and a high resolution CT scan or 
MRI should be done in addition to PET/CT when required by protocol (see Appendix 4: Study 
Procedures Schedule). Follow up PET/CT scans will be done per institutional guidelines post 
treatment or post transplant. A diagnostic quality, contrast enhanced CT scan of the chest, 
abdomen and pelvis (and neck, if done at baseline or if a new suspected area of involvement) 


 
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or/and MRI of any site can be added at any restaging time point upon discretion of the study PI, a 
co-investigator or a treating physician. If at any time point starting from month 3 post 
chemotherapy,  a problem occurs with precertification of a particular PET/CT scan 
(documentation is required for each time point), a diagnostic quality CT scan (as described 
above) or/and MRI (if done at baseline), are acceptable for restaging purposes.   
 
Response Evaluation for Transplant Candidates 
 Restaging CT scan (or/and MRI if positive before treatment) should be performed after Cycle 2 
and prior to stem cell mobilization and restaging PET/CT scan should be performed after Cycle 3 
(see section 6). A patient may proceed to high dose chemotherapy and ASCT after 2 cycles of 
BOCE trial or a third cycle of BOCE regiment may be given after stem cell collection and before 
ASCT upon discretion of TJU hematopoietic stem cell transplant group and in agreement with 
the study PI or her designee. Stem cell collection should be completed within 8 weeks following 
Cycle 2 in order to proceed to Cycle 3. A PET/CT scan should be performed in addition to CT 
scan or/and MRI if patient is proceeding to ASCT after 2 cycles 
 
6.5 Correlative Studies 
6.5.1 Flow Cytometry for CD20 Expression 
CD20 expression will be assessed by flow cytometry as per standard protocol on fresh tissue 
biopsy, if available. If bone marrow is involved, or if there are circulating lymphoma cells in 
peripheral blood flow cytometry analysis for CD20 will be also performed on aspirated bone 
marrow or peripheral blood cells (if available). The intensity of CD20 expression will be 
determined in 3 levels in reference to negative isotope controls: Strongly positive: significant 
shift of abnormal cell population from negative control with no overlap of two populations. 
Weakly positive: shift of abnormal cell population from negative control but overlap is present. 
Negative: no significant shift of abnormal population from negative control.  
 
6.5.2 Immunohistochemistry (IHC) Studies 
Various panels of IHC will be performed based on disease type. The following antibodies will be 
performed on all available tissue samples: CD20, CD3, Ki-67. Additional selected antibodies 
including CD5, CD10, CD23, BCL1, BCL2, BCL6, and MUM1 will be performed according to 
specific disease type. CD20 expression will be assessed on paraffin sections by IHC in all 
available tissue Three levels of CD20 expression intensity are determined using light 
microscopy: strongly positive, weakly positive or negative. 
 
6.5.3 FISH Studies 
Fluorescence in situ hybridization (FISH) will be performed on formalin fixed, paraffin 
embedded tissue or/and on touch-preps, if available. The panel selection is based on specific 
disease type:  
Diffuse large B-cell lymphoma    BCL2, BCL6, cMYC 
Mantle Cell Lymphoma               BCL1 (also cMYC for blastoid variant) 
Transformed lymphoma               BCL2, BCL6, cMYC 
 
6.5.4 Analysis of Epstein Barr Encoded RNA (EBER)   
Presence of Epstein Barr virus will be assessed using in situ hybridization for Epstein Barr 
Encoded RNA (EBER) on tumor tissue sections in all available tissue samples. 


 
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6.5.5 Submission of Blood and Bone Marrow Samples 
In the consent section, subjects will be asked if they are willing to participate in correlative 
studies. Tissues from the subjects who answer “Yes” to “I allow my blood or bone marrow to be 
tested for additional laboratory research studies as a part of the clinical trial” will be utilized for 
correlative studies. Of note, blood samples will be collected for correlative studies only if 
suspected circulating lymphoma cells, based on routine CBC studies or flow cytometry data.  
 
6.5.6 Freezing and Storage 
After adequate tissue has been utilized for the correlative studies, the remained of the fresh tissue 
(lymph node tissue, bone marrow or other tissue obtained for diagnostic purposes and correlative 
studies) will be frozen and stored to be utilized for additional tests as per study protocol or for 
future IRB approved studies. Subjects will be asked if they allow storage and future use of their 
tissue for research purposes. If they refuse, the remained of tissue will not be stored and utilized 
for future studies. See Appendix 3. 
 
6.6 Duration of Therapy 
Treatment may continue for 3 cycles or until one of the following criteria applies: 
 
Stem Cell Transplant after 2 cycles of the study regimen 
 Disease progression, 
 Intercurrent illness that prevents further administration of treatment, 
 Unacceptable adverse event(s), 
 Patient decides to withdraw from the study, or 
 General or specific changes in the patient's condition render the patient unacceptable for 
further treatment in the judgment of the investigator. 
 
6.7 Duration of Follow Up 
 
Patients will be followed for disease status and survival at  3, 6, 9, 12, 18 and 24 months (with a 
window of ± 1 month) post treatment, post ASCT,  removal from the study, or until death, 
whichever occurs first.  Patients removed from the study for unacceptable adverse event(s) will 
have AE(s) followed until resolution or stabilization. 
 
6.8 Follow up/monitoring 
 
After completion of treatment, patients will be followed at a minimum of every 3 months with a 
window of +/- 1 month) for the first year and then at least every 6 months for the second year. 
Patient will be seen and examined by their treating physician along with a research nurse. 
Imaging studies per protocol will be obtained (see Appendix 4: Study Procedures Schedule). 
Whenever possible, the monitoring will occur as part of the routine follow-up visit. 
 
7 Statistical Plan 
7.1 Sample Size Determination 
A total of 9 to 18 patients will be enrolled in Phase I part of the trial. Twenty four patients will be 
enrolled in Phase II part of the trial. This is based on the Simon Optimal Two-Stage Design with 


 
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the assumption that an ORR rate of 25% indicates that the treatment is not effective and an ORR 
rate of 50% indicates that the treatment is effective with alpha (type I error) 0.05 and 80% 
power. The last 6 patients enrolled at the MTD level in Phase I will be included in the Phase II 
part of the study. Thus the estimated maximum sample size will be 36 patients. 
 
7.2 Statistical Methods 
Phase I Design 
In Phase I, three doses and 3-6 subjects per dose with the total of 9-18 subjects will be studied 
(please see the study design table below). We will use a two-stage accrual design at each dose 
considered. We will initially enter 3 subjects at each dose. If none of the three experiences a 
dose-limiting toxicity we will proceed to the next dose. If one of the three experiences a dose-
limiting toxicity, we will accrue 3 more subjects at that dose. If at any time there are two or more 
dose-limiting toxicities (in the 3-6 subjects) on a given dose, dose escalation will be stopped. 
This dose level will be declared the maximally administered dose (highest dose administered). 
Three (3) additional patients will be entered at the next lowest dose level if only 3 patients were 
treated previously at that dose. If >2 DLT at (-1) dose level, the study will be terminated. No 
patient will be treated at a higher dose until the 3 or 6 patients have completed their toxicity 
evaluation period at the current dose. With this plan, a dose with a 50% or greater probability of 
causing a dose-limiting toxicity has at most a 12.5% chance of satisfying the conditions for dose 
escalation after the first 3 subjects and at least a 50% chance of stopping at 3. With the two-
stages (3-6) together, there is at most a 17.2% chance of escalation. The MTD will then be the 
last dose studied or the previous dose, based on clinical judgment of the degree of toxicity seen 
at the last dose. While waiting for the 3 or 6 subjects accrued according to plan to complete their 
toxicity evaluation period, additional subjects may be accrued at the current dose. These 
additional subjects will not count towards the formal plan of stopping at two or more toxicity 
occurrences, but will contribute to the judgment as to the MTD. For determination of Dose 
Limiting Toxicity please see section 8.1 
 
Number of Patients with 
DLT at a Given Dose Level Escalation Decision Rule 
0 out of 3 
Enter 3 patients at the next dose level. 
>2 
Dose escalation will be stopped. This 
dose level will be declared the 
maximally administered dose (highest 
dose administered). Three (3) 
additional patients will be entered at the 
next lowest dose level if only 3 patients 
were treated previously at that dose. If 
>2 DLT at (-1) dose level, the study 
will be terminated. 
1 out of 3 
Enter at least 3 more patients at this 
dose level. 
 If 0 of these 3 additional patients 
experience DLT, proceed to the next 


 
Protocol Version 6.3 
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dose level. 
 If 1 or more of the 3 additional 
patients suffer DLT, then dose 
escalation is stopped, and this dose is 
declared the maximally administered 
dose. Three (3) additional patients 
will be entered at the next lowest 
dose level if only 3 patients were 
treated previously at that dose. 
<1 out of 6 at highest dose 
level below the maximally 
administered dose 
This will be the recommended phase 2 
dose. At least 6 patients must be 
entered at the recommended phase 2 
dose. 
 
Phase I Data Analyses 
Data analysis of phase I studies is descriptive. At each dose level DLT will be assessed during a 
minimum of one cycle period. A dose escalation will be allowed only when all 3 or 6 patients 
have completed at least one cycle of the studied regimen. All estimates of dose-specific rates 
(e.g., response and toxicity) will be presented with corresponding confidence intervals using the 
exact method. The method of Atkinson and Brown will be used for any rate related to definition 
of dose limiting toxicity, due to two-stage sampling. The method of Conover will be used 
otherwise. 
 
After all the patients have been accrued to the Phase I part of the study, the study investigators 
and sponsor will convene to assess safety and toxicity. If there are concerns over the safety of the 
combination therapy, the investigators and the sponsor may terminate the study. Also, if there are 
>2 DLT at (-1) dose level during accrual period, the study will be terminated. 
 
Phase II Design and Sample Size 
We design this trial with the potential for early termination in the case of a poor ORR rate. The 
design will be a two-stage design using the approach of Simon, selecting among admissible 
choices (Jung et al.). Choice of design is guided by a desire to stop the trial early if the actual 
ORR rate is 25% or less. If the ORR rate is 50% or greater, we would like to have a low 
probability of failing to conclude effective.   
 
Since the Phase I subjects will be treated and followed the same as the Phase II subjects, the 
Phase I subjects (6) accrued at the chosen MTD will be considered as accrued to the Phase II 
study as well.  
 
Our chosen design is: 
Look after this number of patients: 
Stop if number of successes is less than: 
9 
3 
24 
10 
 
After testing the treatment on 9 patients in the first stage, the trial will be terminated if 2 or fewer 
respond. After the first 9 patients have been accrued the trial will be on hold for a response 


 
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analysis. Once there are confirmed 3 or more responses (PR or CR) the accrual will continue. 
The trial will be terminated if less than 3 responses were achieved among first 9 accrued patients.  
If the trial goes on to the second stage, a total of 24 patients will be studied. If the total number 
responding is less than or equal to 9, the treatment is rejected. 
 
With this design, we have no more than a 20% chance of concluding ineffective (25% ORR 
rate) when the ORR rate is at least 50%.  Similarly, we have no more than a 5% chance of 
concluding effective (50% ORR rate) when it is ineffective.  If the actual ORR rate is 25% or 
worse, we have at least a 0.60 probability that the trial will stop after the first 9 subjects. Phase II 
design requires a maximum of 24 patients. Thus, including 6 patients from Phase I at MTD with 
Phase II patients, the total of 30 to 36 patients is required for combined Phase I/II study. 
 
7.3 Subject Population(s) for Analysis  
All patients who were enrolled in the study and received any clinical trial material will be 
included in the intent-to-treat analysis. All safety analyses will be performed on the intent-to 
treat population. The efficacy analysis will include any patient who has received at least one dose 
of the investigational drug Ofatumumab. All estimates of rates (e.g., response and toxicity) will 
be presented with corresponding confidence intervals. For ORR rates, the method of Atkinson 
and Brown will be used to allow for the two-stage design; otherwise the method of Conover will 
be used. 
 
7.4 Analysis of Missing Data 
Subjects with unknown or missing responses will be considered as non-responders.  
For endpoints which determine the percentage of responders, subjects with unknown or missing 
response will be assumed to be non-responders, and will be included in the denominator when 
calculating the percentages. 
 
8.0 Safety and Adverse Events 
8.1 Definitions 
Adverse Event 
An adverse event (AE) is any symptom, sign, illness or experience that develops or worsens in 
severity during the course of the study. Intercurrent illnesses or injuries will be regarded as 
adverse events. Abnormal results of diagnostic procedures are considered to be adverse events if 
the abnormality: 
 results in study withdrawal 
 is associated with a serious adverse event 
 is associated with clinical signs or symptoms 
 leads to additional treatment or to further diagnostic tests 
 is considered by the investigator to be of clinical significance 
 
Serious Adverse Event 
Adverse events are classified as serious or non-serious.   
 
A serious adverse event is any AE that is:  
 fatal 
 life-threatening 


 
Protocol Version 6.3 
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 requires or prolongs hospital stay 
 results in persistent or significant disability or incapacity 
 a congenital anomaly or birth defect 
 an important medical event 
 
Important medical events are those that may not be immediately life threatening, but are clearly 
of major clinical significance. They may jeopardize the subject, and may require intervention to 
prevent one of the other serious outcomes noted above. For example, drug overdose or abuse, a 
seizure that did not result in in-patient hospitalization, or intensive treatment of bronchospasm in 
an emergency department would typically be considered serious.  
 
All adverse events that do not meet any of the criteria for serious should be regarded as non-
serious adverse events.  
 
Toxicity will be evaluated according to the NCI Common Terminology Criteria for Adverse 
Events Version 4.0 except for hematologic toxicity. 
 
Hematologic toxicity will be assessed using the NCI working group grading scale as proposed by 
Hallek et al (34). Hematologic toxicity is expected and a grade of cytopenia will be recorded but 
it is not a dose limiting toxicity in this study. Grade 3 and 4 neutropenia, grade 3 and 4 
thrombocytopenia and Grade 4 anemia are expected desirable targets and should not be 
considered SAEs in this trial. Only clinically significant events such as neutropenic fever will be 
captured as an SAE; similarly, grade 4 thrombocytopenia, complicated by bleeding is a 
reportable event. In terms of cytopenias, only persistent grade 4 neutropenia or/and 
thrombocytopenia lasting longer than four weeks as measured by twice weekly CBC 
measurements will be considered an SAE. 
 
Dose-Limiting Toxicity (DLT) 
DLT will be graded according to the National Cancer Institute Common Terminology Criteria 
(NCI CTCAE, Version 4.0). DLT will be defined as any Grade 4 infection, or Grade ≥ 3 non-
hematologic toxicity that persists for 7 days or more. Inability to restart therapy in greater than 8 
weeks after previous cycle due to investigational agent-related toxicity or a delayed count 
recovery will be considered dose limiting. Toxicity must be considered related or possibly 
related to study drug in order to be classified as a DLT or treatment-related Grade 3 or greater 
toxicity. 
The following adverse events will NOT be considered dose limiting: 
 anemia 
 thrombocytopenia 
 neutropenia 
 Alopecia 
 Nausea, vomiting, anorexia 
 Grade 3 fatigue resolving before the next scheduled dose 
 Pain at tumor site due to obvious progression of disease 
 
Infusion reactions to Ofatumumab or Bendamustine which last less than 48 hours. 


 
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Hypersensitivity reactions (Grade ≤ 3 only) without use of prophylactic pre-medications 
 
Adverse Event and Serious Adverse Event Reporting Period 
All Adverse Events (AEs) regardless of relationship to the study drug regimen will be collected  
from the initiation of any study procedures until 60 days following the last administration of 
study treatment. AEs are no longer required to be reported if a subject begins treatment with 
another therapy, including transplant.  
 
Once an investigator determines that an event meets the protocol definition of an SAE, the SAE 
will be reported to NOVARTIS within 24 hours of being notified of the event 
 
All Serious Adverse Events (SAEs) regardless of relationship to the study drug regimen will be 
collected from the initiation of any study procedures until the end of the follow-up period.  SAEs 
are no longer required to be reported if a subject begins treatment with another therapy, including 
transplant. SAEs related to underlying disease or progression of disease do not need to be 
reported to NOVARTIS. 
 
Preexisting Condition 
A preexisting condition is one that is present at the start of the study. A preexisting condition will 
be recorded as an adverse event if the frequency, intensity, or the character of the condition 
worsens during the study period. 
 
General Physical Examination Findings 
At screening, any clinically significant abnormality will be recorded as a preexisting condition.  
At the end of the study, any new clinically significant findings/abnormalities that meet the 
definition of an adverse event will also be recorded and documented as an adverse event.  
 
Post-study Adverse Event 
All unresolved adverse events will be followed by the investigator until the events are resolved, 
the subject is lost to follow-up, or the adverse event is otherwise explained. At the last scheduled 
visit, the investigator will instruct each subject to report any subsequent event(s) that the subject, 
or the subject’s personal physician, believes might reasonably be related to participation in this 
study.    
  
Abnormal Laboratory Values 
A clinical laboratory abnormality will be documented as an adverse event if any one of the 
following conditions is met:  
 The laboratory abnormality is not otherwise refuted by a repeat test to confirm the 
abnormality 
 The abnormality suggests a disease and/or organ toxicity 
 The abnormality is of a degree that requires active management; e.g. change of dose, 
discontinuation of the drug, more frequent follow-up assessments, further diagnostic 
investigation, etc. 
 
Hospitalization, Prolonged Hospitalization or Surgery 
Any adverse event that results in hospitalization or prolonged hospitalization will be documented 


 
Protocol Version 6.3 
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and reported as a serious adverse event unless specifically instructed otherwise in this protocol. 
Slow infusion rate of ofatumumab (due to infusion reaction) needing overnight hospitalization to 
complete the infusion will not be recorded as a serious adverse reaction. Any condition 
responsible for surgery will be documented as an adverse event if the condition meets the criteria 
for and adverse event.  
 
Neither the condition, hospitalization, prolonged hospitalization, nor surgery will be reported as 
an adverse event in the following circumstances: 
 Hospitalization or prolonged hospitalization for diagnostic or elective surgical procedures 
for a preexisting condition. Surgery will not be reported as an outcome of an adverse 
event if the purpose of the surgery was elective or diagnostic and the outcome was 
uneventful. 
 Hospitalization or prolonged hospitalization required to allow efficacy measurement for 
the study. 
 Hospitalization or prolonged hospitalization for therapy of the target disease of the study, 
unless it is a worsening or increase in frequency of hospital admissions as judged by the 
clinical investigator. 
 
8.2 Recording of Adverse Events 
At each contact with the subject, the investigator will seek information on adverse events by 
specific questioning and, as appropriate, by examination. Information on all adverse events will 
be recorded immediately in the source document, and also in the appropriate adverse event 
module of the case report form (CRF). All clearly related signs, symptoms, and abnormal 
diagnostic procedures results will be recorded in the source document, though will be grouped 
under one diagnosis. 
 
All adverse events occurring during the study period must be recorded.  
 
The clinical course of each event will be followed until resolution, stabilization, or until it has 
been determined that the study treatment or participation is not the cause. Serious adverse events 
that are still ongoing at the end of the study period must be followed up to determine the final 
outcome. Any serious adverse event (SAE) brought to the investigator’s attention after the 
subject has completed the study and is considered by the investigator as possibly related to the 
study treatment or study participation will be recorded and reported immediately. 
 
The investigator must determine if an AE/SAE is in some way related to the study drug regimen. 
The relationship should be described as: Unrelated, Unlikely, Possibly, Probably or Definitely 
Related. 
 
8.3 Stopping Rules  
Accrual to the Phase II trial will be stopped if the actual ORR rate is 25% or less. We will 
evaluate the ORR after 9 subjects have been treated and the trial will be terminated if 2 or fewer 
respond. Please see section 7.2 for more information. 
 
8.4 Liver Chemistry Interruption/Stopping Criteria 
The sponsor-investigator is to review all events which meet liver chemistry stopping criteria to 


 
Protocol Version 6.3 
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determine if the event was due to; 
 tumor lysis, disease related liver involvement 
 concomitant chemotherapy  
 other identified cause and to exclude drug induced liver injury (DILI) due to 
Ofatumumab 
 
If the event is determined to be due to causes other than Ofatumumab DILI and improvement is 
observed after withdrawal of Ofatumumab, rechallenge may be attempted if deemed appropriate 
by the sponsor-investigator and in addition to consent of the subject.  
 
Liver Chemistry Interruption/Stopping Criteria: 
1. ALT >3 times upper limit of normal (ULN) and bilirubin >2 times ULN (>35% direct 
bilirubin; bilirubin fractionation required)  
2. ALT >8 times ULN 
3. ALT >5 times ULN for more than 2 weeks 
 
When any of the liver chemistry stopping criteria is met, following will be done: 
 Immediately stop study treatment 
 Hold Ofatumumab for two weeks, repeat liver chemistry testing at least twice weekly, 
and report to sponsor-investigator to discuss the possibility of re-challenging with 
Ofatumumab. 
 Report SAE to NOVARTIS within 24 hours 
 All events of ALT > 3xULN and bilirubin > 2xULN (>35% direct bilirubin) (or 
ALT>3xULN and INR>1.5, if INR measured; INR measurement is not required and the 
threshold value stated will not apply to subjects receiving anticoagulants), termed ‘Hy’s 
Law’, must be reported as an SAE (excluding studies of hepatic impairment or 
cirrhosis). 
 
Liver chemistry follow-up assessments are to be followed until liver chemistries resolve, 
stabilize or return to baseline values. 
 
Liver Chemistry Follow-up Assessments 
The chemistry tests/ assessments below are to be performed at the time of the event and then 
continued and/or discontinued at the discretion/judgment of the sponsor-investigator. 
 Viral hepatitis serology including: 
o Hepatitis A IgM antibody; 
o Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM);  
o Hepatitis C RNA;  
o Cytomegalovirus IgM antibody;   
o Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing);   
o Hepatitis E IgM antibody  
 Serum creatine phosphokinase (CPK) and lactate dehydrogenase (LDH) 
 Fractionate bilirubin, if total bilirubin >2xULN 
 Obtain complete blood count with differential to assess eosinophilia 


 
Protocol Version 6.3 
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 Record the  appearance or worsening clinical symptoms of hepatitis, or hypersensitivity, 
fatigue, decreased appetite, nausea, vomiting, abdominal pain, jaundice, fever, or rash  
 Record use of concomitant medications, acetaminophen, herbal remedies, other over the 
counter medications, or putative hepatotoxins 
 Increased  alcohol use  
 
The following assessments 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.  
 
Stopping Criteria: 
 For subject meeting liver stopping criteria 1:  
o A repeat of  liver chemistries within 24 hours, liver event follow-up assessments 
and close monitoring 
o A specialist or hepatology consultation is recommended 
o Monitor subjects twice weekly until liver chemistries (ALT, AST, alkaline 
phosphatase, bilirubin) resolve, stabilize or return to within baseline values. 
 For subjects meeting criteria 2 or 3:  
o A repeat of  liver chemistries within 24 to 72 hours for repeat liver chemistries 
and liver event follow-up assessments  
o Monitor subjects weekly until liver chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) resolve, stabilize or return to within baseline values 
 After holding Ofatumumab for two weeks:  
o If the treatment is exhibiting efficacy and the subject wants to continue therapy 
after being informed of the results of liver chemistry testing, then the 
Ofatumumab may be re-started.  
o Liver chemistries and follow-up assessments should be monitored at a minimum 
of every 2 weeks until resolution, stabilization, or a return to baseline values, at 
which point monitoring should be continued per protocol 
 Subjects with ALT >3xULN but <5xULN and bilirubin <2xULN without hepatitis 
symptoms or rash, and who may be monitored weekly for at least 4 weeks, then the 
following actions should be taken: 
o Subjects can continue Ofatumumab 
o Weekly repeat of liver chemistries until they resolve, stabilize, or return to 
baseline values, then monitor liver chemistries as per protocol assessment 
schedule 
 
If at any time the subject meets any of the liver chemistry stopping criteria, then proceed as 
described above. 
 
If after 4 weeks of monitoring, ALT<3xULN and bilirubin<2xULN monitor twice monthly until 
liver chemistries normalize or return to within baseline values. 
 


 
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8.5 Data and Safety Monitoring Plan 
It is the responsibility of the Principal Investigator to oversee the safety of the study. This safety 
monitoring will include careful assessment and appropriate reporting of adverse events as noted 
above, as well as the compliance and implementation of the KCC data and safety-monitoring 
plan. Medical monitoring will include a regular assessment of the number and type of serious 
adverse events by both the assigned Medical Monitor and the KCC DSMC. 
 
 
8.5.1 Medical Monitoring and AE/SAE Reporting 
 
The principal investigator has the obligation to report all serious adverse events to the FDA, IRB, 
and Novartis Pharmaceuticals Drug Safety and Epidemiology Department (DS&E). 
All events reported to the FDA by the investigator are to be filed utilizing the Form FDA 3500A 
(MedWatch Form).  
To ensure patient safety, every SAE, regardless of suspected causality, occurring 
 after the patient has provided informed consent and until at least 30 days after the patient has 
stopped study treatment/participation 
 after protocol-specified procedures begin (e.g., placebo run-in, washout period, double-blind 
treatment, etc.) and 30 days after the patient has stopped study treatment 
 after the start of any period in which the study protocol interferes with the standard medical 
treatment given to a patient (e.g., treatment withdrawal during washout period, change in 
treatment to a fixed dose of concomitant medication) and until 30 days after the patient has 
stopped study treatment 
 
must be reported to Novartis U.S. Drug Safety and Epidemiology within 24 hours of learning of 
its occurrence.  
Report to Novartis via Fax:  
 
 U.S. Drug Safety & Epidemiology  at  Fax #: 877-778-9739 
 
Should the designated SAE Fax# be non-functional please send SAEs to the designated 
SAE mailbox: clinicalsafetyop.phuseh@novartis.com 
 
Attach Novartis Coversheet to all SAE submissions 
 
Reference Novartis Study Number COMB157DUS09T 
This includes serious, related, not related, labeled (expected) and, unlabeled (unexpected) 
adverse experiences. All deaths during treatment or within 30 days following completion of 
active protocol therapy must be reported within24 hours. 
Any SAEs experienced after this 30 days period should only be reported to Novartis if the 
investigator suspects a causal relationship to the study drug. Recurrent episodes, complications, 
or progression of the initial SAE must be reported as follow-up to the original episode within 24 
hours of the investigator receiving the follow-up information. A SAE occurring at a different 
time interval or otherwise considered completely unrelated to a previously reported one should 
be reported separately as a new event.  The end date of the first event must be provided. 
The original copy of the SAE Report and the fax confirmation sheet must be kept within the 
Trial Master File at the study site. 


 
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Follow-up information is sent to the same fax number as the original SAE Report Form was sent, 
using a new fax cover sheet, stating that this is a follow-up to the previously reported SAE, and 
giving the date of the original report. Each re-occurrence, complication, or progression of the 
original event should be reported as a follow-up to that event regardless of when it occurs. The 
follow-up information should describe whether the event has resolved or continues, if and how it 
was treated, whether the blind was broken or not (if applicable), and whether the patient 
continued or withdrew from study participation. 
If the SAE is not previously documented in the Ofatumumab Investigator Brochure or Package 
Insert (new occurrence) and is thought to be related to the Novartis study drug, a DS&E 
associate may urgently require further information from the investigator for Health Authority 
reporting. Novartis may need to issue an Investigator Notification (IN), to inform all 
investigators involved in any study with the same drug that this SAE has been reported. 
Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to 
the competent authorities and relevant ethics committees in accordance with Directive 
2001/20/EC or as per national regulatory requirements in participating countries. 
 
 
For medical emergencies, the contact is: 
 
Gaetano Bonifacio MD 
Medical Director 
US CD MA Hematology 
Novartis Pharmaceuticals Corporation                                    
One Health Plaza, 345/4th 
East Hanover, NJ 07936-1080 
Mobile  +1 610 427 3613 
gaetano.bonifacio@novartis.com 
 
 
 
A Medical Monitor is assigned to this study at the Thomas Jefferson University. This is a 
physician/pharmacist who is not directly involved in the trial, and is not currently collaborating with 
the sponsor/investigator on any other trial. The role of the Medical Monitor is to review all 
reportable AEs/SAEs (in real-time) including grading, toxicity assignments, non-reportable AEs 
(quarterly), protocol violations/deviations, as well as all other safety data and activity data observed 
in the ongoing clinical trial occurring at Thomas Jefferson University. The Medical Monitor may 
recommend reporting of adverse events and relevant safety data, and may also recommend 
suspension or termination of the study to the DSMC and TJU IRB.   
 
Every KCC investigator initiated protocol includes requirements for reporting of adverse events 
based on CTC 4.0. All events are reported to the IRB and Medical Monitor using a password 
protected web-site. In addition all serious adverse events (SAEs) are reported to the TJU IRB  
 Investigator/Study Sponsor will be responsible for reporting SAEs to the Food and Drug 
Administration (FDA) if applicable. The investigator is required to submit all serious adverse 
events to the TJU IRB and the Medical Monitor within the timeframes outlined in the below 
table. All AE/SAEs will be reported to the DSMC at the quarterly DSMC review meetings; 
however, if the Medical Monitor determines corrective action is necessary, an “ad hoc” DSMC 


 
Protocol Version 6.3 
52 
meeting will be called. Fatal adverse events related to treatment which are unexpected must be 
reported within 24 hours to the TJU IRB and the DSMC. Fatalities not related to the study 
drug/device must be reported within 5 days. A summary of the reporting procedure is presented 
below.  
 
 
Grade 1 
Grade 2 
Grade 2 
Grade 3 
Grade 3 
Grades 4 
and 5 
 
Unexpected 
and 
Expected 
Unexpected 
Expected 
Unexpected 
with 
Hospitalization 
Unexpected 
without 
Hospitalization 
Expected with 
Hospitalization 
Expected 
without 
Hospitalization 
Unexpected 
and 
Expected 
Unrelated 
Unlikely 
Reviewed 
at Quarterly 
DSMC 
Meeting 
and IRB 
Annual 
Review 
Reviewed 
at Quarterly 
DSMC 
Meeting 
and IRB 
Annual 
Review 
Reviewed 
at 
Quarterly 
DSMC 
Meeting 
and IRB 
Annual 
Review 
5 Working 
Days 
Reviewed at 
Quarterly 
DSMC 
Meeting and 
IRB Annual 
Review 
5 Working 
Days 
Reviewed at 
Quarterly 
DSMC 
Meeting and 
IRB Annual 
Review 
Phase 1 -     
48 Hours   
(Death: 24 
Hours) 
 
Phase 2 -     
5 Working 
Days        
Possible 
Probable 
Definite 
Reviewed 
at Quarterly 
DSMC 
Meeting 
and IRB 
Annual 
Review 
5 working 
days 
Reviewed 
at 
Quarterly 
DSMC 
Meeting 
and IRB 
Annual 
Review 
48 Hours    
(Death: 24 
Hours) 
Phase 1 -       
48 Hours   
 
Phase 2 -       
5 Working 
Days 
48 Hours    
(Death: 24 
Hours) 
Reviewed at 
Quarterly 
DSMC 
Meeting and 
IRB Annual 
Review 
Phase 1 
and Phase 
2 -          
48 Hours     
(Death: 24 
Hours) 
 
 
**NOTE: This table is based on the NCI AE/SAE reporting Guidelines and the TJU IRB Policy and Procedures. 
Please follow the individual protocol AE/SAE reporting guidelines if more stringent reporting procedures are 
specified. 
***See section 8.1 for exceptions to this monitoring plan. 
 
8.5.2 Data and Safety Monitoring Committee 
Data and Safety Monitoring Committee (DSMC) is the Data and Safety Monitoring Board 
(DSMB) for the KCC. The DSMC is a multidisciplinary committee charged with overseeing the 
monitoring of safety of participants in clinical trials, and the conduct, progress, validity, and 
integrity of the data for all clinical trials at the Thomas Jefferson University KCC. The committee 
meets quarterly to review the progress and safety of all active research protocols that are not 
monitored by another safety and data monitoring committee or board. 
 The DSMC meets quarterly. Additional DSMC meetings are scheduled based on the 
nature and number of trials being monitored over a specified time period. The DSMC 


 
Protocol Version 6.3 
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meets (by conference call) within 24 hours following the notification of an unexpected 
adverse event felt to be related to the study drug.  
 Prior to each DSMC meeting, each board member, is provided a printout of all reported 
AEs and SAEs occurring during the reporting period for this clinical trial. The principal 
investigator provides a detailed and comprehensive narrative assessment of current 
adverse events to date, indicating their possible significance and whether these toxicities 
have affected the conduct of the trial. DSMC members are provided with the principal 
investigator’s assessment, a written report summarizing adverse events, safety data, and 
activity data observed during the specified time period described in each protocol, as well 
as recommendations from the Medical Monitor. A review of outcome results (response, 
toxicity and adverse events) and factors external to the study (such as scientific or 
therapeutic developments) is discussed, and the Committee votes on the status of each 
study.  
 A summary of the board’s action is sent to each investigator, the CCRRC and TJU IRBs. 
The DSMC actions may include recommendations/requirements that will lead to 
improved patient safety and/or efficacy, significant benefits or risks that have developed, 
or other changes determined to be necessary. The DSMC may also take note of slow 
accrual or lack of scientific progress, and refer such issues to the CCRRC. The DSMC 
provides the investigator with the rationale for any decision made.  
 
9.0 Data handling and Record Keeping 
9.1 Confidentiality 
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA).  
Those regulations require a signed subject authorization informing the subject of the following:  
 What protected health information (PHI) will be collected from subjects in this study 
 Who will have access to that information and why 
 Who will use or disclose that information 
 The rights of a research subject to revoke their authorization for use of their PHI.  
 
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization. For subjects that have revoked authorization to collect or use PHI, attempts will be 
made to obtain permission to collect at least vital status (i.e. that the subject is alive) at the end of 
their scheduled study period. 
 
9.2 Source Documents 
Source data is all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial.  Source 
data are contained in source documents   Examples of these original documents, and data records 
include: hospital records, clinical and office charts, laboratory notes, memoranda, subjects’ 
diaries or evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies or transcriptions certified after verification as being accurate and complete, 
microfiches, photographic negatives, microfilm or magnetic media, x-rays, subject files, and 
records kept at the pharmacy, at the laboratories, and at medico-technical departments involved 
in the clinical trial. 


 
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9.3 Case Report Forms 
The study case report form (CRF) is the primary data collection instrument for the study.  All 
data requested on the CRF must be recorded.  All missing data must be explained.  If a space on 
the CRF is left blank because the procedure was not done or the question was not asked, write 
“N/D”.  If the item is not applicable to the individual case, write “N/A”.  All entries will be 
printed legibly in black ink.  If any entry error has been made, to correct such an error, draw a 
single straight line through the incorrect entry and enter the correct data above it.  All such 
changes must be initialed and dated.  DO NOT ERASE OR WHITE OUT ERRORS.  For 
clarification of illegible or uncertain entries, print the clarification above the item, then initial and 
date it.  
 
9.4 Records Retention 
It is the investigator’s responsibility to retain study essential documents for at least 2 years after 
the completion and termination of the protocol.  
 
10.0 Study Monitoring, Auditing and Inspecting 
10.1 Study Monitoring Plan 
The investigator will allocate adequate time for monitoring activities. The Investigator will also 
ensure that the medical monitor or other compliance or quality assurance reviewer is given 
access to all the above noted study-related documents and study related facilities (e.g. pharmacy, 
diagnostic laboratory, etc.), and has adequate space to conduct the monitoring visit. 
 
KCC Investigator Initiated Phase I Studies  
Phase I studies require continuous monitoring by the PI of the study with quarterly safety and 
monitoring reports submitted to the CRMO and the DSMC. Each protocol is assigned to a 
medical monitor (a physician or other member of the DSMC who has expertise in the therapeutic 
area of the protocol and is not directly involved in this trial). The medical monitor reviews all 
adverse events (in addition to unexpected adverse events), safety data and activity data observed 
in the ongoing clinical trial at each new dose level, prior to dose escalation.  
 
The PI provides a report to the DSMC of all AE/SAEs, safety and toxicity data, and any 
corrective action that occurred on a quarterly basis. The medical monitor also provides a 
summary of their review. The summary of all discussions of adverse events are submitted to the 
DSMC, and these reports are reviewed during the DSMC meetings that take place quarterly. 
Patients are only identified by initials, and no other personal health information (PHI) is included 
in the reports.  
 
The medical monitor may recommend reporting adverse events and relevant safety data not 
previously reported, and may recommend suspension or termination of the trial based on their 
review of AE/SAE data observed throughout the life of a clinical trial. In such circumstances, 
and “ad hoc” DSMC meeting will be called to discuss corrective action with the PI. If for any 
reason the PI of the trial disagrees with the conclusions of the Medical Monitor or DSMC, the 
issue will be referred to the Associate Director of Clinical Investigations, who will be 
responsible for dispute resolution.  
 


 
Protocol Version 6.3 
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The summary of all discussions of adverse events are included in the KCC investigator’s reports 
to the TJU IRBs as part of its annual progress report. The DSMC and the TJU IRBs may, based 
on the monitor’s recommendation suspend or terminate the trial. The quarterly safety and 
monitoring reports include a statement as to whether this data has invoked any stopping criteria 
in the clinical protocol.  
 
KCC Investigator Initiated Phase II Studies  
Phase II studies require monthly monitoring by the PI of the study with quarterly safety and 
monitoring reports submitted to the CRMO, and the DSMC. Each protocol is assigned to a 
medical monitor (a physician or other member of the DSMC who has expertise in the therapeutic 
area of the protocol and is not directly involved in this trial). The medical monitor reviews all 
adverse events (in addition to unexpected adverse events), safety data and activity data observed 
in the ongoing clinical trial.  
 
The PI provides a report to the DSMC of all AE/SAEs, safety and toxicity data, and any 
corrective action that occurred on a quarterly basis. The medical monitor also provides a 
summary of their review. The summary of all discussions of adverse events are submitted to the 
DSMC, and these reports are reviewed during the DSMC meetings that take place quarterly. 
Patients are only identified by initials, and no other PHI is included in the reports.  
 
The medical monitor may recommend reporting adverse events and relevant safety data not 
previously reported, and may recommend suspension or termination of the trial based on their 
review of AE/SAE data observed throughout the life of a clinical trial. In such circumstances, 
and “ad hoc” DSMC meeting will be called to discuss corrective action with the PI.  
 
The summary of all discussions of adverse events are included in the KCC investigator’s reports 
to the TJU IRBs as part of its annual progress report. The DSMC and the TJU IRB may, based 
on the monitor’s recommendation suspend or terminate the trial. The quarterly safety and 
monitoring reports include a statement as to whether this data has invoked any stopping criteria 
in the clinical protocol.  
10.2 Auditing and Inspecting 
The investigator will permit study-related monitoring, audits, and inspections by the IRB, the 
funding sponsor, government regulatory bodies, and University compliance and quality 
assurance groups of all study related documents (e.g. source documents, regulatory documents, 
data collection instruments, study data etc.).  The investigator will ensure the capability for 
inspections of applicable study-related facilities (e.g. pharmacy, diagnostic laboratory, etc.). 
 
Participation as an investigator in this study implies acceptance of potential inspection by 
government regulatory authorities and applicable University compliance and quality assurance 
offices. 
 
10.2.1 Independent External and Internal Audits  
In addition to review by the DSMC, all studies initiated by KCC investigators are audited by an 
independent auditor once they have achieved 10% of target accrual. However, a study can be 
audited at any time based on recommendations by the IRB, DSMC, CCRRC and/or the Director 


 
Protocol Version 6.3 
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of Clinical Investigations, KCC. Studies are re-audited once they have achieved 50% of target 
accrual. Special audits may be recommended by the IRB, DSMC or CCRRC based on prior 
findings, allegations of scientific misconduct and where significant irregularities are found 
through quality control procedures. Any irregularities identified as part of this process would 
result in a full audit of that study.  
 
In addition to the audits at 10 and 50%, the CRMO randomly audits at least 10 percent of all 
patients entered into therapeutic KCC trials and other trials as necessary, on at least a bi-annual 
basis, to verify that there is a signed and dated patient consent form, the patient has met the 
eligibility criteria, and that SAEs are documented and reported to the TJU IRB.  
 
All audit reports are submitted to the DSMC for review and action (when appropriate). A copy of 
this report and recommended DSMC action is sent to the CCRRC and TJU IRB. The committee 
regards the scientific review process as dynamic and constructive rather than punitive. The 
review process is designed to assist Principal Investigators in ensuring the safety of study 
subjects and the adequacy and accuracy of any data generated. The TJU IRB may, based on the 
DSMC and auditor’s recommendation, suspend or terminate the trial.  
 
11.0 Ethical Considerations 
This study is to be conducted according to US and international standards of Good Clinical 
Practice (FDA Title 21 part 312 and International Conference on Harmonization guidelines), 
applicable government regulations and Institutional research policies and procedures. 
 
This protocol and any amendments will be submitted to a properly constituted independent 
Institutional Review Board (IRB), in agreement with local legal prescriptions, for formal 
approval of the study conduct. The decision of the IRB concerning the conduct of the study will 
be made in writing to the investigator before commencement of this study.   
 
All subjects for this study will be provided a consent form that is compliant with local and 
federal regulations, describing this study and providing sufficient information for subjects to 
make an informed decision about their participation in this study. This consent form will be 
submitted with the protocol for review and approval by the IRB for the study.  The formal 
consent of a subject, using the IRB-approved consent form, must be obtained before that subject 
is submitted to any study procedure. This consent form must be signed by the subject or legally 
acceptable surrogate, and the investigator-designated research professional obtaining the consent.  
 
12.0 Study Finances 
12.1 Funding Source 
The study  was supported by GSKand remaining support to be provided by Novartis  
 
12.2 Conflict of Interest 
None to report 
 
13. Publication Plan 
We intend to publish our results in a peer reviewed journal and to present our data at a reputable 
National or International meeting. The primary responsibility for publication lies with the PI and 


 
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statistician. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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APPENDICES 
 
Appendix 1: Second Line Age Adjusted International Prognostic Index (sAAIPI) 
 
Risk factors: 
Score 
LDH >ULN 
1 
Stage III or IV 
1 
KPS <80% 
1 
 
Low risk (L) with 0 factors, low intermediate (LI) risk with 1 factor, high-intermediate risk (HI) 
with 2 factors, and high risk (H) with all 3 factors present. 
 


 
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Appendix 2: ECOG Performance Status 
 
Grade  
ECOG 
0 
 
Fully active, able to carry on all pre disease performance without 
restriction 
1 
 
Restricted in physically strenuous activity but ambulatory and able to 
carry out work of a light or sedentary nature, e.g., light house work, 
office work 
2 
 
Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than 50% of waking hours 
3 
  
Capable of only limited self-care, confined to bed or chair more than 
50% of waking hours  
4 
Completely disabled. Cannot carry on any self-care. Totally confined to 
bed or chair 
5 
Dead 
 
Ref: 
Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, P.P.: Toxicity And 
Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 1982. 
 


 
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Appendix 3: Tissue Freezing and Storage Procedure 
 
After adequate tissue has been utilized for the diagnostic and correlative studies, the remained of 
the fresh tissue (lymph node tissue, bone marrow or other tissue obtained for diagnostic purposes 
and correlative studies) will be frozen and stored to be utilized for additional correlative tests as 
per protocol (section 6.5) or for future IRB approved studies. Subjects will be asked to sign a 
consent form if they allow their tissue to be stored for additional tests as per current correlative 
protocol and also if they allow it to be used for future research purposes. If they refuse, the 
remained of the collected tissue will not be stored to be utilized for current or for any future 
studies. 
 
Tissue Freezing Procedure  
1. The tissue, approximately 3-5mm thickness or more will be placed into a plastic container 
labeled with the specimen number, person ID number and source of tissue.  
2. The container will be wrapped in foil and a specimen number sticker is placed on the outside 
of the foil. The container with the foil is then put into the liquid nitrogen flask to be snap frozen..  
3. The sample will then be transferred to the –70°C freezer and stored until used for research.. 
4. A log of the sample stored will be maintained in the tissue bank and in the CRMO. The 
following information will be recorded in the log:   
 Specimen ID  
 Name  
 Date of Birth  
 Tissue type  
 Consent form  
 Date Tissue Taken  
 Time to freeze/fix tissue  
 Date blocks processed  
 Number of tumor pieces frozen  
 Additional specimens taken  
 Storage of additional specimens  
 Relevant additional information/comments 
 
 
 


 
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Appendix 4: Study Procedures Schedule 
Procedures 
Screening1 
Treatment10 
 
Follow-up Procedures11 
 
 
Cycle 1 
Cycle 
2 
Cycle 
3 
Post 
treatment 
assessment12 
Treatment 
withdrawal or 
disease progression 
3 months post treatment 
or post ASCT  
6, 9, 12, 18 
and 24 months 
post treatment 
or post ASCT 
Informed Consent 
X 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
Disease History 
X 
 
 
 
 
 
 
 
Therapy History 
X 
 
 
 
 
 
 
 
 
 
Efficacy 
assessment 
 
 
Bone Marrow 
biopsy   
 
X2 
 
 
 
X14 
 
 
 
Lymph 
node/mass 
biopsy 
X3 
 
 
 
X3 
X3 
 
 
CT (or MRI) 
X4 
 
X4 
 
X4 
 
X13 
X13 
PET/CT 
X4 
 
X4 
 
X4 
 
X13 
X13 
Clinical disease 
assessment 
X 
X 
X 
X 
X 
X 
 
 
Disease 
assessment and 
survival 
 
 
 
 
 
 
X 
X 
 
 
Safety 
Assessments  
 
Physical Exam 
X 
X 
X 
X 
X 
 
 
 
ECOG 
performance5 
X 
 
 
 
X 
 
 
 
Height 
X 
 
 
 
 
 
 
 
Weight 
X 
X 
X 
X 
X 
 
 
 
Vital Signs 
X 
X 
X 
X 
X 
 
 
 
12-lead ECG  
X 
 
 
 
 
 
 
 
MUGA or ECHO 
X6 
 
 
 
 
 
 
 
Toxicity 
Assessment 
 
X 
X 
X 
X 
 
 
 
Concomitant 
Medications 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Procedures 
Screening1 
Treatment10 
 
Follow-up Procedures11 
 
 
Cycle 1 
Cycle 
2 
Cycle 
3 
Post 
treatment 
assessment12  
Treatment 
withdrawal or 
disease progression 
3 months post treatment 
or post ASCT  
6, 9, 12, 18 
and 24 months 
post treatment 
or post ASCT 
Lab 
 


 
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Assessments 
Hematology 
(CBC with 
differential) 
X 
X 
X 
X 
 
X 
 
 
Chemistry (CMP-
12), Uric acid, 
LDH, B2M 
X 
X 
X 
X 
 
X 
 
 
Serum Pregnancy 
Test 
X7 
X7 
X7 
X7 
 
X7 
 
 
Hepatitis B&C 
screen8 
X 
 
 
 
 
 
 
 
HIV screen 
X 
 
 
 
 
 
 
 
IgG, IgM, IgA 
X 
 
 
 
X 
X 
 
 
 
 
Dispense Study 
Medication 
 
Ofatumumab 
 
X 
X 
X 
 
 
 
 
Bendamustine 
 
X 
X 
X 
 
 
 
 
Carboplatin 
 
X 
X 
X 
 
 
 
 
Etoposide 
 
X 
X 
X 
 
 
 
 
 
 
Correlative 
studies9 
 
Flow cytometry 
for CD20  
X 
 
 
 
 
 
 
 
IHC including 
CD20, Bcl-2, Bcl-
6, Cyclin D1  
X 
 
 
 
 
 
 
 
FISH: FISH for 
Bcl-2, Bcl-6 and 
MYC 
rearrangement 
X 
 
 
 
 
 
 
 
EBER by in situ 
hybridization 
X 
 
 
 
 
 
 
 
Cryopreservation 
and storage of 
malignant cells 
from diagnostic 
tumor biopsy 
X 
 
 
 
 
 
 
 
1 To be done within 28 days of initiation of Cycle 1, unless otherwise noted. Such 
screening studies as  
2 To be done if involved at the time of initial diagnosis or if clinically indicated 
3 It is strongly recommended (but not mandatory) that additional diagnostic tissue biopsies 
are performed, when possible, to confirm diagnosis, relapse or tumor progression 
4 Imaging studies will be performed before therapy (within 4 weeks of initiation of 
treatment). If patient had a PET/CT scan done within 6 weeks of starting treatment all 
efforts should be made to have a new study done within 4 weeks of starting treatment, 
however, if rejected by the insurance company the patient will still be eligible for the trial 
and the PET/CT that was done with 6 weeks will be counted as baseline study.CT or MRI 
should be done within 4 weeks of initiation of treatment. CT and MRI (if patient had a 


 
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positive MRI before treatment) will be repeated after 2 cycles and PET/CT scan will be 
performed after 3 cycles of therapy. Restaging PET/CT will be performed after Cycle 2 
(in addition to other restaging studies) if stem cell transplant is planned after 2 cycles or if 
tumor progression is suspected based on other restaging studies. CT or/and MRI may be 
repeated after 3 cycles in addition to PET/CT upon discretion of study PI or a treating 
physician. 
5 See Appendix 2 for ECOG performance status assessment 
6 MUGA or ECHO can be performed up to 3 months prior to start of treatment 
7 For women of childbearing age: Serum pregnancy testing should be performed within 3 
days prior to enrollment, prior to each cycle if last test was more than 30 days prior and at 
6 months after last cycle of the study regimen. 
8 Hepatitis B screen should include HepBcAb, HepBsAg, and HepBsAb. If HepBsAg is 
negative and HepBcAb is positive a quantitative PCR analysis for HepB DNA should be 
performed.(see study exclusion criteria)  
9 Strongly recommended but not mandatory 
10 Day 1 study procedures of each cycle can be done up to 72 hours prior to Day 1. ) In the 
event of a prolonged ofatumumab infusion (> 8 hours) it is acceptable to reschedule the 
rest of day 1 chemotherapy to the following day. In that case day 2 and day 3 
chemotherapy will be rescheduled to day 3 and 4, respectively. 
11 Follow up procedures should be performed at Months 3, 6, 9, 12, 18 and 24 months post 
treatment or post ASCT with a window of ± 1 month 
12 Post treatment assessment should be completed between 3-8 weeks post treatment 
13 Follow up PET/CT scans will be done per institutional guidelines post treatment or post 
transplant. A diagnostic quality, contrast enhanced CT scan of the chest, abdomen and 
pelvis (and neck, if done at baseline or if a new suspected area of involvement) or/and 
MRI of any site can be added at any restaging time point upon discretion of the study PI, 
a co-investigator or a treating physician. If at any time point starting from month 3 post 
chemotherapy,  a problem occurs with precertification of a particular PET/CT scan 
(documentation is required for each time point), a diagnostic quality CT scan (as 
described above) or/and MRI (if done at baseline), are acceptable for restaging purposes  
14 To be done if positive at screening 


 
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Appendix 5 
 
Revised Response Criteria for Malignant Lymphoma. 
Cheson BD, Pfistner B, Juweid ME, et al.. J Clin Oncol 2007;25:579–86 
 
CR 
1. Complete disappearance of all detectable clinical evidence of disease and disease-related 
symptoms if present before therapy. 
 
2a. Typically FDG-avid lymphoma: in patients with no pretreatment PET scan or when the PET 
scan was positive before therapy, a post-treatment residual mass of any size is permitted as long 
as it is PET negative.  
 
2b. Variably FDG-avid lymphomas/FDG avidity unknown: in patients without a pretreatment 
PET scan, or if a pretreatment PET scan was negative, all lymph nodes and nodal masses must 
have regressed on CT 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 long axis and 
more than 1.0 cm in their short axis before treatment must have decreased to ≤ 1.0 cm in their 
short axis after treatment.  
 
3. The spleen and/or liver, if considered enlarged before therapy on the basis of a physical 
examination or CT scan, should not be palpable on physical examination and should be 
considered normal size by imaging studies, and nodules related to lymphoma should disappear. 
However, determination of splenic involvement is not always reliable because a spleen 
considered normal in size may still contain lymphoma, whereas an enlarged spleen may reflect 
variations in anatomy, blood volume, the use of hematopoietic growth factors, or causes other 
than lymphoma.  
 
4. If the bone marrow was involved by lymphoma before treatment, the infiltrate must have 
cleared on repeat bone marrow biopsy. The biopsy sample on which this determination is made 
must be adequate (with a goal of > 20 mm unilateral core). If the sample is indeterminate by 
morphology, it should be negative by immunohistochemistry. A sample that is negative by 
immunohistochemistry but that demonstrates a small population of clonal lymphocytes by flow 
cytometry will be considered a CR until data become available demonstrating a clear difference 
in patient outcome.  
 
CRu 
The use of the above definition for CR and that below for PR eliminates the category of CRu. 
 
PR 
The designation of PR requires all of the following:  
 


 
Protocol Version 6.3 
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1. At least a 50% decrease in sum of the product of the diameters (SPD) of up to six 
of the largest dominant nodes or nodal masses. These nodes or masses should be 
selected according to all of the following: they should be clearly measurable in at 
least 2 perpendicular dimensions; if possible they should be from disparate 
regions of the body; and they should include mediastinal and retroperitoneal areas 
of disease whenever these sites are involved.  
 
2. No increase should be observed in the size of other nodes, liver, or spleen. 
 
3. Splenic and hepatic nodules must regress by ≥ 50% in their SPD or, for single nodules, in 
the greatest transverse diameter. 
 
4. With the exception of splenic and hepatic nodules, involvement of other organs is usually 
assessable and no measurable disease should be present.  
 
5. Bone marrow assessment is irrelevant for determination of a PR if the sample was 
positive before treatment. However, if positive, the cell type should be specified (eg, 
large-cell lymphoma or small neoplastic B cells). Patients who achieve a CR by the 
above criteria, but who have persistent morphologic bone marrow involvement will be 
considered partial responders.  
 
When the bone marrow was involved before therapy and a clinical CR was achieved, but with no 
bone marrow assessment after treatment, patients should be considered partial responders.  
 
6. No new sites of disease should be observed. 
 
7. Typically FDG-avid lymphoma: for patients with no pretreatment PET scan or if the PET 
scan was positive before therapy, the post-treatment PET should be positive in at least 
one previously involved site.  
 
8. Variably FDG-avid lymphomas/FDG-avidity unknown: for patients without a 
pretreatment PET scan, or if a pretreatment PET scan was negative, CT criteria should be 
used.  
 
In patients with follicular lymphoma or mantle-cell lymphoma, a PET scan is only indicated with 
one or at most two residual masses that have regressed by more than 50% on CT; those with 
more than two residual lesions are unlikely to be PET negative and should be considered partial 
responders.  
 
Stable Disease 
Stable disease (SD) is defined as the following:  
 


 
Protocol Version 6.3 
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1. A patient is considered to have SD when he or she fails to attain the criteria 
needed for a CR or PR, but does not fulfill those for progressive disease (see 
Relapsed Disease [after CR]/Progressive Disease [after PR, SD]).  
 
2. Typically FGD-avid lymphomas: the PET should be positive at prior sites of 
disease with no new areas of involvement on the post-treatment CT or PET.  
 
3. Variably FDG-avid lymphomas/FDG-avidity unknown: for patients without a 
pretreatment PET scan or if the pretreatment PET was negative, there must be no 
change in the size of the previous lesions on the post-treatment CT scan.  
 
Relapsed Disease (after CR)/Progressive Disease (after PR, SD) 
Lymph nodes should be considered abnormal if the long axis is more than 1.5 cm regardless of 
the short axis. If a lymph node has a long axis of 1.1 to 1.5 cm, it should only be considered 
abnormal if its short axis is more than 1.0. Lymph nodes ≤ 1.0 × ≤ 1.0 cm will not be considered 
as abnormal for relapse or progressive disease.  
 
1. Appearance of any new lesion more than 1.5 cm in any axis during or at the end of 
therapy, even if other lesions are decreasing in size. Increased FDG uptake in a 
previously unaffected site should only be considered relapsed or progressive disease after 
confirmation with other modalities. In patients with no prior history of pulmonary 
lymphoma, new lung nodules identified by CT are mostly benign. Thus, a therapeutic 
decision should not be made solely on the basis of the PET without histologic 
confirmation.  
 
2. At least a 50% increase from nadir in the SPD of any previously involved nodes, or in a 
single involved node, or the size of other lesions (eg, splenic or hepatic nodules). To be 
considered progressive disease, a lymph node with a diameter of the short axis of less 
than 1.0 cm must increase by ≥ 50% and to a size of 1.5 × 1.5 cm or more than 1.5 cm in 
the long axis.  
 
3. At least a 50% increase in the longest diameter of any single previously identified node 
more than 1 cm in its short axis. 
 
4. Lesions should be PET positive if observed in a typical FDG-avid lymphoma or the 
lesion was PET positive before therapy unless the lesion is too small to be detected with 
current PET systems (< 1.5 cm in its long axis by CT).  
 
Measurable extranodal disease should be assessed in a manner similar to that for nodal disease. 
For these recommendations, the spleen is considered nodal disease. Disease that is only 
assessable (eg, pleural effusions, bone lesions) will be recorded as present or absent only, unless, 
while an abnormality is still noted by imaging studies or physical examination, it is found to be 
histologically negative.