Phase II Trial of Alemtuzumab (Campath) and Dose-Adjusted EPOCH-Rituximab (DA-EPOCH-R) in Relapsed or Refractory Diffuse Large B-Cell and Hodgkin Lymphomas
Phase: PHASE2
Conditions: Hodgkin Lymphoma, Diffuse Large B-Cell Lymphoma
Sponsor: National Cancer Institute (NCI)

Abbreviated Title:  EPOCH-RC in recurrent lymphoma 
Version Date:  08/03/2018 
 
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Abbreviated Title:  EPOCH-RC in recurrent lymphoma 
 
CC Protocol #:  10-C-0011 J 
 
Version Date:  08/03/2018 
 
NCT Number:   NCT01030900 
 
PHASE II TRIAL OF ALEMTUZUMAB (CAMPATH) AND DOSE-ADJUSTED 
EPOCH-RITUXIMAB (DA-EPOCH-R) IN RELAPSED OR REFRACTORY DIFFUSE 
LARGE B-CELL AND HODGKIN LYMPHOMAS  
 
 
NCI Principal Investigator:  Wyndham H. Wilson, M.D., Ph.D. A-F 
Lymphoid Malignancies Branch (LYMB)  
Center for Cancer Research (CCR) 
National Cancer Institute (NCI) 
National Institutes of Health (NIH) 
Building 10, Room 4N115  
9000 Rockville Pike 
Bethesda, MD 20892 
Phone:  240-760-6092  
Email:  wilsonw@mail.nih.gov  
 
 
Commercial Agents:  
EPOCH-R = etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, rituximab, 
alemtuzumab 
Investigational Agents: 
Not applicable. 
 

Abbreviated Title:  EPOCH-RC in recurrent lymphoma 
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PRÉCIS 
Background: 
• Two signatures of the microenvironment were recently identified that are predictive of 
outcome in patients with newly diagnosed DLBCL treated with R-CHOP. These 
signatures, called ‘stromal 1’ and ‘stromal 2’, are associated with genes expressed by 
infiltrating mononuclear cells. The stromal 2 signature, which includes genes associated 
with angiogenesis, is predictive of an inferior outcome. Based on these observations, we 
are interested in targeting the reactive cells in the microenvironment as a therapeutic 
strategy in patients with relapsed and refractory DLBCL. Along the same principles, we 
are also including patients with relapsed Hodgkin lymphoma (HL). The surrounding 
reactive cells around Hodgkin Reed Sternberg (HRS) cells are now not thought to be 
bystander cells and they appear to provide important survival signals to HRS cells.  
• CD52 is one such promising target that is highly expressed in most of these infiltrating 
cells and on most DLBCL although not on HRS cells specifically. Anti-CD52 antibodies 
may have therapeutic value by depleting reactive B and T cells, and monocytes from the 
microenvironment. 
• The dose of alemtuzumab in combination with DA-EPOCH is 30 mg IV, as determined 
by a prior study done in patients with untreated peripheral T-cell lymphoma. The main 
toxicities of this combination are myelosuppression and opportunistic infections. 
• An important component of this study will be to obtain tumor tissue for gene expression 
profiling and to assess microenvironment signatures and look at other molecular 
signatures and targets before treatment and in patients who progress and ultimately 
correlate response and outcome with these various end-points.  
Objective:  
• Assess response, progression free survival (PFS) and overall survival (OS) in 
relapsed/refractory DLBCL and Hodgkin Lymphoma. 
Eligibility: 
• Previously treated or refractory classical large B-cell lymphomas, Grey-zone lymphoma 
and Hodgkin lymphoma, including Lymphocyte predominant Hodgkin Lymphoma 
(LPHL). 
• Age ≥ 18 years with adequate organ functions. 
• HIV negative and no active CNS lymphoma. 
Study Design: 
• Patients will receive 30mg of Alemtuzumab on day 1 of therapy, followed by Rituximab 
on day 1 and dose-adjusted EPOCH chemotherapy days 1-5, up to six cycles of therapy. 
• Tumor biopsies will be done before treatment, after 1 cycle of therapy and at relapse. 
• It is anticipated that up to 10-15 patients per year may be enrolled onto this trial. Thus, 
accrual of up to 52 patients is expected to require approximately 4-5 years. 

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TABLE OF CONTENTS 
PRÉCIS ........................................................................................................................................... 2 
TABLE OF CONTENTS ................................................................................................................ 3 
1 
INTRODUCTION .................................................................................................................. 5 
1.1 
Study Objectives .......................................................................................................... 5 
1.2 
Background and Rationale ........................................................................................... 5 
2 
ELIGIBILITY ASSESSMENT AND ENROLLMENT ....................................................... 14 
2.1 
Eligibility Criteria ...................................................................................................... 14 
2.2 
Screening Evaluation ................................................................................................. 15 
2.3 
Patient Registration .................................................................................................... 15 
3 
STUDY IMPLEMENTATION ............................................................................................ 16 
3.1 
Study Design .............................................................................................................. 16 
3.2 
Study Drug Administration (Via Central Catheter) ................................................... 16 
3.3 
Dose Modifications for Toxicities ............................................................................. 19 
3.4 
Study Calendar ........................................................................................................... 22 
3.5 
Concurrent Therapies (continued until CD4 count is >100 post-treatment) ............. 23 
3.6 
Post-Treatment Evaluation ........................................................................................ 24 
3.7 
Criteria for Removal from Protocol Therapy and Off Study Criteria ....................... 24 
4 
SUPPORTIVE CARE ........................................................................................................... 24 
4.1 
Prophylaxis for Hepatitis B reactivation .................................................................... 24 
4.2 
CMV Antigenemia ..................................................................................................... 25 
4.3 
Febrile Neutropenia ................................................................................................... 25 
4.4 
Symptomatic Anemia ................................................................................................ 25 
4.5 
Thrombocytopenia ..................................................................................................... 25 
4.6 
Central Venous Access (Required for EPOCH Administration) ............................... 25 
4.7 
Tumor Lysis Syndrome (Dose 1 only) ...................................................................... 26 
4.8 
GI Prophylaxis ........................................................................................................... 26 
5 
BIOSPECIMEN COLLECTION .......................................................................................... 26 
5.1 
Procedures for Sample Collection ............................................................................. 26 
5.2 
Sample Storage, Tracking and Disposition ............................................................... 26 
6 
DATA COLLECTION AND EVALUATION ..................................................................... 28 
6.1 
Data Collection .......................................................................................................... 28 

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6.2 
Response Criteria ....................................................................................................... 30 
6.3 
Toxicity Criteria ......................................................................................................... 30 
7 
SAFETY REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING PLAN
 
31 
7.1 
Definitions ................................................................................................................. 31 
7.2 
NCI-IRB and Clinical Director (CD) Reporting ....................................................... 32 
7.3 
Data and Safety Monitoring Plan .............................................................................. 33 
8 
STATISTICAL CONSIDERATIONS.................................................................................. 33 
9 
COLLABORATIVE AGREEMENTS ................................................................................. 34 
10 HUMAN SUBJECTS PROTECTION ................................................................................. 34 
10.1 
Rationale for Subject Selection ................................................................................. 34 
10.2 
Participation of Children ............................................................................................ 34 
10.3 
Participation of Subjects Unable to Give Consent .................................................... 34 
10.4 
Evaluation of Benefits and Risks/Discomforts .......................................................... 35 
10.5 
Risks/Benefits Analysis ............................................................................................. 35 
10.6 
Consent Process and Documentation ......................................................................... 36 
11 PHARMACEUTICAL INFORMATION ............................................................................. 36 
11.1 
Alemtuzumab ............................................................................................................. 36 
11.2 
Rituximab .................................................................................................................. 38 
11.3 
Doxorubicin HCL ...................................................................................................... 40 
11.4 
Etoposide ................................................................................................................... 41 
11.5 
Vincristine sulfate ...................................................................................................... 41 
11.6 
Administration of Vincristine/Doxorubicin/Etoposide .............................................. 42 
11.7 
Cyclophosphamide .................................................................................................... 42 
11.8 
Prednisone .................................................................................................................. 43 
11.9 
Filgrastim ................................................................................................................... 44 
12 REFERENCES ..................................................................................................................... 45 
13 APPENDICES ...................................................................................................................... 49 
13.1 
Appendix 1: EPOCH-RC Chemotherapy .................................................................. 49 
13.2 
Appendix 2: EPOCH Admixture, Preparation: and Administration ......................... 50 
13.3 
Appendix 3: Performance Status Criteria .................................................................. 51 
 
 
 

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1 
INTRODUCTION 
1.1 
STUDY OBJECTIVES 
1.1.1 Primary Objective  
Assess response, progression free survival (PFS) and overall survival (OS) in relapsed/refractory 
DLBCL and Hodgkin lymphoma. 
1.1.2 Secondary Objective 
Correlate clinical outcomes with microenvironment/stromal molecular signatures by gene 
expression profiling and immunohistochemistry on study and at relapse after DA-EPOCH-RC. 
1.2 
BACKGROUND AND RATIONALE  
1.2.1 Hypothesis  
Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma 
(NHL) – although the addition of rituximab to anthracycline-based chemotherapy has 
significantly improved the outcome of patients with the disease, it remains incurable in up to 
50% of cases. We are interested in building upon insights from the molecular characterization of 
DLBCL, which includes the identification of three distinct subtypes (ABC, GCB and PMBL) by 
gene expression profiling – these subtypes are associated with different prognoses 1. This has 
paved the way for the development of therapeutic strategies that target specific pathways. 
Indeed, we recently demonstrated that the ABC type may be preferentially targeted (when 
compared to the GCB type) by the addition of bortezomib to anthracycline-based chemotherapy 
2.  
Recent work led by Dr. Staudt’s group has identified two signatures of the microenvironment 
that are predictive of R-CHOP outcome in DLBCL3. These signatures, called stromal 1 and 
stromal 2, are associated with genes expressed by infiltrating mononuclear cells including 
macrophages, natural killer cells, T-cells and myeloid cells. The stromal 2 signature, which 
includes genes associated with angiogenesis, is predictive of an inferior outcome.  Based on 
these observations, we are interested in targeting the microenvironment as a therapeutic strategy.  
 
The microenvironment is usually tumor dependent and may involve tumor-induced interactions. 
It is comprised of tumor cells, stroma, blood vessels, infiltrating inflammatory cells and a variety 
of other associated tissue cells. Potential strategies include targeting the infiltrating “normal” 
cells and/or tumor angiogenesis. We hypothesize that targeting the infiltrating cells more 

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specifically is a potentially important strategy because the microenvironment may promote 
tumor survival through multiple mechanisms, such as angiogenesis and pro-survival signals. 
Immune cells present in the tumor microenvironment include those mediating adaptive 
immunity, T lymphocytes, dendritic cells and occasional B cells, as well as effectors of innate 
immunity, macrophages, polymorphonuclear leukocytes and natural killer cells4. Although 
various immune effector cells (e.g. cytotoxic T lymphocytes) are recruited to the tumor site, their 
anti-tumor functions may be downregulated in response to tumor-derived signals. This is because 
the tumor microenvironment is enriched in regulatory T cells (Treg), tumor-associated 
macrophages (TAM) as well as myeloid suppressor cells (MSC)5-7. All three immune cell types 
act in concert to promote tumor growth and suppress immune cell functions. It has been 
proposed that NF-κB pathway plays a key role in activation of signaling in cancer cells as well as 
tumor-infiltrating leukocytes. NF-κB activation in these cells leads to secretion of TNF-α or 
other pro-inflammatory cytokines (e.g. IL-6 and IL-8) which are responsible for cell 
proliferation, angiogenesis and tumor-cell migration (see figure below) 8, 9. 
 
 
Regulatory T cells (Treg) are capable of suppressing proliferation of other T cells in the 
microenvironment through contact-dependent mechanisms or IL-10 and TGF-  secretion10-12. 
Likewise, TAMs inhibit lymphocyte functions through release of inhibitory cytokines such as 
IL-10, prostaglandins or reactive oxygen species (ROS) 13, 14. Myeloid suppressor cells (MSC) 
are bone marrow-derived immature dendritic cells15. They, on the other hand, promote tumor 
growth and suppress immune cell functions through copious production of an enzyme involved 
in L-arginine metabolism, arginase 1, which synergizes with inducible nitric oxide synthase 
(iNOS) to increase superoxide and nitric oxide production, thereby blunting lymphocyte 
responses16  
 

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A promising therapeutic target is CD52 which is highly expressed on most DLBCL, including 
both ABC and GCB types, and on many of the infiltrating cells (monocytes, macrophages, 
dendritic cells and myeloid precursors) in the microenvironment (Gene Expression Profiling of 
CD52 shown below). Furthermore, Rodig et al. reported CD52 expression by 
immunohistochemical techniques in 75% of DLBCL17. 
 
 
 
 
 
 
We are also interested in investigating the efficacy of this combination in patients with relapsed 
or refractory Hodgkin lymphoma (HL). Hodgkin's lymphoma is characterized by an infiltration 
of many different types of cells of the immune system into the lymphoma tissue, including T 
cells, B cells, plasma cells, neutrophils, eosinophils and mast cells, such that the Hodgkin reed 
Sternberg (HRS) cells themselves usually represent only about 1% of cells in the tumor. There is 
evidence that many of the cells are actively attracted by HRS cells. For example, HRS cells 
secrete CCL5 (RANTES), CCL17 (TARC) and CCL22, which attract TH2 cells and Treg cells18-
20. The secretion of IL-5, CCL5, CCL28 and granulocyte–macrophage colony-stimulating factor 
by HRS cells presumably causes the recruitment of eosinophils into the Hodgkin's lymphoma 
microenvironment. CCL5 additionally attracts mast cells. HRS cells also secrete IL-8, which 
attracts neutrophils. These reactive cells are not bystander cells, as previously thought. By 
contrast, they frequently provide survival signals to HRS cells21.  The role of the 
microenvironment in supporting the survival and growth of HRS cells is best illustrated by the 
difficulty of establishing HRS-derived cell lines. Several observations indicate that HRS cells are 
dependent on survival signals received from other cells: it is difficult to grow HRS cells in 
culture; HRS cells do not survive in immunodeficient mice; HRS cells are rarely found in 
peripheral blood; and, even when they metastasize into non-lymphoid organs, they are embedded 

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in their typical microenvironment22. Some examples of these survival signals include triggering 
of CD40 signalling23, activation of transmembrane activator and calcium-modulator and 
cyclophilin-ligand interactor (TACI) and B-cell maturation antigen (BCMA) through production 
of their ligand APRIL by neutrophils 24, and perhaps activation of CD30 through CD30L-
expressing mast cells and eosinophils 25 26.  
 
 
 
 
HRS cells also orchestrate their cellular microenvironment to evade an attack by cytotoxic T 
cells or natural killer cells. A considerable fraction of infiltrating CD4+ T cells are Treg cells, 
which have been shown to have immunosuppressive activity on Hodgkin's lymphoma-infiltrating 
cytotoxic T cells 27. HRS cells may further modulate their cellular microenvironment by shifting 
the TH response from an anti-cellular TH1 response to a humoral TH2 response, which often has 
tumor-promoting activities. HRS cells also produce the immunosuppressive cytokines IL-10 and 
TGF , and galectin 1 and prostaglandin E2, which inhibit T-cell effector functions 28, 29 30. 
Therefore, it is ironic that the host’s own immune cells are providing survival factors to the 
malignant cells, creating an ‘immune-betrayal’ phenomenon. Eliminating these reactive cells 
from the microenvironment may deprive HRS cells from critical survival factors and may lead to 
their growth arrest and death. CD52 is not expressed by HRS cells; however, anti-CD52 
antibodies may have therapeutic values in HL by depleting reactive B and T cells and monocytes 
from the microenvironment. Therefore, alemtuzumab, a monoclonal antibody to CD52, is a very 
interesting drug to investigate in both these diseases, given the high CD52 expression in DLBCL 
tumor cells and in the surrounding microenvironment of both these tumors. 
Over the past few years, we have been conducting a study of alemtuzumab in combination with 
DA-EPOCH in untreated peripheral T-cell lymphoma (PTCL) and have determined the safe dose 
of alemtuzumab in combination with DA-EPOCH to be 30 mg IV31. The main toxicities were 
myelosuppression and opportunistic infections. 
Based on our hypothesis, we wish to investigate this combination (DA-EPOCH-RC) in patients 
with relapsed/refractory aggressive DLBCL and Hodgkin lymphoma. An important component 
of this study will be to obtain tumor tissue for gene expression profiling and to assess 
microenvironment signatures and look at other molecular signatures and targets before treatment, 
after 1 cycle of therapy and in patients who progress. Ultimately, we would like to correlate the 

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responses and outcomes with these various end-points. Of the DLBCL subtypes, we are 
particularly interested in investigating the efficacy of this combination in T-cell rich DLBCL and 
in elucidating the molecular signature of these tumors and correlating that with response. These 
tumors have not been well molecularly characterized and may significantly benefit from the 
addition of alemtuzumab.  
1.2.2 EPOCH in Relapsed lymphomas 
The dose-adjusted EPOCH (DA-EPOCH) regimen was initially studied in 131 patients with 
relapsed or resistant lymphomas32.  46% of the group generally had a poor prognosis as 
determined by a high-intermediate or high International Prognostic Index (IPI) scores. All 
patients were extensively pretreated having received a median of 8 (1-17) different drugs. 57% 
of patients had received all 5 drugs of the DA-EPOCH regimen and 88% had received at least 4 
of the agents.  All but 4 (6%) patients had previously received doxorubicin. Among 125 
assessable patients, 93 (74%) achieved objective responses, including 30 (24%) complete and 63 
(50%) partial responses.  To determine if the infusional schedule increased efficacy, we analyzed 
the response to EPOCH in patients who showed no response to their last combination regimen 
(i.e. resistant disease). In this group of 42 patients, 57% responded to EPOCH. Among patients 
with chemotherapy-sensitive disease, 83% responded with 33% complete responses as shown in 
the table below.    
 
 
 
 
 
High-dose therapy with stem-cell transplant (SCT) is generally believed to provide the best 
outcome for patients with chemosensitive relapsed aggressive lymphomas. Hence a clinically 
important role for salvage chemotherapy is to cyto-reduce patients who are candidates for SCT. 
In this study, 28 patients with aggressive lymphomas who had relapsed after CR, 89% responded 
to EPOCH, including 54% who had complete responses, and became potential candidates for 
SCT. Notably, among the 33 patients with sensitive aggressive lymphomas who did not receive a 
stem cell transplant, 18% were event-free and 37% were alive at 5 years, suggesting that EPOCH 
alone may provide effective salvage for a proportion of patients. Furthermore, 19 patients who 
had chemotherapy-resistant disease, 7 (37%) responded to EPOCH, including 1 CR.  Overall, 
patients had a median OS of 17.5 months with 41% and 26%, respectively, alive at 3 and 6 years, 
and a median EFS of 7 months, with 15% and 10%, respectively, event-free at 3 and 6 years. The 
main toxicities included brief neutropenia, usually less than 4 days and occurring around day 10 
to 14 of treatment, and minimal gastrointestinal toxicity. Thrombocytopenia below 50,000/L 
occurred on 24% of cycles, and neutropenia occurred on 48% of cycles with hospitalization for 
neutropenia with fever on 18% of cycles.  There were three infection-related deaths. 
Neurological toxicity necessitating vincristine reduction occurred in 10% of cycles. Cardiac 
toxicity, a major limitation of doxorubicin, was rarely seen (3% of patients) despite no maximum 
allowable doxorubicin exposure. We observed a modest and clinically insignificant decline in the 
median EF over multiple cycles of EPOCH; a paired t test (p2) analysis comparing cycle 0-1 vs. 
cycle 2-3, cycle 4-5 and cycle  6 revealed a difference of -2.58%, (0.13); -5.5%, (0.0038) and -
    
Category 
No 
CR (%) 
PR (%) 
RR (%) 
 
 
 
 
 
 
 
 
   Total 
125 
30 
(24%:) 
62 
(50%:) 
92 
 (74%) 
      Sensitive Disease 
81 
27 
(33%:) 
40 
(49%:) 
67 
 (83%) 
      Resistant  Disease 42 
2 
(5%:) 
22 
(52%:) 
24 
 (57%) 
      Dox-Resistant 
20 
0 
(0%) 
10 
(50%) 
10  
(50%) 
       
      No of Regimens  
 
 
 
 
 
 
 
         1 
67 
21 
(31%:) 
33 
(51%:) 
54 
 (81%) 
         2 
26 
5 
(19%) 
14 
(54%:) 
19 
 (73%) 
          3 
30 
3 
(10%) 
14 
(47%:) 
17 
 (57%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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6.32%, (0.020), respectively.  Although the patients were heavily pretreated, the toxicity profile 
of EPOCH allows delivery of 71%, 92%, 92% and 93% of planned cyclophosphamide, 
doxorubicin, vincristine and etoposide, respectively.  
1.2.3 EPOCH-Rituximab in Relapsed lymphomas 
With the advent of Rituximab and its addition to CHOP, that significantly improved the outcome 
of DLBCL and R-CHOP soon became the new standard in untreated DLBCL33-35. At our 
institution we have also shown that DA-EPOCH-R to be an effective therapy in untreated 
DLBCL. Jermann et al. reported the use of EPOCH-Rituximab combination as salvage therapy 
in a phase II study36. Patients with relapsed or refractory CD20-positive large B-cell and mantle-
cell lymphoma were offered treatment with rituximab 375 mg/m2 intravenously (i.v.) on day 1, 
doxorubicin 15 mg/m2 as a continuous i.v. infusion on days 2-4, etoposide 65 mg/m2 as a 
continuous i.v. infusion on days 2-4, vincristine 0.5 mg as a continuous i.v. infusion on days 2-4, 
cyclophosphamide 750 mg/m2 i.v. on day 5 and prednisone 60 mg/m2 orally on days 1-14. Fifty 
patients, with a median age of 56 years (range 23-72), entered the study. Twenty-five had 
primary diffuse large B-cell lymphoma, 18 transformed large B-cell lymphoma and seven 
mantle-cell lymphoma. The median number of prior chemotherapy regimens was 1.7 (range one 
to four). The median number of treatment cycles was four (range one to six). Objective responses 
were obtained in 68% of patients (28% complete responses, 40% partial responses). Nineteen 
patients received consolidating high-dose chemotherapy with autologous stem-cell 
transplantation. The median follow-up was 33 months. Three patients developed a secondary 
myelodysplastic syndrome. The median overall survival was 17.9 months; the projected overall 
survival at 1, 2 and 3 years was 66, 42 and 35%, respectively. The median event-free survival 
was 11.8 months; the projected event-free survival at 1, 2 and 3 years was 50, 30 and 26%, 
respectively.  
1.2.4 EPOCH-Bortezomib in Relapsed DLBCL 
We have published our results correlating the outcomes of the different molecular subtypes of 
DLBCL with DA-EPOCH-R37. We analyzed 72 untreated patients with GCB and ABC DLBCL. 
Similar to recent findings with R-CHOP, the ABC subtype tended to be associated with a worse 
PFS compared with GCB DLBCL. These findings suggest that DA-EPOCH-R outcome is 
impacted by the biology associated with ABC subtype, possibly driven by NFκB activation1, 38, 
39. 
To further study the hypothesis that inhibition of NFκB might sensitize ABC but not GCB 
DLBCL to chemotherapy. We did a study combining bortezomib, a proteasome inhibitor, with 
DA-EPOCH (DA-EPOCH-B) in 49 patients with relapsed or refractory DLBCL to investigate if 
ABC compared to GCB DLBCL was more responsive to DA-EPOCH-B2. In vitro, bortezomib 
blocks degradation of phosphorylated IκBα and consequently inhibited NFκB activity in ABC 
DLBCL cell lines. The study was divided into 2 parts (see figure below), in Part A patients 
received bortezomib alone if they were clinically able; patients who progressed or was too ill to 
justify bortezomib alone, they received DA-EPOCH-B in part B.  

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Among 23 patients in part A, there was only 1 partial response, indicating bortezomib alone has 
no activity. Overall, all 44 patients in Part B, 15 (34%) responded including 8 complete 
responses. Similar response rates were also seen in the 27 patients with de novo DLBCL. Among 
all patients with de novo DLBCL, the median survival was 8 months. However, when we 
analyzed the responses and overall survival in the de novo GCB and ABC DLBCL patients who 
received DA-EPOCH-B, there were significant differences between the 2 groups. The overall 
response rate was 13% in GCB DLBCL compared to 83% in ABC DLBCL (P = 0.0004). It was 
particularly striking that 41.5% of patients with ABC DLBCL achieved complete remission 
compared to only 6.5% for those with GCB DLBCL. The median overall survival was 3.4 and 
10.8 months, respectively (P = 0.0026) for the ABC and GCB subtypes (see figure below). This 
study highlights the fact that because of genetic differences between the DLBCL subtypes, 
preferential activity to a targeted agent may be seen in one particular subtype over another. This 
further underscores the importance of pairing molecular characterization and clinical outcome in 
DLBCL for the rational development of targeted agents in this disease. 
 
 
1.2.5 EPOCH-Alemtuzumab in untreated T-cell lymphomas 
Alemtuzumab is a humanized antilymphocyte monoclonal antibody engineered by grafting the 
rodent hypervariable complementarily determining regions into a human immunoglobulin 
molecule. It is directed at CD52, a 12 amino acid protein that is highly glycosylated and linked to 
the cell membrane by phosphytidylinositolglycan linkage. CD52 is highly expressed on 
membrane lipid shafts of all B and T lymphocytes at most stages of differentiation (except 
plasma cells), as well as on monocytes, macrophages, eosinophils, natural killer cells and 
dendritic cells40-42. However, monocytes appear to be resistant to Alemtuzumab-mediated lysis. 
Monocytes disappear from the peripheral circulation but reappear shortly after treatment 

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suggesting a sequestration without lysis or regeneration from a precursor pool that is CD52-
negative. It is estimated that there are 5 x 10
5 antibody sites per lymphocyte and the antigen does 
not modulate from the cell surface. Alemtuzumab is thought to mediate cell lysis through 
complement43, 44 or antibody-dependent cell-mediated cytotoxicity45-47. Recent studies have also 
shown Alemtuzumab may induce rapid cell death in vitro through both a non-classic caspase-
independent48, 49 and caspase dependent pathways50, 51. The function of CD52 is not known but a 
recent paper suggested that CD52 may contribute to the activation of T-regulatory cells52.  
The combination of Alemtuzumab and DA-EPOCH chemotherapy has been studied in 29 
patients with untreated CD52-positive T-cell lymphomas6. A single infusion of Alemtuzumab 
(30, 60, or 90 mg) was given over 12 hours before each cycle of chemotherapy; patients were 
premedicated with prednisone 12 hours before the Alemtuzumab infusion was initiated. DA-
EPOCH was initiated immediately following completion of the Alemtuzumab infusion. Toxicity 
during the first cycle of treatment was used to determine Alemtuzumab dose escalation. Patients 
were treated with escalated doses of Alemtuzumab in cohorts of three patients; 4 patients were 
treated with 30 mg, and subsequent cohorts were treated with 60 and 90 mg. All but 3 were stage 
III or IV at presentation.  
Among the 28 patients evaluated for response there were 15 complete remissions, 8 partial 
remissions, 2 progressive diseases and 4 who were not evaluable for response.  The median 
duration of complete response is 9 months with nine patients in continuous complete remission 
for 3-58 months.   Most patients experienced grade 1–2 allergic and infusional reactions 
manifested as fever, chills, and urticaria. However, 4 patients developed bone marrow aplasia 
that prevented further treatment, 1 patient at the 30mg dose level, 1 patient at the 60 mg dose 
level (cycle 3 and 5) and 2 patients at the 90 mg dose level (cycle 4 and 5) of Alemtuzumab. 
Three of these four patients were CMV antigen positive and were treated with oral or intravenous 
ganciclovir. There was more myelosuppression in patients treated with campath and EPOCH 
compared with those treated with EPOCH alone, 29% vs. 8% had platelet counts of less than 
25K, 100% vs. 60% for grade 4 neutropenia, 35% vs. 15% incidence of febrile neutropenia. But 
with the 30 mg dose of Alemtuzumab myelosuppression was equivalent to that observed with 
EPOCH alone or in combination with rituximab.  
We evaluated the ability to dose escalate EPOCH chemotherapy in patients treated with 
Alemtuzumab and found that there was no significant difference in dose escalation or reduction 
with the regimen.  All but one patient developed grade 4 lymphopenia. Documented infections 
were common and the most common pathogens detected were viral with 20 patients 
experiencing viral infection or reactivation.  The most common virus detected was 
cytomegalovirus that was generally asymptomatic and detected only by a positive CMV PCR 
reaction.  Another viral pathogen not commonly seen with EPOCH alone or with rituximab was 
hemorrhagic cystitis associated with BK virus infection in the urine, occurring in 8 patients, 
which resolved despite continued treatment. Four patients had rising EBV DNA titers in the 
blood but there were no cases of EBV lymphoproliferative disease.  Two patients had 
reactivation of HSV despite prophylaxis.  Other viral infections included influenza, rotavirus and 
respiratory syncytial virus.  Bacterial infections, both gram positive and gram negative, occurred 
in 11 patients with staphylococcal infections as the most common organism isolated.  Four 
patients had fungus isolated but only one was thought to have tissue invasion. Four patients died 
during treatment with Alemtuzumab and EPOCH.  Two patients died of neutropenic sepsis, one 
died of disseminated toxoplasmosis, and one had a witnessed cardiac arrest during EPOCH 

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chemotherapy infusion that was thought to be related to cardiac arrhythmia. The 30 mg dose 
level of Alemtuzumab appears safe to administer in combination with DA-EPOCH and there has 
been no bone marrow suppression that prevented completion of therapy in any patient treated at 
the 30 mg dose of Alemtuzumab.  Based on the results of this study, the 30mg dose was chosen 
as the treatment dose for Alemtuzumab in our current study and we have also incorporated CMV 
and toxoplasmosis prophylaxis routinely for all patients.  
1.2.6 EPOCH in Relapsed Hodgkin Lymphoma 
The EPOCH infusional regimen has also shown to be effective and well tolerated and should be 
considered as salvage therapy prior to stem cell transplant or for palliation in patient with 
incurable Hodgkin lymphoma. We performed a study in 54 patients with relapsed/refractory 
Hodgkin lymphoma53. Patients received fixed dose EPOCH chemotherapy (etoposide 200 
mg/m2, vincristine 1.6 mg/m2 (no cap) and doxorubicin 40 mg/m2 CIVI x 96-hrs D1-4; 
cyclophosphamide 750 mg/m2 IV D5 and prednisone 60 mg/m2 daily D1-6) with G-CSF q21 
days. Histology included nodular sclerosis 34 (64%), mixed cellularity 3 (25%), and lymphocyte 
depleted 5 (9%) classical HL, and nodular lymphocyte predominant HL 1 (2%). Most of the 
patient had advanced disease, with stage III in 11 (21%) and IV in 30 (56%). In addition, 24 
patients (45%) had more than 2 prior regimens. Overall, 44% of patients achieved complete 
remissions, and a progression-free survival (PFS) and overall survival (OS) of 41% and 21% 
respectively, with a median follow-up of 68 months. The median progression-free (PFS) and 
overall survivals (OS) are 10 and 40 months at 68 months median follow-up. Among 33 pts who 
underwent stem-cell transplant, median PFS was 15 months. 
Combination of Rituximab and chemotherapy in Relapsed Hodgkin Lymphoma: CD20 antigen is 
infrequently expressed by HRS cells. The approach of using rituximab to deplete the CD20+ B 
cells from the HL microenvironment was studied by investigators from MD Anderson. A total of 
22 heavily pretreated patients with classical HL were treated with 6-weekly doses of rituximab, 
of whom six demonstrated CD20 expression by HRS cells. In all, five patients (22%) achieved 
partial or complete remissions and eight additional patients had stable disease54. In a follow-up 
study, the same investigators combined rituximab with ABVD chemotherapy to treat patients 
with newly diagnosed classical HL, and with gemcitabine to treat patients with relapsed classical 
HL In the first study, 52 patients with classical HL were treated with rituximab plus ABVD55. 
With a median follow-up of 32 months, the estimated event-free survival (EFS) was 82% and 
overall survival 100%. Importantly, the EFS was improved for all risk categories: for patients 
with a prognostic score of 0–1 the EFS was 92%, for scores 0–2, EFS was 86% and for scores 3–
5, it was 73%. These data are encouraging, but has not been confirmed in a randomized trial. In 
the second study, rituximab was combined with gemcitabine for the treatment of patients with 
relapsed/refractory classical HL56. The median number of prior treatment regimens was four 
(range one to six) and 17 (65%) were refractory to their last regimen. Of the patients studied, 
14 patients (54%) had received prior SCT, and 21 patients (81%) were previously treated with 
platinum-based therapy. Treatment was reasonably well-tolerated, with the most frequent 
toxicity being thrombocytopenia and neutropenia. A total of 13 patients (50%) responded to 
rituximab plus gemcitabine therapy, regardless of CD20 expression by HRS cells. These results 
compared favorably with the reported single agent activity of gemcitabine in less heavily 
pretreated patients.  
Targeting the microenvironment with DA-EPOCH-R-C is a novel approach. We hypothesize that 
eliminating the reactive cells from the microenvironment may deprive malignant cells from 

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critical survival factors leading to cell death. Therefore, an important aspect of this study is to 
further understand these interactions which may lead to the identification of new molecular 
signatures and targets. Ultimately, the goal of this approach is to improve outcomes in patients 
with relapsed/refractory aggressive DLBCL and Hodgkin lymphoma. 
 
2 
ELIGIBILITY ASSESSMENT AND ENROLLMENT 
2.1 
ELIGIBILITY CRITERIA 
2.1.1 Inclusion Criteria 
2.1.1.1 Previously treated or refractory large B-cell lymphomas, Grey-zone lymphoma, 
Hodgkin Lymphoma, including Lymphocyte predominant Hodgkin Lymphoma (LPHL) 
2.1.1.2 Confirmed pathological diagnosis by the Laboratory of Pathology, NCI.  
2.1.1.3 Age 18 years.  
2.1.1.4 ECOG performance 0-2 
2.1.1.5 Laboratory tests: ANC  1000/mm3, platelet  75,000/mm3. Creatinine 1.5 mg/dL or 
creatinine clearance  60 ml/min; AST and ALT  5x ULN. Total bilirubin < 2.0 mg/dl 
except < 5mg/dL in patients with Gilbert’s (as defined as > 80% unconjugated 
hyperbilirubinemia without other known cause); unless impairment due to organ 
involvement by lymphoma. 
2.1.2 Exclusion Criteria 
2.1.2.1 Active symptomatic ischemic heart disease, myocardial infarction or congestive heart 
failure within the past year. If ECHO is obtained, the LVEF should exceed 40%. 
2.1.2.2 HIV positive, because of the unknown effects of combined therapy with chemotherapy 
and an immunosuppressive agent on HIV progression 
2.1.2.3 Female subject of child-bearing potential not willing to use an acceptable method of 
birth control (i.e. a hormonal contraceptive, intra-uterine device, diaphragm with 
spermicide, condom with spermicide, or abstinence) for the duration of the study and 
two years beyond treatment completion. 
2.1.2.4 Female subject pregnant or breast-feeding. Confirmation that the subject is not pregnant 
must be established by a negative serum β-human chorionic gonadotrophin (β-hCG) 
pregnancy test result obtained during screening. Pregnancy testing is not required for 
women without child-bearing potential. 
2.1.2.5 Male subject unwilling to use an acceptable method for contraception for the duration 
of the study and one year beyond treatment completion. 
2.1.2.6 Invasive or active malignancy in past 2 years. 
2.1.2.7 Serious concomitant medical illnesses that would jeopardize the patient’s ability to 
receive the regimen with reasonable safety. 
2.1.2.8 Active CNS lymphoma. These patient have a poor prognosis and because they 
frequently develop progressive neurological dysfunction that would confound the 

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evaluation of neurological and other adverse events. 
2.1.2.9 Systemic cytotoxic therapy within 3 weeks of treatment. 
2.2 
SCREENING EVALUATION  
Evaluation pre-treatment (Tests to be done within 4 weeks of treatment except laboratory tests in 
2.2.2 and 2.2.8 must be done within 72 hours of treatment): 
2.2.1 Complete history and physical examination with assessment of performance status 
2.2.2 Laboratory tests: CBC/differential; prothrombin time, partial thromboplastin time; total 
and direct bilirubin, AST, ALT, LDH, alkaline phosphatase; albumin, calcium, 
phosphate, uric acid, creatinine (creatinine clearance if serum creatinine > 1.5 mg/dl), 
and electrolytes. 
2.2.3 Tumor biopsies will be obtained for flow cytometry for assessment of CD52 staining if 
accessible tissue is available. Where possible, tumor biopsies will be obtained by core 
needle biopsy or surgery pre-treatment.  Laparotomy, thoracotomy, or biopsy of 
relatively inaccessible lymph nodes (i.e. high axillary nodes) will only be performed if 
needed for definitive diagnosis and not for research purposes alone. 
2.2.4 HIV antibody; hepatitis B surface and core antigen; hepatitis C; and anti-HCV antibody 
2.2.5 CMV, EBV and toxoplasmosis serologies 
2.2.6 CMV antigen by PCR, serum BK virus by PCR, EBV viral load 
2.2.7 Urinalysis and urine for BK virus by PCR 
2.2.8 Urine HCG in women of childbearing potential. 
2.2.9 Imaging Studies: CT chest, abdomen, and pelvis; CT or MRI of head if   neurological 
signs or symptoms suggestive of lymphomatous involvement are present. 
2.2.10 Electrocardiogram 
2.2.11 Clinical PET (fluorine 18-FDG) scan within two weeks of starting treatment, but may be 
waived if this will delay treatment. 
2.2.12 Unilateral bone marrow aspiration and biopsy. 
2.2.13 Lumbar puncture for cell count, chemistry, cytology, flow cytometry if indicated.  
2.3 
PATIENT REGISTRATION 
Authorized staff must register an eligible candidate with NCI Central Registration Office (CRO) 
within 24 hours of signing consent.  A registration Eligibility Checklist from the web site 
(http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) must be completed and sent via 
encrypted email to: NCI Central Registration Office at ncicentralregistration-l@mail.nih.gov.  
After confirmation of eligibility at Central Registration Office, CRO staff will call pharmacy to 
advise them of the acceptance of the patient on the protocol prior to the release of any 
investigational agents.  Verification of Registration will be forwarded electronically via e-mail to 
the research team. A recorder is available during non-working hours.  

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3 
STUDY IMPLEMENTATION 
3.1 
STUDY DESIGN 
This is a phase II trial of Alemtuzumab in combination with DA-EPOCH-R given every 21 days 
for a total of 6 cycles of treatment.  Six cycles of therapy will be administered based on clinical 
response evaluation.  If a patient has progressive disease at any point during therapy, he/she will 
be removed from protocol treatment.  Patients who are eligible for transplant will receive 2 
cycles beyond stable disease or stop when they achieve CR. Patients not eligible for transplant 
will receive 2 cycles beyond stable disease, or 6 cycles if they achieve CR. 
 
3.2 
STUDY DRUG ADMINISTRATION (VIA CENTRAL CATHETER) 
3.2.1 DA-EPOCH-R-Alemtuzumab Chemotherapy 
See also Appendix 1. 
Alemtuzumab will be given on day 1 of each treatment cycle. Patients will receive each 
treatment cycle until unacceptable toxicity, documentation of disease progression, completion of 
six cycles of therapy or other reasons for patient withdrawal, whichever comes first.   
Patients should be pre-medicated as described in section 3.2.4.  Alemtuzumab will be 
administered as an IV infusion over approximately 12 hours. Alemtuzumab must not be 
administered via IV push or bolus.  If infusional toxicities are observed, the infusion may be 
stopped for up to 60 minutes and resumed when toxicity resolved to baseline, or to grade 1 or 
less. If the patient has not had resolution of infusional toxicities within 60 minutes, contact the 
investigator for guidelines on when to resume infusion. 
If anaphylaxis (Grade 4) hypersensitivity reactions occur, further treatment with Alemtuzumab 
will be discontinued.  Hypersensitivity reactions should be managed according to procedures 
outlined in Table 1. Meperidine 25 mg IV should be administered for treatment of patients with 
severe rigors.  
 

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  Table 1 Treatment Guidelines for Management of Hypersensitivity Reactions 
 
 
Treatment Guidelines 
Severity of Symptoms 
Alemtuzumab 
Mild  
• Stop Alemtuzumab infusion until the patient is evaluated. 
• Following evaluation, the infusion may be restarted under 
observation and monitor subject; complete Alemtuzumab infusion 
at the initial planned rate. 
• Additional diphenhydramine 25-50 mg oral may be administered at 
the discretion of the treating physician. Chills without rigors can be 
managed with warm blankets.  
Localized cutaneous reactions 
such as mild pruritus, 
flushing, rash and chills 
Moderate  
Generalized pruritus, 
flushing, rash, dyspnea, fever, 
chills, rigors, and hypotension 
with systolic blood pressure 
>80 mmHg  
• Stop Alemtuzumab infusion 
• Administer diphenhydramine 50 mg IV and monitor patient until 
symptoms resolve. Resume Alemtuzumab at one-half the initial 
infusion rate after recovery of symptoms; if symptoms develop after 
restarting the infusion, the infusion should be stopped and no 
additional Alemtuzumab should be administered at that time. 
• Additional oral or IV antihistamine may be administered. A 
maximum dose of diphenhydramine of 100 mg in a 6 hour period 
should not be exceeded.  Rigors should be managed with IV 
meperidine 25 mg every 5-10 minutes to a maximum of 100 mg.  
• Give oral diphenhydramine, 50 mg and acetaminophen 650 mg 30 
minutes prior to the next scheduled dose of Alemtuzumab. 
Severe or Any reaction such 
as bronchospasm, generalized 
urticaria, angioedema, or 
systolic BP 80 mmHg) 
• Immediately discontinue Alemtuzumab infusion 
• Bronchospasm, hypotension unresponsive to intravenous fluids, or 
angioedema may require administration of epinephrine 1 mg 
subcutaneously and/or diphenhydramine 50 mg IV with 
methylprednisolone 100 mg IV or dexamethasone 20 mg IV, as 
needed, as well as supplemental oxygen. 
• Hypotension should be managed with intravenous fluids but if 
unresponsive may require more aggressive intervention such as 
phenylephrine infusion. 
• Monitor patient until resolution of symptoms.   
Anaphylaxis  
Defined as a reaction that is 
life threatening and requires 
pressor and/or ventilator 
support or shock associated 
with acidemia and impairing 
vital organ function due to 
tissue hypoperfusion 
• Discontinue further treatment with Alemtuzumab 
3.2.2 Dose-Adjusted EPOCH-RC Regimen 
All patients initiate therapy at Dose Level 1 of DA-EPOCH-RC shown below. Subsequent 
treatment doses are determined by hematological toxicity experienced on the previous cycle 
according to the dose-adjustment paradigm in Section 3.3.2. Dose adjustment is based on 

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measurements of twice weekly CBC only (e.g., Monday and Thursday, or Tuesday and Friday), 
even if additional CBCs are obtained. 
Cycle 1 Doses: 
Drug  
Dose 
Route 
Treatment Days 
Infused Agents1  
 
 
 
Alemtuzumab 
30 mg 
IV 
day 1 
Rituximab 
375 mg/m2 
IV 
day 1 
Etoposide  
50 mg/m2/day 
CIV 
1,2,3,4 (96 hours) 
Doxorubicin 
10 mg/ m2/day 
CIV 
1,2,3,4 (96 hours) 
Vincristine 
0.4 mg/ m2/day 
CIV 
1,2,3,4 (96 hours) 
Bolus Agents 
 
 
 
Cyclophosphamide2 
750 mg/m2/day 
IV 
day 5 
Prednisone3  
60 mg/m2 twice daily 
PO 
day 0-54 
Filgrastim 
480 mcg 
SC 
days 6 to ANC recovery  
5000/mm3 
 
1Begin the Rituximab immediately after Alemtuzumab infusion has completed. For the first cycle of 
treatment, Rituximab and the EPOCH infusion may be infused on days 2-6 if the Alemtuzumab 
infusion is prolonged due to infusion reaction. 
 
1Begin the infusional agents immediately after Rituximab infusion has completed. 
 
1Infusional agents should be administered through a central venous access device.  
 
2Begin cyclophosphamide immediately after infusions are completed and administer over 30 
minutes. 
3Begin Prednisone 8-12 hours before start of Alemtuzumab with second dose given just prior to 
Alemtuzumab. 
4A total of 10 doses of Prednisone 60 mg/m2 will be administered over 5 days. 
3.2.3 Table of doses per level for adjusted agents:   
Drugs 
Drug Doses per Dose Levels 
-2 
-1 
1 
2 
3 
4 
5 
6 
Doxorubicin (mg/m2/day) 
10 
10 
10 
12 
14.4 
17.3 
20.7 
24.8 
Etoposide (mg/m2/day) 
50 
50 
50 
60 
72 
86.4 
103.7 
124.4 
Cyclophosphamide (mg/m2/day) 
480 
600 
750 
900 
1080 
1296 
1555 
1866 
3.2.4 Premedication for Monoclonal Antibody Infusions  
Premedicate 30-90 minutes before Alemtuzumab infusion with   
• 650 mg acetaminophen PO 
• 50 mg diphenhydramine PO 
• Prednisone 60 mg/ m2 PO.  This would be the second dose of the 60 mg/ m2 bid 
prednisone regimen that is part of the EPOCH therapy.  The first dose is given 8-12 hours 
before Alemtuzumab. 

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Prophylaxis for tumor lysis syndrome will be administered at the discretion of the Principal 
Investigator according to institutional practice.  Hydration and urine alkalinization will be 
administered according to the discretion of the Principal Investigator. 
Premedicate 30-60 minutes before rituximab infusion with 
• 650 mg acetaminophen PO 
• 50 mg diphenhydramine PO 
Rituximab infusion should begin immediately after the Alemtuzumab infusion has completed. 
See Section 9.2.4 for specific Rituximab administration instructions. There will be no dose 
adjustments for Rituximab. 
3.3 
DOSE MODIFICATIONS FOR TOXICITIES 
3.3.1 Discontinue Alemtuzumab for: 
• 
Grade 4 non-hematological toxicity other than easily correctable metabolic toxicities or 
infection. 
• 
Grade 3 infusional or allergic toxicity 
3.3.2 EPOCH Dose Adjustments  
3.3.2.1 Hematological Toxicity 
No dose adjustments at cycle 1 will be made for patients that have low neutrophil count or 
platelet count due to bone marrow involvement of disease. Drug doses may be modified from the 
following algorithm at the discretion of the investigator for severe life-threatening toxicity such 
as ICU admissions for sepsis. When two different rules give different answers for a particular 
dose decision, use the lower of the two dose options. 
3.3.2.2 Dose-Adjustment Paradigm  
 
 
 
 
 
 
 
 
 
 
 
 
• Dose adjustments above starting dose level (level 1) apply to etoposide, doxorubicin and 
cyclophosphamide 
• Dose adjustments below starting dose level (level 1) apply to cyclophosphamide only.  
• Drug Doses based on previous cycle ANC nadir: 
 
➢ If Nadir ANC  500/l on all measurements  
:         1 dose level above last cycle  
➢ If Nadir ANC  500/l on 1 or 2 measurements :        Same dose level as last cycle   
➢ If Nadir ANC  500/l  3 measurements(see**) :         1 dose level below last cycle 
Or 
➢ If nadir platelet  25,000/l on 1 measurement :         1 dose level below last cycle.  
• Proceed with the next cycle of therapy if ANC  1000/l and platelets  75,000/l on day 21, 
and filgrastim was stopped 24 hours before beginning treatment. 

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• If ANC < 1000/l or platelets < 75,000/l on day 21, delay up to 1 week.  Filgrastim 480 
mcg every day may be started for ANC < 1000/l and stopped 24 hours before treatment.  If 
counts still low after 1 week delay,  1 dose level below last cycle.  
**Important: Measurement of ANC nadir based on twice weekly CBC only and must be 3 
days apart.  Only use twice weekly CBC for dose-adjustment, even if additional CBC’s are 
obtained.  
3.3.2.3 NON-HEMATOLOGICAL TOXICITY 
a. Sensory neuropathy  
Grade 
Vincristine Dose (%) 
2 
100 
3 
 50 
4 
 0 
b. Motor neuropathy 
Grade 
Vincristine Dose (%) 
1 
100 
2 
75 
3 
25 
4 
0 
If neuropathy resolves to a lower grade, doses for that lower grade may be reinstituted at 
investigator discretion. If the grade of neuropathy increases after being re-escalated, doses must 
be reduced for the appropriate toxicity grade and may not be re-escalated, even if neuropathy 
resolves again to a lower grade. 
c. Hepatic Dysfunction  
Vincristine dose will be decreased for elevated bilirubin as follows: 
Bilirubin (mg/dL) Vincristine Dose 
>1.5 - <3.0 
decrease by 25%* 
≥ 3.0 
decrease by 50%* 
Vincristine dose will be re-escalated as hyperbilirubinemia improves.  
d. Ileus 
Constipation commonly occurs in patients receiving vincristine so patients should 
receive stool softeners as indicated.  Occasionally, symptomatic ileus may occur and 
this should be treated with a vincristine dose reduction.  Because the severity of ileus 
is dose related, it is usually unnecessary to stop the vincristine altogether.  
Furthermore, because the therapy administered in this study is potentially curative, 
every effort should be made to not unnecessarily reduce vincristine doses.  The 
following guidelines for symptomatic ileus on a previous cycle should be followed.       
1. Clinical ileus < 8 days with abdominal pain requiring narcotics and/or persistent 
nausea/vomiting >2 days: Reduce vincristine dose 25%. 

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2. Clinical ileus 8-12 days with abdominal pain requiring narcotics and/or persistent 
nausea/vomiting > 2 days: Reduce vincristine dose 50%.         
3. Clinical ileus > 12 days with abdominal pain requiring narcotics and/or persistent 
nausea/vomiting > 2 days: Hold vincristine on next cycle.  May restart at 50% 
reduction on subsequent cycle. 
Recommended Bowel Regimen – goal of at least one soft bowel motion every 24 
hours while on study 
Adults: Sodium Docusate 100mg capsule; take one to two capsules once a day Day 
1-7 of each cycle. If needed can double the frequency to two capsules every 12 
hours. If needed add oral lactulose 15-30 ml prn/ q 6 hourly 
e. Renal dysfunction secondary to lymphoma 
Etoposide should be reduced 25% on cycle one for creatinine clearance < 50 
cc/min.  Etoposide should be returned to full dose (or escalated if indicated) once 
creatinine clearance > 50 cc/min.  No other dose modifications for abnormal renal 
indices will be made for enrolled patients.  
f. Other Non-Hematological Toxicity  
Symptom grade Management 
 grade 2 
Treat symptomatically 
 grade 3 
Hold next dose until  grade 1 and, if further therapy is 
medically indicated 
• 
Reduce by 1 dose level 
If further toxicity at the reduced dose level 
• 
 reduce by another dose level 
After 2 dose reductions 
• 
patient will be removed from study 
 
3.3.3 Dose Modification for Obese Patients 
All dosing is based on the patient’s BSA as calculated from actual weight. There is no clearly 
documented adverse impact of treatment of obese patients when dosing is performed according 
to actual body weight.  Failure to use actual body weight in the calculation of drug dosages will 
be considered a major protocol deviation. 
3.3.4 Rituximab Infusional-related Adverse Events 
Pretreatment for rituximab with diphenhydramine and acetaminophen using standard medical 
practice will be used in all patients. Side effects of rituximab may be infusion rate related and 
may be reduced by slower administration or premedication. Thus, dose reductions of rituximab 
will not be made. Rituximab will be discontinued for the duration of the cycles in patients with 
grade 4 allergic reactions.  At the discretion of the PI, rituximab may be administered on the 
following cycles using slower infusion rates. 

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3.4 
STUDY CALENDAR 
Studies 
Pre-
therapyA 
Day -1 or day 1 
of each cycle 
Bi-weekly 
during therapy 
Post cycles   
4 & 6 
Follow-
upB 
Hx; PE; VS; PS   
x 
x 
 
 
x 
Tumor Measurement 
x 
 
 
x 
 
CBC/diff 
xF 
x 
x 
 
x 
Electrolytes, Creatinine/BUN, ALT, 
AST, Bilirubin, LDH, Ca++, Phos, Mg 
xF 
x 
 
 
x 
CMV PCR  
x 
x 
 
 
x 
HIV and Hepatitis B and C serology, 
Pregnancy Test 
x 
 
 
 
 
Lymphocyte TBNK panel 
x 
 
 
x 
x 
Toxoplasmosis serologies, BK 
antigenemia, EBV Viral load, urine 
BK 
x 
x 
 
 
 
20 mL red top for serum storage 
x 
x 
 
 
x 
PET scan C 
x 
 
 
x (after 6 
only)C 
 
CT chest/abdomen/pelvisD 
x 
 
 
x 
x 
Bone marrow biopsy & aspirate E and 
peripheral blood for flow cytometry 
where indicated  
x 
 
 
xE 
 
Tumor biopsy G 
x 
 
 
 
 
A: Initial assessment may be performed within 4 weeks prior to starting treatment.  
B:  Follow-up to occur as per section 3.7.1. 
C: Clinical PET scans may be performed at other time points throughout this protocol if the 
investigator deems it medically necessary. If obtaining PET scan will delay initiation of 
treatment, pre-treatment PET scan may be waived. PET may be obtained at the first post-
treatment restaging in patients in CRu.   
D: Extent of CT scans may be limited to assess sites of prior disease.   
E:  If flow cytometry or bone marrow positive, repeat test as indicated until negative  
F:  These laboratory tests must be obtained within one week of initial treatment.   
G: Where possible, tumor biopsies will be obtained by core needle biopsy or surgery pre-
treatment and after 1 cycle of treatment. Snap freeze and store tissue biopsies at -80°C.  

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3.4.1 Day 1 all cycles and day 21 last cycle: CBC/differential; electrolytes; mineral panel; 
AST, ALT, Bilirubin, LDH, Toxoplasmosis serologies, BK antigenemia and CMV PCR.  
3.4.2 During cycles: CBC/differential BIW.  
3.4.3 Restaging: Day 21, cycles 4 and 6.  Repeat all initially positive staging tests, including 
peripheral blood flow cytometry. 
3.4.4 Biopsies may be obtained for cytogenetics, immunophenotype, molecular analyses 
including Fluorescent In Situ Hybridization and polymerase chain reaction. Tissue will be 
frozen for microarray analysis.  A fresh tissue biopsy of accessible lymph node or a core 
needle biopsy using a 16-18 gauge needle will be obtained if possible without major 
surgery or requirement for general anesthesia. Standard techniques will be used for 
biopsies which may include CT and/or ultrasound guided biopsy. The pretreatment lymph 
node biopsy will be used to perform all standard diagnostic tests. In addition, we will 
extract RNA and protein for research studies such as microarray.  If patient consent is 
obtained, tumor tissue may be stored for future research assays which are related to this 
study and do not pose an increase in patient risk. General anesthesia will not be 
performed to obtain biopsies for research purposes but may be necessary when biopsies 
are medically indicated. However, conscious sedation may be used to obtain research 
biopsies. If a biopsy needs to be performed for medical reasons under general anesthesia, 
the obtained sample might be used for research purposes. 
3.5 
CONCURRENT THERAPIES (CONTINUED UNTIL CD4 COUNT IS >100 POST-TREATMENT)  
3.5.1 Pneumocystis jiroveci and Toxoplasmosis prophylaxis: Recommendations: 
Trimethoprim/sulfamethoxazole 1 DS P.O. twice daily for three days each week. 
Monday, Wednesday, Friday is the preferred schedule.  
• For patients who are allergic to trimethoprim/sulfamethoxazole: Alternatives include, 
in this order: aerosolized pentamidine administered every 3-4 weeks, atovaquone 
1500 mg orally once a day and lastly Dapsone 50 - 100 mg orally once a day or 100 
mg orally 2x/week. Atovaquone should be taken with food for improved absorption. 
• Patients with positive toxoplasma antibodies should receive atovaquone 1500 mg 
orally once a day (instead of trimethoprim/sulfamethoxazole) and have their blood 
monitored on a weekly basis for Toxoplasma gondii by PCR. Atovaquone should be 
taken with food for improved absorption. 

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3.5.2 Herpes Simplex prophylaxis: Recommendation: acyclovir 400 mg twice daily or 
famciclovir 500 mg twice daily. 
3.5.3 Fungal prophylaxis: Fluconazole will be administered as prophylaxis for fungal 
infections (200 mg daily).  Fluconazole should be held during EPOCH infusions because 
of pharmacokinetic interactions. 
3.6 
POST-TREATMENT EVALUATION 
3.6.1 For patients with response: Restage sites of disease q3 months for the first year, then q4 
months for the second year, and then q6 months for 1 years, and yearly thereafter until 
disease progression. Laboratory tests: CBC/differential, mineral panel, electrolytes, AST, 
ALT, Bilirubin, and LDH.  The timing for these visits may be adjusted + 2 months. 
3.6.2 Obtain lymphocyte TBNK panel and CMV PCR levels at all restaging visits until the 
CD4 count is greater than 100. 
3.7 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA 
3.7.1 Criteria for removal from protocol therapy 
• Patient completes therapy as outlined in section 3.1 
• Progressive disease  
• Intercurrent illness that prevents further administration of treatment 
• General or specific changes in a patient’s condition that render the patient unacceptable 
for further treatment as determined by that principal investigator 
• Patient requests to be withdrawn from active therapy 
3.7.2 Off Study Criteria 
• 
Death 
• 
Patient non-compliance which affects safety or endpoints of the study 
• 
Patient voluntary withdrawal 
• 
Physician’s determination that withdrawal is in the patient’s best interest 
• 
Study is stopped or cancelled 
3.7.3 Off Protocol Therapy and Off-Study Procedure  
Authorized staff must contact the Central Registration Office (CRO) when a patient is taken off 
protocol therapy and when a subject is taken off-study. A Participant Status Updates Form from 
the website (http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) main page must be 
completed and sent via encrypted email to: NCI Central Registration Office at 
ncicentralregistration-l@mail.nih.gov.  
4 
SUPPORTIVE CARE 
4.1 
PROPHYLAXIS FOR HEPATITIS B REACTIVATION  
Patients who are positive for Hepatitis B core antibody (anti-HBc) and not acutely infected are at 
varying risk for reactivation of Hepatitis B.  These patients will have quantitative PCR testing 
performed for Hepatitis B virus. Additionally, patients at high and moderate risk will receive 
appropriate prophylaxis for hepatitis B reactivation, e.g., lamivudine 100mg PO daily to continue 

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until 8 weeks after last chemotherapy with repeat quantitative PCR performed 4-8 weeks after 
stopping prophylaxis. 
 
anti-HBc 
HBsAg 
Anti-HBs 
Risk 
HBV PCR 
Prophylaxis 
+ or − 
+ 
+ or − 
High 
pre-tx,  
post 2, 4, 6 cycles 
Yes 
+ 
− 
− 
Moderate 
pre-tx,  
post 2, 4, 6 cycles 
Yes 
+ 
− 
+ 
Low 
pre-tx,  
post 3, 6 cycles 
No 
if PCR − 
4.2 
CMV ANTIGENEMIA  
Patient management will be handled on a case-by-case basis in conjunction with the infectious 
diseases service. 
4.3 
FEBRILE NEUTROPENIA  
Febrile neutropenia is a life-threatening complication requiring urgent broad-spectrum 
antibiotics.  Management may be as an inpatient or outpatient depending on the clinical situation. 
4.4 
SYMPTOMATIC ANEMIA  
Symptomatic anemia should be treated with appropriate red blood cell support, and is 
recommended if the hemoglobin falls below 8 mg/dl. Only irradiated leukodepleted blood 
products should be used.   
4.5 
THROMBOCYTOPENIA  
Thrombocytopenia should be treated conservatively.  In the absence of bleeding or planned 
invasive procedures, platelet transfusions should be given for platelets < 10,000/mm3.  If 
invasive procedures are planned or the patient develops bleeding, platelet transfusions should be 
administered in accordance with standard of practice, usually maintaining a platelet count > 
50,000/mm3. 
4.6 
CENTRAL VENOUS ACCESS (REQUIRED FOR EPOCH ADMINISTRATION) 
Possible lines include:  
• temporary internal jugular line (preferred);  
• PICC lines via the brachial vein;  
• semi-permanent HICKMAN,  
• GROSHONG catheters or medi-port implanted devices.   
All devices will have nursing supervision to include patient self-care and cleaning/flushing of the 
devices. 

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4.7 
TUMOR LYSIS SYNDROME (DOSE 1 ONLY)  
At the discretion of the principal investigator, patients with high tumor burden may be treated 
with allopurinol 600 mg p.o. x 1 dose followed by 300 mg p.o. daily for up to 7 days. 
Hospitalization with aggressive IV hydration and urinary alkalization may be used. 
4.8 
GI PROPHYLAXIS 
Omeprazole 20mg p.o. daily is given to patients for the entire duration while patient is on 
chemotherapy. 
5 
BIOSPECIMEN COLLECTION 
5.1 
PROCEDURES FOR SAMPLE COLLECTION 
Sample collection is outlined in Section 3.   
5.2 
SAMPLE STORAGE, TRACKING AND DISPOSITION 
All specimens obtained in the protocol are used as defined in the protocol.  Samples will be 
ordered in CRIS and tracked through a Clinical Trial Data Management system.  Should a CRIS 
screen not be available, the CRIS downtime procedures will be followed.  Samples will not be 
sent outside NIH without IRB notification and an executed MTA.  
5.2.1 Procedures for stored serum specimens  
The Clinical Support Laboratory, Leidos Biomedical Research, Inc., processes and cryopreserves 
samples in support of IRB-approved, NCI clinical trials.  All laboratory personnel with access to 
patient information annually complete the NIH online course in Protection of Human 
Subjects.  The laboratory is CLIA certified for CD4 immunophenotyping and all laboratory areas 
operate under a Quality Assurance Plan with documented Standard Operating Procedures that are 
reviewed annually.  Laboratory personnel are assessed for competency prior to being permitted 
to work with patient samples.  Efforts to ensure protection of patient information include: 
• The laboratory is located in a controlled access building and laboratory doors are kept 
locked at all times. Visitors to the laboratory are required to be accompanied by 
laboratory staff at all times.   
• Hard copy records or electronic copies of documents containing patient information are 
kept in the locked laboratory or other controlled access locations.    
• An electronic database is used to store information related to patient samples processed 
by the laboratory.   
• The database resides on a dedicated program server that is kept in a central, locked 
computer facility.   
• The facility is supported by two IT specialists who maintain up to date security features 
including virus and firewall protection.   
• Program access is limited to specified computers as designated by the laboratory 
director.  Each of these computers has a password restricted login screen.   
• The database sample entry program itself is accessed through a password protected entry 
screen.   

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• The database program has different levels of access approval to limit unauthorized 
changes to specimen records and the program maintains a sample history.   
• Upon specimen receipt each sample is assigned a unique, sequential laboratory accession 
ID number.  All products generated by the laboratory that will be stored either in the 
laboratory freezers or at a central repository facility are identified by this accession ID. 
• Inventory information will be stored at the vial level and each vial will be labeled with 
both a sample ID and a vial sequence number.   
• Vial labels do not contain any personal identifier information.    
• Samples are stored inventoried in locked laboratory freezers and are routinely transferred 
to the NCI-Frederick repository facilities for long term storage.  These facilities are 
operated under subcontract to Leidos Biomedical Research, Inc.    
• Access to stored clinical samples is restricted.  Investigators establish sample collections 
under “Source Codes” and the investigator responsible for the collections, typically the 
protocol Principal Investigator, specifies who has access to the collection.  Specific 
permissions will be required to view, input or withdraw samples from a collection. 
Sample withdrawal requests submitted to approved laboratory staff by anyone other than 
the repository source code owner are submitted to the source code owner for approval.  
The repository facility will also notify the Source Code holder of any submitted requests 
for sample withdrawal.   
• It is the responsibility of the Source Code holder (generally the NCI Principal 
Investigator) to ensure that samples requested and approved for withdrawal are being 
used in a manner consistent with IRB approval.   
• The Clinical Support Laboratory does perform testing services that may be requested by 
clinical investigators including, but not limited to, immunophenotyping by flow 
cytometry and cytokine testing using ELISA or multiplex platforms.   
• When requests are submitted by the NCI investigator for shipment of samples outside of 
the NIH it is the policy of the laboratory to request documentation that a Material 
Transfer Agreement is in place that covers the specimen transfer.  The laboratory does not 
provide patient identifier information as part of the transfer process but may, at the 
discretion of the NCI investigator, group samples from individual patients when that is 
critical to the testing process.    
• The NCI investigator responsible for the sample collection is responsible for ensuring 
appropriate IRB approvals are in place and that a Material Transfer Agreement has been 
executed prior to requesting the laboratory to ship samples outside of the NIH.   
5.2.2 Procedures for Collecting, Processing and Storing of Tumor Biopsies and/or Peripheral 
Blood Cells 
• Orders for tumor biopsies and research blood samples collections should be placed in 
CRIS (Clinical Research Information System, Clinical Research Center, NIH, Bethesda, 
MD) 
• Tumor biopsies will be submitted in native condition to the Department of Pathology, 
NCI, NIH and handled according to routine procedures. Material released for research 
studies will be documented on form NIH 2803-1. Initial processing of samples for 
research will depend on the size of the tumor biopsy. For core biopsies the research 

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sample will typically consist of 2 cores in a microcentrifuge vial snap frozen on dry ice. 
Surgical lymph node biopsies may in addition be processed for single cell suspension, 
additional vials of snap frozen tissue and OCT embedded tissue. 
• Tumor and normal blood cells may be viably frozen, typically at concentrations of 20-
100x106/mL in FCS with 10% DMSO using a temperature controlled freezing process to 
optimize sample viability. Samples will be transferred to Nitrogen tanks for long term 
storage.  
• Tumor and normal blood cells can be further processed. Additional purification may be 
carried out by selection with magnetic beads binding to appropriate surface molecules, 
typically CD19. For analysis cells may be lysed to obtain RNA (using Qiagen 
manufactured kits are similar) or proteins (salt and/or triton containing buffers with 
addition of protease and phosphatase inhibitors). Integrity of RNA is monitored by gel 
electrophoresis and concentration of RNA or protein is measured spectrophotometrically.  
• Research sample inventory and storage: All research samples are assigned a unique 
number and cataloged. Viably frozen cells are stored in a temperature controlled, alarm 
secured Nitrogen tank. Tumor biopsies and processed biologic material (RNA, protein) is 
stored at -80C in a temperature controlled, alarm secured -80C freezer.  
• Tumor tissue may be stored by the NCI Department of Hematopathology for future 
research assays which are related to this study and do not pose an increase in patient risk.  
Tissue that is given to the technician will be assigned an accession number (HP#) in the 
HP Case Log book.   A Patient background sheet will be filled out and filed with any 
accompanying paperwork in the black notebook.  Final reports and any supplemental 
reports that follow will be added to these notebooks which are located in Room 2N110.  
• Frozen Specimens: Tissue snap frozen or embedded in OCT is wrapped in aluminum foil 
labeled with the patient's name and accession number (HP#), put into a zip-lock bag, and 
stored in liquid nitrogen freezer.  The liquid nitrogen freezers are monitored daily for 
temperature variations. A FileMaker Pro data base called HP Patient Information and 
Specimen Inventory is used for tracking the samples. 
5.2.3 Protocol Completion/Sample Destruction 
Any specimens that are remaining at the completion of the protocol will be stored in the 
conditions described below for an indefinite amount of time.  
The PI will report destroyed samples to the IRB if samples become unsalvageable because of 
environmental factors (ex. broken freezer or lack of dry ice in a shipping container) or if a patient 
withdraws consent. Samples will also be reported as lost if they are lost in transit between 
facilities or misplaced by a researcher.  Freezer problems, lost samples or other problems 
associated with samples will also be reported to the IRB, the NCI Clinical Director, and the 
office of the CCR, NCI. 
6 
DATA COLLECTION AND EVALUATION 
6.1 
DATA COLLECTION   
The PI will be responsible for overseeing entry of data into an in-house password protected 
electronic system (C3D) and ensuring data accuracy, consistency and timeliness. The principal 
investigator, associate investigators/research nurses and/or a contracted data manager will assist 

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with the data management efforts. All data obtained during the conduct of the protocol will be 
kept in secure network drives or in approved alternative sites that comply with NIH security 
standards. Primary and final analyzed data will have identifiers so that research data can be 
attributed to an individual human subject participant. 
All patients must have signed an Informed Consent and an on-study confirmation of eligibility 
form will be filled out before entering on the study.   
Complete records must be maintained on each patient; these will consist of the hospital chart 
with any supplementary information obtained from outside laboratories, radiology reports, or 
physician's records. These records will serve as the primary source material that forms the basis 
for the research record.  The primary source documentation will assure the following:  on-study 
information, including patient eligibility data and patient history; specialty forms for pathology, 
radiation, or surgery; and off-study summary sheet, including a final assessment by the treating 
physician.  
All adverse events (AEs), including clinically significant abnormal findings on laboratory 
evaluations, regardless of severity, will be followed until return to baseline or stabilization of 
event. Patients will be followed for adverse events for a minimum of 30 days after removal from 
study treatment or until off-study, whichever comes first. Serious adverse events that occur more 
than 30 days after the last administration of investigational agent/intervention and have an 
attribution of at least possibly related to the agent/intervention should be recorded and reported 
as per sections 7.2.   
An abnormal laboratory value will be recorded in the database as an AE only if the laboratory 
abnormality is characterized by any of the following: 
• Results in discontinuation from the study 
• Is associated with clinical signs or symptoms  
• Requires treatment or any other therapeutic intervention 
• Is associated with death or another serious adverse event, including hospitalization.  
• Is judged by the Investigator to be of significant clinical impact 
• If any abnormal laboratory result is considered clinically significant, the investigator will 
provide details about the action taken with respect to the test drug and about the patient’s 
outcome. 
6.1.1 Data Collection/Recording Exceptions 
As the toxicity profile of EPOCH-R is well defined and published, grade 1 clinical adverse 
events will not be recorded in the database.  All hospitalizations, regardless of reason, will be 
recorded in the database with the reason of hospitalization and the duration of hospitalization 
noted. 
6.1.2 Other Information 
End of study procedures: Data will be stored according to HHS, FDA regulations and NIH 
Intramural Records Retention Schedule as applicable.  
Loss or destruction of data: Should we become aware that a major breach in our plan to protect 
subject confidentiality and trial data has occurred, the IRB will be notified. 

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6.2 
RESPONSE CRITERIA  
From the International Workshop to Standardize Response Criteria for non-Hodgkin’s 
Lymphomas. Responses must last for at least 4 weeks off treatment.  
Complete Remission (CR): Complete disappearance of all detectable clinical and radiographic 
evidence of disease and disappearance of all disease related symptoms if present before therapy 
and normalization of those biochemical abnormalities (for example LDH) definitely assignable 
to the lymphoma.  All lymph nodes must have regressed to normal size (less than or equal to 1.5 
cm in greatest diameter if > 1.5 cm before therapy).  Previously involved nodes that were 1.1 to 
1.5 cm in greatest diameter must have decreased to less than or equal to 1 cm or by more than 75 
percent in the sum of the products of the greatest diameters.  The spleen, if considered to be 
enlarged before therapy, must have regressed in size and not be palpable on physical 
examination.  The bone marrow must show no evidence of disease by histology.  Flow 
cytometry, molecular or cytogenetic studies will not be used to determine response.  Response 
must persist for 1 month. 
Complete response unconfirmed (CRu): As per complete remission criterion except that if a 
residual node is greater than 1.5 cm, it must have decreased by greater than 75 percent in the sum 
of the products of the perpendicular diameters.   
Partial Response (PR):   50% decreased in SPD of 6 largest dominant nodes or nodal masses. 
No increase in size of nodes, liver or spleen and no new sites of disease.  Splenic and hepatic 
nodules must regress by  50% in the SPD.  Bone marrow is irrelevant for determination of a 
PR.    
Relapsed disease (CR, CRu) requires the following: Appearance of any new lesion or increase by 
≥ 50% in the size of the previously involved sites. Greater than or equal to 50% increase in 
greatest diameter of any previously identified node > 1 cm in its shortest axis or in the SPD of 
more than one node.  
Progressive disease (PR, non-responders) requires the following: ≥ 50% increase from nadir in 
the SPD of any previously identified abnormal node for PRs or non-responders. Appearance of 
any new lesion during or at the end of therapy. 
Stable Disease (SD):  is defined as less than a PR but not progressive disease. 
ALL assessment of clinical response will be made according to the NCI guidelines.  The major 
criteria for judging response will include physical examination and examination of blood and 
bone marrow.  All laboratory studies that are abnormal prior to study will be repeated to 
document the degree of maximal response. 
6.3 
TOXICITY CRITERIA 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0 will be utilized for adverse event reporting.  All 
appropriate treatment areas should have access to a copy of the CTCAE version 4.0.  A list of 
adverse events that have occurred or might occur (Reported Adverse Events and Potential Risks) 
can be found in Section 8 (Pharmaceutical Information).  A copy of the CTCAE version 4.0 can 
be downloaded from the CTEP web site (http://ctep.cancer.gov/reporting/ctc.html). Effective 
with Amendment G version date 05/08/2014, the CTCAE version to be used for adverse event 
reporting was changed from version 3.0 to version 4.0.  

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7 
SAFETY REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING 
PLAN 
7.1 
DEFINITIONS 
7.1.1 Adverse Event 
Any untoward medical occurrence in a human subject, including any abnormal sign (for 
example, abnormal physical exam or laboratory finding), symptom, or disease, temporally 
associated with the subject’s participation in research, whether or not considered related to the 
subject’s participation in the research.   
7.1.2 Suspected adverse reaction 
Suspected adverse reaction means any adverse event for which there is a reasonable possibility 
that the drug caused the adverse event. For the purposes of IND safety reporting, ‘reasonable 
possibility’ means there is evidence to suggest a causal relationship between the drug and the 
adverse event. A suspected adverse reaction implies a lesser degree of certainty about causality 
than adverse reaction, which means any adverse event caused by a drug. 
7.1.3 Unexpected adverse reaction 
An adverse event or suspected adverse reaction is considered “unexpected” if it is not listed in 
the investigator brochure or is not listed at the specificity or severity that has been observed; or, 
if an investigator brochure is not required or available, is not consistent with the risk information 
described in the general investigational plan or elsewhere in the current application. 
"Unexpected”, also refers to adverse events or suspected adverse reactions that are mentioned in 
the investigator brochure as occurring with a class of drugs or as anticipated from the 
pharmacological properties of the drug, but are not specifically mentioned as occurring with the 
particular drug under investigation. 
7.1.4 Serious 
An Unanticipated Problem or Protocol Deviation is serious if it meets the definition of a Serious 
Adverse Event or if it compromises the safety, welfare or rights of subjects or others. 
7.1.5 Serious Adverse Event 
An adverse event or suspected adverse reaction is considered serious if in the view of the 
investigator or the sponsor, it results in any of the following: 
• 
Death 
• 
A life-threatening adverse drug experience 
• 
Inpatient hospitalization or prolongation of existing hospitalization 
• 
Persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
• 
A congenital anomaly/birth defect 
• 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. 

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7.1.6 Disability 
A substantial disruption of a person’s ability to conduct normal life functions. 
7.1.7 Life-threatening adverse drug experience 
Any adverse event or suspected adverse reaction that places the patient or subject, in the view of 
the investigator or sponsor, at immediate risk of death from the reaction as it occurred, i.e., it 
does not include a reaction that had it occurred in a more severe form, might have caused death. 
7.1.8 Protocol Deviation (NIH Definition) 
Any change, divergence, or departure from the IRB-approved research protocol. 
7.1.9 Non-compliance (NIH Definition) 
The failure to comply with applicable NIH Human Research Protections Program (HRPP) 
policies, IRB requirements, or regulatory requirements for the protection of human research 
subjects. 
7.1.10 Unanticipated Problem 
Any incident, experience, or outcome that: 
• 
Is unexpected in terms of nature, severity, or frequency in relation to  
(a) the research risks that are described in the IRB-approved research protocol and 
informed consent document; Investigator’s Brochure or other study documents, and 
(b) the characteristics of the subject population being studied; AND 
• 
Is related or possibly related to participation in the research; AND 
• 
Suggests that the research places subjects or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized. 
7.2 
NCI-IRB AND CLINICAL DIRECTOR (CD) REPORTING 
7.2.1 NCI-IRB and NCI CD Expedited Reporting of Unanticipated Problems and Deaths 
The Protocol PI will report to the NCI-IRB and NCI CD: 
• All deaths, except deaths due to progressive disease  
• All Protocol Deviations 
• All Unanticipated Problems 
• All non-compliance 
Reports must be received within 7 days of PI awareness via iRIS. 
7.2.2 NCI-IRB Requirements for PI Reporting at Continuing Review 
The protocol PI will report to the NCI-IRB:  
1. A summary of all protocol deviations in a tabular format to include the date the deviation 
occurred, a brief description of the deviation and any corrective action. 
2. A summary of any instances of non-compliance 
3. A tabular summary of the following adverse events: 

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• All Grade 2 unexpected events that are possibly, probably or definitely related to the 
research;  
• All Grade 3 and 4 events that are possibly, probably or definitely related to the research; 
• All Grade 5 events regardless of attribution;  
• All Serious Events regardless of attribution.  
NOTE: Grade 1 events are not required to be reported.  
7.2.3 NCI-IRB Reporting of IND Safety Reports 
Only IND Safety Reports that meet the definition of an unanticipated problem will need to be 
reported to the NCI IRB. 
7.3 
DATA AND SAFETY MONITORING PLAN 
The clinical research team will meet on a regular basis when patients are being actively treated 
on the trial to discuss each patient. Decisions about dose level enrollment and dose escalation if 
applicable will be made based on the toxicity data from prior patients.  
All data will be collected in a timely manner and reviewed by the principal investigator or a lead 
associate investigator. Adverse events will be reported as required above. Any safety concerns, 
new information that might affect either the ethical and or scientific conduct of the trial, or 
protocol deviations will be immediately reported to the IRB using iRIS. 
The principal investigator will review adverse event and response data on each patient to ensure 
safety and data accuracy. The principal investigator will personally conduct or supervise the 
investigation and provide appropriate delegation of responsibilities to other members of the 
research staff.  
The monitoring of this study will be done by the PI/Lead associate investigator on an ongoing 
manner so a DSMB or Safety Monitoring Committee will not be used. 
8 
STATISTICAL CONSIDERATIONS 
The primary objectives of this study will be to determine if there is a moderately large fraction of 
patients who exhibit a clinical response to EPOCH-RC in relapsed or refractory DLBCL and to 
evaluate the safety and toxicity of this regimen. 
The study will be conducted as a two-stage Simon optimal design (Simon R, Controlled Clinical 
Trials, 10:1-10, 1989) in order to rule out an unacceptably low 25% clinical response rate 
(PR+CR: p0=0.25) in favor of a targeted rate consistent with 45% (p1=0.45).  With alpha=0.10 
(probability of accepting a poor regimen=0.10) and beta = 0.10 (probability of rejecting a good 
regimen=0.10), the study will initially enroll 14 evaluable patients, and if 0 to 3 of the 14 are 
able to have a response then no further patients will be accrued. Response will be evaluated after 
6 cycles or 18 weeks. If 4 or more of the first 14 patients have a response, then accrual would 
continue until a total of 44 patients have been treated.   A temporary pause in the accrual may be 
necessary to ensure that enrollment to the second stage is warranted. If there are 4 to 14 patients 
with a response in the total of 44 patients, then this would be an uninterestingly low rate, while if 
there were 15 or more patients of the 44 who have a response, this would be sufficiently 
interesting to warrant further study of this agent in these patients. Under the null hypothesis 
(25% response rate), the probability of early termination is 52%. 

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At the end of the study, patients will be determined as to whether they are of ABC or GCB 
subtype, and exploratory evaluations will be made of the response rates in the two subtypes. In 
addition to evaluating clinical response, progression free survival and overall survival will be 
estimated using a Kaplan-Meier curve.  The results obtained in this study will be compared in an 
informal manner to those of other previous studies. 
Toxicity will also be evaluated and monitored as patients are accrued to the trial. If at any point 
in the accrual to the trial, there are greater than 1/3 of patients who have an SAE, then the trial 
will suspend accrual, and the study will either be terminated or have the drug regimen modified 
to allow a safer outcome. It is anticipated that up to 10-15 patients per year may be enrolled onto 
this trial. Thus, accrual of up to 44 evaluable patients is expected to require approximately 3-4 
years.  In order to allow for a small number of unavailable patients, the accrual ceiling will be set 
at 47. 
Effective with Amendment G, version date 05/08/2014, the accrual ceiling will be increased to 
52 to allow for continued enrolment of patients with relapsed T cell histiocyte-rich Diffuse Large 
B cell Lymphoma and advanced Lymphocyte Predominant Hodgkin Lymphoma. This will allow 
access to this potentially lifesaving treatment, for patients with these two histologies.  
9 
COLLABORATIVE AGREEMENTS 
No collaborative agreements (e.g., MTA, CTA, CRADA, etc.) apply to this protocol at this time.   
10 HUMAN SUBJECTS PROTECTION 
10.1 RATIONALE FOR SUBJECT SELECTION  
Large cell lymphomas and Hodgkin Lymphoma affect all races and genders.  However, males are 
more likely than females to be affected and this will be reflected in the gender distribution of our 
cases.  This trial is directed at assessing Alemtuzumab in combination with EPOCH-R 
chemotherapy.  We have selected patients with relapsed disease and have developed the trial 
design to recognize that some may be potentially curable and others are not.  Additionally, 
pregnant or nursing mothers are excluded because of the potential teratogenic effects of therapy. 
10.2 PARTICIPATION OF CHILDREN 
Patients under the age of 18 are excluded because inclusion of an occasional younger patient will 
not provide generalizable information that would justify their inclusion on this study. Pediatric 
patients with recurrent large B cell lymphoma are extremely rare and are treated on pediatric 
studies. In addition, tumor biopsies will be performed.   
10.3 PARTICIPATION OF SUBJECTS UNABLE TO GIVE CONSENT 
Adults unable to give consent were excluded from enrolling in the protocol.  However, re-
consent may be necessary and there is a possibility, though unlikely, that subjects could become 
decisionally impaired. For this reason and because there is the prospect of direct benefit to 
subjects from treatment, including ongoing follow-up for detection of early relapse, all subjects 
will be offered the opportunity to fill in their wishes for research and care, and assign a substitute 
decision maker on the “NIH Advance Directive for Health Care and Medical Research 
Participation”. 

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Note: The PI or AI will contact the NIH Ability to Consent Assessment Team (ACAT) for 
evaluation as needed for the following: an independent assessment of whether an individual has 
the capacity to provide consent; assistance in identifying and assessing an appropriate surrogate 
when indicated; and/or an assessment of the capacity to appoint a surrogate.  For those subjects 
meeting the above criteria that become incapacitated and do not have pre-determined substitute 
decision maker, the procedures described in MAS Policy 87-4 and NIH HRPP SOP 14E for 
appointing a surrogate decision maker for adult subjects who are (a) decisionally impaired, and 
(b) who do not have a legal guardian or durable power of attorney, will be followed. 
10.4 EVALUATION OF BENEFITS AND RISKS/DISCOMFORTS 
The potential benefits to the subject are that the patient may achieve a partial or complete 
remission.  The benefits of combinations of chemotherapy and monoclonal antibodies may 
produce remissions that cannot be achieved with either approach alone.  The main danger to 
participants in this study is drug toxicity. Chemotherapy may produce bleeding or infectious 
complications as a result of chemotherapy-induced myelosuppression. Alemtuzumab causes 
immunosuppression which may be made more severe as a result of combining it with 
chemotherapy. 
10.5 RISKS/BENEFITS ANALYSIS  
Patients eligible for this protocol may derive benefit from DA-EPOCH-R based on prior research 
results. However, they will also be subjected to the toxicity associated with EPOCH-rituximab 
infusional chemotherapy, which include myelosuppression, stomatitis, numbness or tingling in 
the extremities, motor weakness, and the need for transfusion or hospitalization due to 
complications of treatment noted.  There may be adverse effects due to the combination of agents 
that is not seen when either is given alone. But this potential toxicity of this combination is 
reasonable in relation to the potential benefit to this group of patients who have treatable 
diseases. Additionally, the knowledge that will be gained from this trial is potentially important 
and may be of direct benefit to patients. Patients will require biopsies both to determine the 
diagnosis as well as for research purposes. Needle biopsy is minimally invasive and is typically a 
very safe procedure. The benefits of percutaneous biopsy often far outweigh the risks. However, 
as with all invasive procedures, certain risks do exist. Depending upon the site being biopsied 
and the type of biopsy being performed, risks can include infection of the biopsy area, 
development of a hematoma and bleeding. Rarely more significant complications can occur 
when structures near the biopsy target are entered with the needle (for example, puncture of lung 
or bowel). As far as possible surgical biopsies will not be performed unless medically indicated 
and will not be performed for research purposes. Surgical biopsy has some additional risks 
versus needle biopsy. Surgical biopsy carries a small risk of mortality (due to risks of anesthesia) 
and causes moderate chances of bleeding, infection, wound healing problems. General anesthesia 
will not be performed to obtain biopsies for research purposes but may be necessary when 
biopsies are medically indicated. However, conscious sedation may be used to obtain research 
biopsies.  
The risks and benefits of participation for adults who become unable to consent during 
participation are no different than those described for less vulnerable patients.   

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10.6 CONSENT PROCESS AND DOCUMENTATION  
All patients are thoroughly screened for eligibility prior to admission onto this study. All patients 
age 18 and over, will read and sign the informed consent document prior to enrollment. Members 
of the protocol team will describe the protocol, alternative therapies, and risks and benefits of 
each to the individual signing the consent. The specific requirements, objectives, and potential 
risks and benefits will be discussed.  The informed consent document is given to the patient, who 
is asked to review the document, discuss it with his/her family and write down questions to 
discuss with the principal investigator or treating physician.  The patient is informed that 
participation is voluntary and that he/she may withdraw at any time without loss of benefits 
without consequence.  The patient or their legal representative must sign the consent document 
prior to receiving any protocol related treatment. The patient will receive a copy of the signed 
consent. 
10.6.1 Telephone re-consent 
The informed consent document will be sent to the subject.  An explanation of the study will be 
provided over the telephone after the subject has had the opportunity to read the consent form.  
The subject will sign and date the informed consent. A witness to the subject’s signature will 
sign and date the consent. 
The original informed consent document will be sent back to the consenting investigator who 
will sign and date the consent form with the date the consent was obtained via telephone.   
A fully executed copy will be returned via mail for the subject’s records. 
The informed consent process will be documented on a progress note by the consenting 
investigator. 
11 PHARMACEUTICAL INFORMATION 
• 
Qualified personnel who are familiar with procedures that minimize undue exposure to 
themselves and to the environment should undertake the preparation, handling, and safe 
disposal of chemotherapeutic agents in a self-contained, protective environment.  
• 
Discard unused portions of injectable chemotherapeutic agents that do not contain a 
bacteriostatic agent or are prepared with unpreserved diluents (i.e., Sterile Water for 
Injection USP or 0.9% Sodium Chloride for Injection USP) within eight hours of vial 
entry to minimize the risk of bacterial contamination.   
• 
The total administered dose of chemotherapy may be rounded up or down within a 
range of 5% of the actual calculated dose.   
11.1 ALEMTUZUMAB  
11.1.1 Availability 
Available through the Campath Distribution Program (The Sanofi Foundation for North America 
1-877-422-6728). Vials are provided through this program upon completion of a patient specific 
request form. Prior to submission of a drug request the patient must provide authorization for the 
release of medical information (NIH-527). Refer to the Pharmacy Department or Clinical 
Pharmacy Specialist for additional details on drug procurement. 

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11.1.2 Formulation  
Alemtuzumab causes the lysis of lymphocytes by fixing to CD52, a highly expressed, non-
modulating antigen on the surface of lymphocytes. It mediates the lysis of lymphocytes via 
complement and antibody-dependent cell-mediated cytotoxicity mechanisms.  
Alemtuzumab is supplied as a clear glass vial containing 30 mg Alemtuzumab in 1 mL of 
solution (8.0 mg sodium chloride, 1.44 mg dibasic sodium phosphate, 0.2 mg potassium 
chloride, 0.2 mg monobasic potassium phosphate, 0.1 mg polysorbate 80, and 0.187 mg 
disodium edentate dehydrate). No preservatives are added. Each carton contains three 
Alemtuzumab vials (NDC 50419-357-03) or one Alemtuzumab vial (NDC 50419-357-01). 
11.1.3 Storage & Stability 
Vials of Alemtuzumab should be stored at a temperature of 2-8°C and protected from light. The 
desired dose of 30 mg. should be drawn up into a syringe from the ampoule and further diluted in 
250 ml of 0.9% sodium chloride. The vial contains no preservatives and is intended for single 
use only; the vial should be discarded with any unused portion after 6 hours. An internal NIH 
Pharmacy (Pharmaceutical Development Section) conducted study demonstrated 24 hour 
stability of Alemtuzumab when diluted in 0.9% sodium chloride to a concentration range of 6.67 
mcg/mL to 120 mcg/mL at room temperature (Goldspiel JT, et.al. Stability of alemtuzumab 
solutions at room temperature. Am J Health-Syst Pharm, accepted for publication 2012). 
Alemtuzumab solutions prepared in the concentration range described above may be stored at 
room temperature (15-30°C) for up to 24 hours. Alemtuzumab solutions should be protected 
from light. 
11.1.4 Administration 
The Alemtuzumab solution should be given IV over approximately 12 hours. Patients should be 
premedicated with 50 mg of diphenhydramine, 650 mg of acetaminophen and two 60 mg/m
2 
doses of prednisone as indicated in section 3.2.4 before the infusion. During the alemtuzumab 
infusion, the patient’s vital signs (blood pressure, pulse, respirations, temperature) should be 
monitored as follows:  
• During Cycle 1: every 15 minutes times 4 or until stable and then hourly until the 
infusion is discontinued.  
• During subsequent cycles: one hour after infusion starts; then every 4 hours for the 
duration of the infusion, as long as patient is stable and has no signs/symptoms of 
reaction. 
11.1.5 Toxicity 
The majority of adverse events seen in trial have been administration related and of short 
duration. Serious adverse events, some of which fatal, have been observed in association with 
treatment of Alemtuzumab  
Infusional reactions occur in most patients. They commonly consist of rigors, fever, headache, 
nausea, vomiting and diarrhea, rash, pruritus, dyspnea and hypotension. Acute infusional 
reaction may also include chills, abdominal and back pain, bronchospasm, angioedema, 
tachyarrhythmia etc. These reactions are most prominent during the first dose of Alemtuzumab 
administration and improve with subsequent treatments. To reduce the frequency and severity of 

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the first dose reaction, a step-up dose escalation schedule and proper premedication should be 
used. 
Myelosuppression: Anemia, neutropenia, thrombocytopenia, prolonged and profound 
lymphopenia  
Infections: common bacterial (pneumonia and sepsis) or opportunistic infections (e.g. 
Pneumocystis carinii pneumonia, oral candidiasis, herpes zoster, CMV reactivation, 
cryptococcosis). 
Reported adverse events by organ systems:  
• Body as a whole: Allergic reaction, rigors, fever, chills, headache, back and abdominal 
pain, infection, fatigue  
• Cardiovascular: Hypertension, hypotension, tachycardia, Atrial arrhythmia, ventricular 
tachycardia, angina and myocardial infarction, peripheral vasoconstriction  
• Digestive: anorexia, nausea, vomiting, diarrhea, constipation, dyspepsia, liver function 
abnormality  
• Hematological: Neutropenia, lymphopenia, thrombocytopenia, anemia, DIC, hemolysis, 
eosinophil disorder, bleeding (GI, gum, ecchymosis)  
• Muscular Skeletal: Myalgia, Arthritis, bone pain, hypotonia, tremor  
• Metabolic and nutritional: Tumor lysis syndrome, acidosis  
• Nervous system: Dizziness, confusion, somnolence, peripheral neuropathy, Cerebral 
hemorrhage, speech disorder, mental status changes, paresthesia, syncope, depression, 
aphasia  
• Pulmonary: Bronchospasm, cough, Pleural effusion, pulmonary edema, interstitial 
pneumonitis  
• Skin/subcutaneous: Angioedema, facial flushing, diaphoresis, pruritis, rash, urticaria, 
injection site reaction (subcutaneous route)  
• Urogenital: Hematuria, oliguria, polyuria, urinary retention, urinary tract infection, 
impotence  
• Tinnitus  
11.2 RITUXIMAB 
11.2.1 Availability 
The NIH Clinical Center Pharmacy Dept. will purchase rituximab from commercial sources. 
Rituximab is provided in pharmaceutical grade glass vials containing 10 mL (100 mg) or 50 mL 
(500 mg) at a concentration of 10 mg of protein per milliliter. Please refer to the FDA-approved 
package insert for rituximab for product information, extensive preparation instructions, and a 
comprehensive list of adverse events.  
11.2.2 Storage & Stability 
Rituximab for clinical use should be stored in a secure refrigerator at 2 to 8o C. After dilution, 
rituximab is stable at 2-8 degrees C (36-46 degrees F) for 24 hours and at room temperature for 
an additional 24 hours.  

A b brev i ate d Title:  E P O C H -R C i n rec urre nt l y m p h o ma  
Versi o n D ate:   0 8/ 0 3/ 2 0 1 8  
 
3 9  
1 1. 2. 3  Pre parati o n  
Rit u xi ma b will  be dil ute d t o a fi nal v ol u me of 0. 9 % S o di u m C hl ori de or 5 % De xtr ose I njecti o n 
t o pre pare a sta n dar d pr o d uct wit h c o nce ntr ati o n of 2 m g/ ml.  Ca uti o n s h o ul d be ta ke n d uri n g the 
pre parati o n of t he dr u g, as s ha ki n g ca n ca use a g gre gati o n a n d preci pitati o n of t he a nti b o d y.  
1 1. 2. 4  A d mi nistrati o n  
A peri p heral or ce ntral i ntra ve n o us li ne will be est a blis he d. D uri n g rit u xi ma b i nf usi o n, a patie nt's 
vital si g ns ( bl o o d press ur e, p ulse, res pir a ti o n, te m perat ur e) s h o ul d be m o nit ore d acc or di n g t o t he 
sta n dar d of care. Me dicati o ns rea dil y a vaila ble f or t he e mer ge n c y ma na ge m e nt of a na p h ylact oi d 
reacti o ns s h o ul d i ncl u de: e pi ne p hri ne ( 1: 1 0 0 0, 1 m g/ m L) f or s u bc uta ne o us i njecti o n, 
di p he n h y dra mi ne h y dr oc hl ori de f or i ntra v e n o us i njecti o n, a n d res uscitati o n e q ui p me nt.  
Pr o p h yla xis a gai nst h y perse nsiti vit y a n d i nf usi o n -relate d reacti o ns ass ociat e d wit h rit u xi ma b will 
i ncl u de aceta mi n o p he n 6 5 0 m g a n d di p he n h y dra mi ne h y dr oc hl ori de 5 0 m g a d mi nistere d 3 0 t o 
6 0 mi n utes pri or t o starti n g rit u xi ma b . 
Rit u xi ma b will be a d mi nistere d as a n i ntra ve n o us i nf usi o n at 3 7 5 m g/ m 2 o n da y 1 of eac h c ycl e 
of E P O C H -R C j ust after t he Ale mt uz u ma b i nf usi o n has c o m plete d a n d  i m me diatel y pri or t o 
starti n g et o p osi de + d o x or u bici n + vi ncristi ne a d mi nistrati o n.  
 
First d ose : 
T he i nitial d ose rate at t h e ti me of t he first rit u xi ma b i nf usi o n s h o ul d be 5 0 m g/ h o ur ( 2 5 
m L/ hr) f or t he first 3 0 mi n utes. If n o t o xicit y is see n, t he d ose rate ma y be escalate d 
gra d uall y i n 5 0 m g/ h o ur ( 2 5 m L/ h) i ncre me nts at 3 0 mi n ute i nter vals) t o a ma xi m u m of 
4 0 0 m g/ h o ur ( ma xi m u m rate = 2 0 0 m L/ h).  
Sec o n d a n d S u bse q ue nt D oses (select t he a p pr o pri ate a d mi nistr ati o n ti mi n g):  
9 0 -mi n ute A d mi nistr ati o n  
If t he first d ose of rit u xi ma b was well t olerate d, s u bse q ue nt d oses ma y be a d mi nistere d 
o ver 9 0 mi n utes wit h 2 0 % of t he t otal d ose gi ve n i n t he first 3 0 mi n utes, a n d re mai ni n g 
8 0 % of t he t otal d ose a d mi nistere d o ver t he s u bse q ue nt 6 0 mi n utes; e. g.:  
 
T w o -Ste p Rate Escalati o n  
V ol u me t o a d mi nister ( X  m L)  
1st p orti o n ( 0 –  3 0  mi n utes)  
T otal D ose ( m g)
2
´ 0. 2 = X m L ( o ver 3 0  mi n)  
2 n d p orti o n ( 3 0 –  9 0  mi n utes)  
T otal D ose ( m g)
2
´ 0. 8 = X m L ( o ver 6 0  mi n)  
 
S peci al N ote : T he 9 0-mi n ute i nf usi o n sc he me is n ot rec o m me n de d f or pati e nts wit h 
cli nicall y si g nifica nt car di o vasc ular diseas e or hi g h circ ulati n g l y m p h o c yt e c o u nts 
(≥5 0 0 0/ mc L).  
 
St a n d ar d A d mi nistr ati o n f or Sec o n d & S u bse q ue nt I nf usi o ns  
Patie nts w h o t olerate i nitial treat me nt wit h o ut e x perie nci n g i nf usi o n -relate d a d verse 
effects b ut f or w h o m t he 9 0 -mi n ute i nf usi o n sc he me d uri n g s u bs e q ue nt treat me nts is 

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considered inappropriate, may receive subsequent rituximab doses at the Standard Rate 
for Subsequent Infusions, which is as follows: 
 
Begin at an initial rate of 100 mg/hour (50 mL/h) for 30 minutes. If administration is 
well tolerated, the administration rate may be escalated gradually in 100-mg/hour (50-
mL/h) at 30-minute intervals to a maximum rate of 400 mg/hour (maximum rate = 200 
mL/h). 
CAUTION:  DO NOT ADMINISTER AS AN INTRAVENOUS PUSH OR BOLUS.   
11.2.5 Toxicity 
The most severe serious adverse events associated with rituximab include severe infusion 
reactions, tumor lysis syndrome, and severe mucocutaneous reactions. Severe infusion reactions 
consisting of hypoxia, pulmonary infiltrates, acute respiratory distress syndrome, myocardial 
infarction, ventricular fibrillation or cardiogenic shock may be fatal. Most reported fatal 
reactions occurred within 24 hours of the first dose of rituximab. 
Tumor lysis syndrome resulting in renal failure has been described, and occasional fatalities 
noted. Tumor lysis syndrome is more likely in patients with high numbers of circulating 
malignant cells (≥ 25,000/µL). 
Severe mucocutaneous reactions associated with rituximab include Stevens-Johnson syndrome 
and toxic epidermal necrolysis. The onset of these reactions has been from 1-3 weeks. 
Less severe infusion reactions are common with rituximab. These include fever, chills, and 
dyspnea. The mechanism of rituximab infusion reactions is thought to be secondary to release of 
cytokines. If a reaction occurs, then the infusion should be stopped until the symptoms resolve, 
and then restarted at a 50% slower rate. 
Recent reports describe hepatitis B reactivation with fulminant hepatitis, hepatic failure and 
death in some patients with hematologic malignancies treated with rituximab. The majority of 
these patients received rituximab in combination with chemotherapy. The median time to 
diagnosis of hepatitis was approximately 4 months after starting rituximab and approximately 1 
month after the last dose. 
11.3 DOXORUBICIN HCL  
11.3.1 Availability 
Commercially available as a lyophilized powder for reconstitution in 10, 20, 50, and 100mg 
vials.  Also available as a 2 mg/mL solution for injection in 10, 20, 50, and 200mg vials.Please 
refer to the FDA-approved package insert for doxorubicin for product information, extensive 
preparation instructions, and a comprehensive list of adverse events. 
11.3.2 Toxicities 
Hematologic: Leukopenia (dose-limiting), thrombocytopenia, anemia. Nadir in 10-14 days with 
recovery usually in 21 days. 
Dermatologic: alopecia (usually complete; reversible) radiation recall reactions; increased 
sensitivity to sunlight. 
Gastrointestinal: nausea and vomiting (doxorubicin is generally considered moderately to highly 
emetogenic), anorexia, diarrhea, mucositis (stomatitis, esophagitis). 

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Cardiovascular: cardiomyopathy may occur and is related to total cumulative lifetime dose. The 
risk for cardiomyopathy increases with total doses > 450 mg/m2. ECG changes and less often, 
arrhythmias, are seen. Rarely, sudden death has occurred. 
Other: Red discoloration of urine for 24-48 hours after drug administration. Doxorubicin is a 
vesicant and can cause tissue necrosis if extravasated, especially at the concentration usually 
employed for bolus injections (i.e., 2 mg/mL). 
Fluconazole should not be given during EPOCH infusional chemotherapy because of 
pharmacologic interactions 
11.4 ETOPOSIDE  
11.4.1 Availability 
Commercially available as a 20 mg/mL solution for injection in 5, 25, and 50 mL vials.  Each 
mL contains 2 mg citric acid, 30 mg benzyl alcohol, 80 mg polysorbate 80, 650 mg of 
polyethylene glycol 300, and 30.5% alcohol. Please refer to the FDA-approved package insert 
for etoposide for product information, extensive preparation instructions, and a comprehensive 
list of adverse events. 
11.4.2 Toxicity 
Myelosuppression, predominantly neutropenia and thrombocytopenia, is the most common 
toxicity associated with etoposide. Nausea and vomiting range from mild to severe in severity, 
depending on the dose. Mucositis is also more common at the dose used in this study. Alopecia 
is likely. Hypotension is associated with too rapid administration of etoposide. This would be 
unlikely to occur in this trial. 
Fluconazole should not be given during EPOCH infusional chemotherapy because of 
pharmacologic interactions 
11.5 VINCRISTINE SULFATE  
11.5.1 Availability 
Commercially available as a 1 mg/mL solution for injection in 1, 2, and 5 mL vials. Each ml 
contains 100 mg mannitol, 1.3 mg methylparaben, and 0.2 mg propylparaben. Drug should be 
stored at 2-8oC and should be protected from light.  Please refer to the FDA-approved package 
insert for vincristine sulfate for product information, extensive preparation instructions, and a 
comprehensive list of adverse events. 
11.5.2 Toxicity 
The most common toxicity associated with vincristine is neurotoxicity. Peripheral manifestations 
of neurotoxicity include: numbness of extremities, paresthesias, loss of deep tendon reflexes, 
neuropathic pain and muscle weakness. GI manifestations of neurotoxicity include constipation, 
and adynamic ileus. Cranial nerve manifestations include: diplopia, hoarseness, tinnitus, jaw pain 
(the latter usually occurring with the first dose of vincristine). Orthostatic hypotension & SIADH 
may also be seen. Vincristine is a vesicant and may cause tissue necrosis upon extravasation. 
This is more likely with bolus injections as opposed to dilute infusions. 
Fluconazole should not be given during EPOCH infusional chemotherapy because of 
pharmacologic interactions 

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11.6 ADMINISTRATION OF VINCRISTINE/DOXORUBICIN/ETOPOSIDE 
Stability studies conducted by the Pharmaceutical Development Section, Pharmacy Department, 
NIH Clinical Center, have demonstrated that admixtures of vincristine, doxorubicin, and 
etoposide in 0.9% Sodium Chloride Injection, USP (0.9%NS) at concentrations, respectively, of 
1, 25, and 125 mcg/mL; 1.4, 35, and 175 mcg/mL; 2, 50, and 250 mcg/mL; and 2.8, 70, 350 
mcg/mL are stable for at least 36 hours at room temperature when protected from light. Also, 
admixtures containing vincristine, doxorubicin, and etoposide concentrations of 1.6, 40, and 200 
mcg/mL are stable for at least 30 hours at 32°C. 
For this study, etoposide, doxorubicin, and vincristine comprising a daily dose (a 24-hour 
supply) will be diluted in 0.9%NS. Product containers will be replaced every 24 hours to 
complete the planned duration of infusional treatment. Product volumes will be determined by 
the amount of etoposide present in a 24-hour supply of medication. For daily etoposide doses 
≤130 mg, admixtures will be diluted in approximately 500 mL 0.9%NS.  For daily etoposide 
doses >130 mg, admixtures will be diluted in approximately 1000 mL 0.9%NS. 
Etoposide + doxorubicin + vincristine admixtures will be administered by continuous IV 
infusion over 96 hours with a suitable rate controller pump via a central venous access device. 
11.7 CYCLOPHOSPHAMIDE  
11.7.1 Availability 
Commercially available as a lyophilized powder for reconstitution in 100 mg, 200 mg, 500 mg, 1 
gram, and 2 gram vials. Please refer to the FDA-approved package insert for cyclophosphamide 
for product information, extensive preparation instructions, and a comprehensive list of adverse 
events. 
11.7.2 Preparation 
Reconstitute with appropriate amounts of Sodium Chloride Injection (0.9%NS) to produce a 
solution with final concentration of 20 mg/ml.   
11.7.3 Storage & Stability 
Intact vials should be stored at room temperature storage (not to exceed 30oC). Reconstituted 
solution is stable up to 6 days if refrigerated (2-8oC).  Discard solution after storage for 24 hours 
at room temperature. 
11.7.4 Administration 
Cyclophosphamide will be diluted in 100 mL of 5% Dextrose Injection or 0.9%NS and infused 
over 30 minutes. Hydration Guidelines:  All patients should receive 0.9%NS at the following 
volumes (based on cyclophosphamide dose levels) and rates with half the specified volume given 
before starting cyclophosphamide administration and half the volume given after completion of 
the cyclophosphamide administration.   

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Cyclophosphamide 
Dosage Levels 
Fluid Volume and Administration Rate 
1 & 2 
1000 mL 0.9%NS @ 300 – 500 mL/h 
Levels 3, 4, & 5 
2000 mL 0.9%NS @ 300 – 500 mL/h 
Levels 6 
2500 mL 0.9%NS @ 300 – 500 mL/h 
11.7.5 Toxicity 
Myelosuppression, hemorrhagic cystitis (patients must be well-hydrated before, during, and after 
treatment and have adequate renal function). Syndrome of inappropriate antidiuretic hormone 
(SIADH), fatigue, alopecia, anorexia, nausea, vomiting, hyperuricemia, azoospermia, 
amenorrhea, cardiotoxicity (myocardial necrosis) usually at doses higher than those used in this 
study. 
11.7.6 Drug Interactions 
Cyclophosphamide undergoes metabolic activation via cytochrome P450 3A4 in the liver and 
may potentially interact with any drug affecting the same isoenzyme. Inhibitors of 3A4 (e.g., 
itraconazole) could theoretically inhibit activation and inducers of 3A4 (e.g., phenytoin) could 
theoretically enhance activation of cyclophosphamide to active alkylating species. For the most 
part, such interactions have not yet been documented clinically. 
11.8 PREDNISONE  
11.8.1 Availability 
Commercially available in a large number of oral dosage strengths including pills and liquid 
formulations. Please refer to the FDA-approved package insert for prednisone for product 
information, and a comprehensive list of adverse events. 
11.8.2 Storage & Stability 
Tablets, solutions and syrup should be stored in tightly closed containers at temperatures 
between 15-30oC. 
11.8.3 Administration 
• Oral. Prednisone utilization will be simplified by using only 20- and 50-mg tablets to 
produce individual doses and by stratifying prednisone doses by a patient’s body surface area 
(BSA), as follows: 
BSA (m2) 
Each Dose 
1.25 – 1.49 80 mg 
1.5 – 1.83 
100 mg 
1.84 – 2.16 120 mg 
2.17 – 2.41 140 mg 
2.42 – 2.6 
150 mg 
2.7 – 3 
170 mg 
11.8.4 Toxicity 
Side effects likely to be encountered with intermittent high doses include: GI (dyspepsia, 
ulceration), insomnia, and hyperglycemia. Occasionally a “withdrawal syndrome” after short-

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term high doses, such as in this study, manifest muscle aches and pains. Immunosuppression 
with risk of infection is also seen. 
11.9 FILGRASTIM  
11.9.1 Availability  
Commercially available as a clear sterile solution in single use vials containing 300 mcg (1 mL 
vial) and 480 mcg (1.6 mL vial). Please refer to the FDA-approved package insert for filgrastim 
for product information, extensive preparation instructions, and a comprehensive list of adverse 
events. 
11.9.2 Storage & Stability 
Filgrastim will be stored at 2-8oC and is stable for at least 1 year when maintained under 
refrigeration.  DO NOT FREEZE and DO NOT SHAKE the drug product. Final concentration is 
300 mcg/ml.  
11.9.3 Administration 
Filgrastim will be given by subcutaneous injection; patient or other caregiver will be instructed 
on proper injection technique.  
11.9.4 Toxicity 
The most common side effect associated with filgrastim is medullary bone pain. Bone pain is 
usually reported as mild or moderate and, if necessary, may be treated with non-opioid or opioid 
analgesics. Rare anaphylactic reactions with the first dose; Local reactions at injection sites; 
Constitutional symptoms; increased alkaline phosphatase, LDH, uric acid; worsening of pre-
existing inflammatory conditions. 

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13 APPENDICES 
13.1 APPENDIX 1: EPOCH-RC CHEMOTHERAPY 
 
Drug 
 
Total dose* 
(mg/m2/d) 
 
Route 
Day 
1  2  3  4    5    6                                                 22 
 
 
 
Alemtuzumab  
30 mg  
   
  IV 
   x 
 
 
 
 
Rituximab 
 
 
375 mg/m2  
 
 IV  
x 
 
 
 
 
 
 
Etoposide 
           50 mg/m2/day 
CIV 
    x-x-x-x- 
Vincristine 
          0.4 mg/m2/day 
CIV 
    x-x-x-x- 
Doxorubicin            10 mg/m2/day  
 CIV     x-x-x-x- 
Cyclophosphamide 
750 mg/m2 
 
  IV 
                  x 
Prednisone 
 
60 mg/m2/day BID 
 PO 
    x-x-x-x-x 
Filgrastim 
 
   
480 mcg QD  
 
  SC 
                  x until ANC recovery > 
5000/mm3 
New cycle begins 
 
 
 
 
 
 
 
                                            
  x  
*First cycle doses. Refer to Section 3.2.2 for dose escalations and Section 3.3.2 for dose 
modifications 
For the first cycle of treatment, Rituximab and the EPOCH infusion may be infused on days 2-6 
if the Alemtuzumab infusion is prolonged due to infusion reactions. 

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13.2 APPENDIX 2: EPOCH ADMIXTURE, PREPARATION: AND ADMINISTRATION  
Preparation 
All 3-in-1 admixtures dispensed from the Pharmacy will contain a 24-hour supply of etoposide, 
doxorubicin, and vincristine, PLUS 40 mL overfill (excess) fluid and a proportional amount of 
drug to compensate for volume lost in parenteral product containers and administration set 
tubing. 
Etoposide Dose 
Volume of Fluid 
Containing a Daily Dose 
Volume of Overfill 
(fluid + drug) 
Total Volume in the Product 
(including overfill) 
≤ 130 mg 
528 mL 
40 mL 
568 mL 
> 130 mg 
1056 mL 
40 mL 
1096 mL 
Before dispensing 3-in-1 admixtures, Pharmacy staff will: 
 
[1] Purge all air from the drug product container, 
 
[2] Attach an administration set appropriate for use with a portable pump, 
 
[3] The set will be primed close to its distal tip, and 
 
[4] The set will be capped with a Luer-locking cap. 
Pre-printed product labeling will identify the ‘Total Volume To Infuse’ and the ‘Volume of 
Overfill (fluid + drug)’. 
Bags will be exchanged daily for four consecutive days to complete a 96-hour drug infusion 
(unless treatment is interrupted or discontinued due to un-anticipated events). 
Administration 
Portable pumps used to administer etoposide + doxorubicin + vincristine admixtures will be 
programmed to deliver one of two fixed volumes at one of two corresponding fixed rates based 
on the amount of etoposide and fluid that is ordered (see the table, below). 
Etoposide Dose 
Total Volume to 
Infuse per 
24 hours 
Volume of Overfill 
(drug-containing 
fluid)* 
Administration 
Rate 
≤ 130 mg 
528 mL 
40 mL 
22 mL/hour 
> 130 mg 
1056 mL 
40 mL 
44 mL/hour 
* DO NOT attempt to infuse the overfill. 
 
At the end of an infusion, some residual fluid is expected because 
overfill (excess fluid and drug) was added; however, nurses are 
asked to return to the Pharmacy for measurement any drug 
containers that appear to contain a greater amount of residual drug 
than expected.  
Example at right: The amount of fluid remaining in a bag after 
completing a 24-hour infusion (1056 mL delivered).  
 
 
 

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51
13.3 APPENDIX 3: PERFORMANCE STATUS CRITERIA 
 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to 
carry 
on 
all 
pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In 
bed 
<50% 
of 
the 
time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, 
fatal 
processes 
progressing rapidly. 
5 
Dead. 
0 
Dead.