Clinical trial NCT01030900
Conditions: Hodgkin Lymphoma Diffuse Large B-Cell Lymphoma
Keywords: Immunosuppression Microenvironment Hodgkin Lymphoma Microarray B-Cell Lymphoma Diffuse Large B-Cell Lymphoma
Sponsor: National Cancer Institute (NCI)
Start date: 2009-10-22; Completion date: 2021-08-06
Enrollment: 50 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Background:

* Studies conducted at the National Cancer Institute suggest that certain chemotherapy drugs may be more effective if given by continuous infusion into the vein rather than by the standard method of rapid intravenous injection. One combination of six chemotherapy drugs, known as etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (EPOCH-R), has had a high degree of effectiveness in people with certain kinds of cancer.
* Recent evidence also indicates that the effects of chemotherapy may be improved by combining the treatment with monoclonal antibodies, which are purified proteins that are specially made to attach to foreign substances such as cancer cells. A monoclonal antibody called campath (alemtuzumab) has been manufactured to attach to a protein called Campath-1 antigen (CD52) that may target tumor cells or the surrounding inflammatory cells.
* Researchers are interested in developing new treatments for large B-cell lymphoma or Hodgkin lymphoma that can best be treated with chemotherapy. This protocol is specifically for people with diffuse large B-cell or Hodgkin lymphomas that have not responded to standard treatments.

Objectives:

\- To test whether giving campath (alemtuzumab) in combination with continuous infusion EPOCH-R chemotherapy will improve the outcome of lymphoma treatment.

Eligibility:

\- Individuals 18 years of age and older who have large B-cell lymphoma or Hodgkin lymphoma that has not responded well to standard treatments.

Design:

* During the study, patients will receive standard EPOCH-R chemotherapy, which includes the following drugs: etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab. The additional drug, campath, will be given by intravenous (IV) infusion on the first day of treatment over several hours.
* When the campath IV infusion and rituximab IV infusion are complete, the drugs doxorubicin, etoposide, and vincristine will each be given by continuous IV infusion over the next 4 days (that is, continuously for a total of 96 hours). Cyclophosphamide will be given by IV infusion over several hours on Day 5. Prednisone will be given by mouth twice each day for 5 days.
* Patients may be given other drugs to treat the side effects of chemotherapy, to prevent possible infections, and to improve white blood cell counts.
* The campath-EPOCH-R therapy will be repeated every 21 days, as a cycle of therapy, for a total of 6 cycles. Following the fourth and sixth treatment cycles (approximately weeks 12 and 18) of campath-EPOCH-R treatment, study researchers will perform blood tests and computed tomography (CT)/magnetic resonance imaging (MRI) scans on all patients to assess their response to the treatment.

Detailed description:
Background:

Two signatures of the microenvironment were recently identified that are predictive of outcome in patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL), treated with rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride (doxorubicin hydrochloride), vincristine (Oncovin) and prednisone (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.

* Campath-1 antigen (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 dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (DA-EPOCH) is 30 mg intravenous (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.

Objectives:

\- 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 greater than or equal to 18 years with adequate organ functions.
* Human immunodeficiency virus (HIV) negative and no active central nervous system (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.

Arms: arm 1: Etoposide, Prednisone, Vincristine, Cyclophosphamide, Doxorubicin (EPOCH) + Rituximab + campath every 3 weeks for six cycles
Interventions: intervention 1: Campath intervention 2: Rituximab intervention 3: EPOCH
Intervention descriptions: intervention 1: campath plus etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin (EPOCH) and rituximab every 3 weeks for up to 6 cycles intervention 2: rituximab plus etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin (EPOCH) and campath every 3 weeks for up to 6 cycles intervention 3: Etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin (EPOCH) plus rituximab and campath every 3 weeks for up to 6 cycles

Protocol documents:
Prot_SAP_000.pdf: 
Abbreviated Title:  EPOCH-RC in recurrent lymphoma 
Version Date:  08/03/2018 
 
1
 
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 
Version Date:  08/03/2018 
 
2
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. 


Abbreviated Title:  EPOCH-RC in recurrent lymphoma 
Version Date:  08/03/2018 
 
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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 
 
 
 


Abbreviated Title:  EPOCH-RC in recurrent lymphoma 
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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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8
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 


Abbreviated Title:  EPOCH-RC in recurrent lymphoma 
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9
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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12
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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14
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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15
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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16
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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28
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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38
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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40
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-


Abbreviated Title:  EPOCH-RC in recurrent lymphoma 
Version Date:  08/03/2018 
 
44
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. 


Abbreviated Title:  EPOCH-RC in recurrent lymphoma 
Version Date:  08/03/2018 
 
45
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33. Coiffier B, Lepage E, Briere J, et al. CHOP chemotherapy plus rituximab compared with 
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relapsed, refractory or transformed B-cell lymphomas: results of a phase II study. Ann Oncol 
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41. Buggins AG, Mufti GJ, Salisbury J, et al. Peripheral blood but not tissue dendritic cells 
express CD52 and are depleted by treatment with alemtuzumab. Blood 2002;100:1715-20. 
42. Ratzinger G, Reagan JL, Heller G, Busam KJ, Young JW. Differential CD52 expression by 
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CAMPATH-1 (CDw52) antigen. Mol Immunol 1993;30:1089-96. 
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derived material. Clin Exp Immunol 1992;87:105-10. 
48. Mone AP, Cheney C, Banks AL, et al. Alemtuzumab induces caspase-independent cell 
death in human chronic lymphocytic leukemia cells through a lipid raft-dependent mechanism. 
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49. Stanglmaier M, Reis S, Hallek M. Rituximab and alemtuzumab induce a nonclassic, 
caspase-independent apoptotic pathway in B-lymphoid cell lines and in chronic lymphocytic 
leukemia cells. Ann Hematol 2004;83:634-45. 
50. Smolewski P, Szmigielska-Kaplon A, Cebula B, et al. Proapoptotic activity of alemtuzumab 
alone and in combination with rituximab or purine nucleoside analogues in chronic lymphocytic 
leukemia cells. Leuk Lymphoma 2005;46:87-100. 
51. Nuckel H, Frey UH, Roth A, Duhrsen U, Siffert W. Alemtuzumab induces enhanced 
apoptosis in vitro in B-cells from patients with chronic lymphocytic leukemia by antibody-
dependent cellular cytotoxicity. Eur J Pharmacol 2005;514:217-24. 
52. Watanabe T, Masuyama J, Sohma Y, et al. CD52 is a novel costimulatory molecule for 
induction of CD4+ regulatory T cells. Clin Immunol 2006;120:247-59. 
53. Dunleavy K BJ, Steinberg S. Phase II study of EPOCH infusional chemotherapy in relapsed 
or refractory Hodgkin lymphoma. A report on toxicity, efficacy and prognostic indicators of 
outcome. JCO SCO Annual Meeting Proceedings 2004;22:6598. 
54. Younes A, Romaguera J, Hagemeister F, et al. A pilot study of rituximab in patients with 
recurrent, classic Hodgkin disease. Cancer 2003;98:310-4. 
55. Younes A FL, Goy A. Results of rituximab plus ABVD in 65 newly diagnosed patients with 
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in patients with recurrent or refractory Hodgkin lymphoma. Cancer 2008;112:831-6. 


Abbreviated Title:  EPOCH-RC in recurrent lymphoma 
Version Date:  08/03/2018 
 
49
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. 


Abbreviated Title:  EPOCH-RC in recurrent lymphoma 
Version Date:  08/03/2018 
 
50
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).  
 
 
 


Abbreviated Title:  EPOCH-RC in recurrent lymphoma 
Version Date:  08/03/2018 
 
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. 

ICF_001.pdf: 
MEDICAL RECORD 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
INSTITUTE: 
National Cancer Institute 
STUDY NUMBER: 
10-C-0011 
PRINCIPAL INVESTIGATOR: 
Wyndham H. Wilson, M.D., Ph.D. 
STUDY TITLE:  
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 
Continuing Review Approved by the IRB on 09/24/18  
Amendment Approved by the IRB on 09/04/18 (J) 
Date posted to web:  10/06/18 
Standard 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
NIH-2514-1 (07-09) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent (1) 
 
 
INTRODUCTION 
We invite you to take part in a research study at the National Institutes of Health (NIH). 
First, we want you to know that: 
Taking part in NIH research is entirely voluntary.  
You may choose not to take part, or you may withdraw from the study at any time.  In 
either case, you will not lose any benefits to which you are otherwise entitled.  However, 
to receive care at the NIH, you must be taking part in a study or be under evaluation for 
study participation. 
You may receive no benefit from taking part.  The research may give us knowledge that 
may help people in the future. 
Second, some people have personal, religious or ethical beliefs that may limit the kinds of medical 
or research treatments they would want to receive (such as blood transfusions).  If you have such 
beliefs, please discuss them with your NIH doctors or research team before you agree to the study. 
Now we will describe this research study.  Before you decide to take part, please take as much 
time as you need to ask any questions and discuss this study with anyone at NIH, or with family, 
friends or your personal physician or other health professional.   
Why is this study being done?  
The general purpose of this study is to develop treatments for lymphoma that are more effective 
than existing therapies.  The experimental part of this treatment program is to test whether giving 
campath (alemtuzumab) in combination with continuous infusion EPOCH-rituximab 
chemotherapy will improve the outcome of therapy of your lymphoma.  In this study five 
chemotherapy drugs are given together in an intensive combination called EPOCH. In addition, 
you will receive a drug called rituximab.  EPOCH-R contains drugs which are standard for the 
treatment of lymphomas.  Because higher doses of chemotherapy may increase the benefit, the 
doses of several drugs in EPOCH-R may be increased on each cycle if you tolerated them on the 
previous cycle.     


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research 
Study 
STUDY NUMBER: 10-C-0011 
CONTINUATION: page 2 of 16 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
Why are you being asked to take part in this study? 
You have a disease called Diffuse Large B-cell lymphoma or Hodgkin lymphoma which your 
doctors think would be best treated with chemotherapy. This protocol is specifically for people 
with diffuse large B-cell or Hodgkin lymphomas, as we are trying to find better treatments for 
these types of lymphoma.   
How many people will take part in this study?  
Approximately 52 subjects will participate in this study.  
Description of Research Study 
Studies conducted at the National Cancer Institute suggest that certain chemotherapy drugs may 
be more effective if given by continuous infusion into the vein rather than by the standard method 
of rapid intravenous injection.  One such combination, which we call EPOCH (each letter stands 
for one of the drugs used in the combination), seems to have a high degree of effectiveness in 
patients whose tumors have stopped responding to standard regimens.  Recent evidence also 
indicates that the effects of chemotherapy may be improved by combination with monoclonal 
antibodies.  Monoclonal antibodies are purified proteins that are specially made to attach to pieces 
of foreign substances (such as cancer cells) with the goal of inactivating them.  A monoclonal 
antibody, called campath (Alemtuzumab), has been manufactured to attach to a protein called 
CD52 that may target your tumor cells or the surrounding inflammatory cells.  Rituximab is 
another monoclonal antibody that you will receive which binds to a specific molecule (called 
CD20) present on most B-cells and is part of standard therapy. We performed a study using the 
combination of EPOCH and campath in other types of lymphomas. Based on this previous study, 
we have experience with this combination of drugs, especially with regards to its safety and the 
optimal doses of the drug used. Most patients experienced mild infusional reactions, manifesting 
as fever, chills and rash. Documented infections were common and the most common were viral 
infections. The most common virus detected was cytomegalovirus which generally did not produce 
symptoms and is detected only by a blood test. Other types of infections seen were bacterial and 
fungal infections but these occurred less frequently. Based on positive results we have had in the 
past treating lymphomas with EPOCH combined with rituximab or campath, we now plan to test 
this combination of EPOCH-RC in patients who have previously been treated with chemotherapy 
and have either relapsed or are refractory to the prior chemotherapy regimen. Up to 52 patients 
will be treated on this study. All of the drugs used in this protocol have been FDA approved. 
What will happen if you take part in this research study?   
Before you begin the study 
In order to determine if you are eligible for this study, several tests need to be done.  This period 
of evaluation may take up to three weeks and may be done on an outpatient basis.  Evaluation may 
include some or all of the following tests: standard blood tests, 24 hour collections of urine, tests 
of lung and heart function, computerized tomography (CT) scans, nuclear medicine scans of the 
body (called a PET scan), bone marrow biopsies and biopsies of suspected areas of tumor.   


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research 
Study 
STUDY NUMBER: 10-C-0011 
CONTINUATION: page 3 of 16 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
During the study 
EPOCH-R-Campath chemotherapy treatment: The chemotherapy regimen known as EPOCH-
RC will be given by intravenous (IV) infusion through a “central line,” an IV catheter (or tube) 
placed in a large vein in your arm or chest.  You will be admitted to the hospital for the infusion 
of the monoclonal antibody therapy on this protocol but may receive the chemotherapy infusion 
as an outpatient. Patients will receive dose adjusted (DA) EPOCH-R chemotherapy which includes 
the following drugs: etoposide (E), prednisone (P), vincristine (O), cyclophosphamide (C), 
doxorubicin (H), and rituximab (R). The drug campath will be given by IV infusion on the first 
day of treatment over several hours. When this infusion is completed, the drug rituximab will be 
given by IV infusion over several hours. When the rituximab IV infusion is complete, the drugs 
doxorubicin, etoposide, and vincristine will each be given by continuous IV infusion over the next 
4 days (that is, continuously for a total of 96 hours). Cyclophosphamide will be given by IV 
infusion on Day 5 after you have received the previous chemotherapy drugs. Prednisone will be 
given by mouth (orally) twice each day for 5 days. You will take the first dose of prednisone 8-12 
hours before starting the campath. 
You will receive the drug filgrastim by subcutaneous (under the skin) injection starting on Day 6 
to increase white blood cell counts. Filgrastim will be continued until your white blood counts 
have reached acceptable levels. The dose of doxorubicin, etoposide, and/or cyclophosphamide 
may be “adjusted” up or down depending on your white blood cell count. You will be given a drug 
commonly known as Bactrim to be taken by mouth (orally) three times a week (for example, on a 
Monday-Wednesday-Friday schedule) to guard against possible infections. You will receive a drug 
called fluconazole to prevent fungal infections, and a drug called acyclovir to prevent certain viral 
infections. You will also receive a drug each day to be taken by mouth (orally) to guard against 
stomach ulcers, such as omeprazole. In addition, you will receive colace, or equivalent, by mouth 
twice daily to prevent constipation. If constipation becomes severe, you may also receive the 
laxative known as lactulose. 
The EPOCH-RC therapy will be repeated every twenty-one (21) days, which is known as a “cycle” 
of therapy, for a total of 6 cycles. Following the fourth and sixth treatment cycles (approximately 
weeks 12 and 18) of EPOCH-RC, your doctor will evaluate you with blood tests and CT/MRI 
scans.  


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research 
Study 
STUDY NUMBER: 10-C-0011 
CONTINUATION: page 4 of 16 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
EPOCH-RC Treatment Schema 
 
Day of Treatment 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 11 12 13 … 21* 
Campath 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Rituximab 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Etoposide 
 
X → 
 
 
 
 
 
 
 
 
Prednisone 
X 
X 
X X X X  
 
 
 
 
 
 
 
 
 
Vincristine 
 
X → 
 
 
 
 
 
 
 
 
Cyclophosphamide 
 
 
 
 
 
X  
 
 
 
 
 
 
 
 
 
Doxorubicin 
 
X → 
 
 
 
 
 
 
 
 
Filgrastim 
 
 
 
 
 
 
X** → 
 
 
 
 
 
 
 
* This twenty-one day (21) period will be known as a “cycle” of therapy. Therapy will be repeated 
for a total of 6 cycles. During the course of treatment, you may also receive the following drugs: 
Bactrim, fluconazole, acyclovir, omeprazole, and colace.  On the first cycle of therapy the start of 
rituximab and EPOCH chemotherapy may be delayed until the following day if toxicity during the 
campath infusion caused a prolonged infusion time. 
** Filgrastim will continue to be given to you until your blood counts have reached acceptable 
levels. 
Research tests:  We would like to perform research studies on your blood and tumor tissue to look 
at different genes and proteins that may be involved in the development of your lymphoma or the 
reaction of the immune system.  We will not examine mutations of genes from your normal tissue 
without obtaining additional permission from you.  We plan to do a tissue biopsy before you start 
treatment and after the first cycle of therapy.  Biopsies of tumor will be done with local or general 
anesthesia.  The tumor biopsies are being performed for two reasons; first to confirm your 
diagnosis and second to perform research tests on the tumor.  These biopsies will give us important 
information about your tumor. Biopsies requiring major surgery (opening the chest or abdomen) 
will only be done if necessary for medical care and will not be done for experimental purposes.  It 
is important, however, for you to understand that in some cases, biopsies of tumor may be done 
primarily for experimental purposes.  These biopsies are optional for participation in the study but 
are important to help us learn how to better treat diffuse large B-cell and Hodgkin lymphomas. 
 
 
 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research 
Study 
STUDY NUMBER: 10-C-0011 
CONTINUATION: page 5 of 16 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
Optional Post Cycle 1 Biopsy  
The biopsy to be performed is exclusively for research purposes and will not benefit you.  It might 
help other people in the future.   
When you are finished taking the drugs (treatment) 
If all evidence of disease has disappeared, we will schedule periodic visits to the Clinical Center 
for follow-up examination and tests.  If the disease does not disappear entirely or if it should recur 
after having disappeared for a period of time, then you may need further therapy.  At that time, 
you will be given the opportunity of participating in additional research protocols that may be 
appropriate for you.  If no such protocols are available, you will be returned to the care of your 
local physician.  We will continue to contact you and/or your local physician to see how you are 
doing even after you have completed treatment on this protocol. It is important to stress that 
participation in this protocol does not mean you will receive long-term medical care here at the 
Clinical Center.  
Birth Control 
If you are a woman who is breast feeding or pregnant, you may not take part in the study because 
we don’t know how this medicine would affect your baby or your unborn child. If you are a woman 
who can become pregnant, or are the partner of a woman who can become pregnant, you will need 
to practice an effective form of birth control before starting study treatment, during study 
treatment, and for 24 months after you finish study treatment.  If you think that you or your partner 
is pregnant, you should tell your study doctor or nurse at once. For male subjects, you should 
practice contraception for the duration of the study and 12 months after completion of treatment. 
Effective forms of birth control include:  
• abstinence  
• intrauterine device (IUD) 
• hormonal [birth control pills, injections, or implants] 
• tubal ligation 
• vasectomy 
Risks or Discomforts of Participation 
What side effects or risks can I expect from being in this study?  
Risks associated with procedures  
The risks associated with bone marrow biopsies are pain, bleeding and local infection.  Risks of 
tissue biopsies include pain, bleeding, infection, and the risks to the particular area undergoing 
surgery.  A biopsy of tumor may require general anesthesia but only for the purpose of making a 
diagnosis. General anesthesia will not be performed to obtain biopsies for research purposes.  


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research 
Study 
STUDY NUMBER: 10-C-0011 
CONTINUATION: page 6 of 16 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
General anesthesia itself is generally very safe but has a very small risk of major complications 
such as heart attack or stroke.  The surgical and anesthetic risks will be explained to you in more 
detail at the time of surgery, if this is needed. 
You may be required to undergo a lumbar puncture if indicated. A small amount of spinal fluid 
(about 1-2 teaspoons) is removed and will be tested for the presence of lymphoma cells.  A lumbar 
puncture is done by inserting a small sterile needle through the skin and muscle, going between 
the bones of the spine in the lower back until the needle punctures the spinal canal covering.  The 
spinal fluid will then drain out through the needle on its own. 
In order to receive this treatment, you will need to have a central venous catheter.  This is catheter 
is placed under the skin of the chest wall and enters a major vein in the chest.  There are several 
types of catheters including those which must be removed after each cycle of chemotherapy 
(temporary type) and those which may be kept for the duration of therapy (permanent type).  These 
options will be discussed with you.  The risks associated with placing some catheters include pain, 
bleeding, infection and collapsed lung.  The long term risks of the catheter include infection, and 
clotting of your veins.  If these occur, it may be necessary to remove the catheter.  These risks will 
be explained to you in more detail at the time of insertion.  
You may have side effects while on the study. Every one taking part in the study will be watched 
carefully for any side effects. However, doctors don’t know all the side effects that may happen. 
Side effects may be mild or serious. Your health care team may give you medicines to help lessen 
side effects. In some cases, side effects can be serious or long-lasting or may never go away. There 
is also the risk of death from either the treatment or your disease. 
You should talk to your doctor about any side effects that you have while taking part in the study. 
Most of the side effects related to the treatment are listed in this form, but they will vary from 
person to person.  There may be other side effects that we don't know about.   
Side Effects of Campath 
Likely: These side effects occur in greater than 50% of patients 
• Mild flu-like symptoms such as chills, fever (usually occur only with the first dose and 
decreased or absent with each following dose).  Stopping or increasing the time it takes to 
give you campath may make these side effects go away.   
• Decreased white blood cells (including normal T-cells), which may increase the risk of 
infection (bacterial, viral, fungal, parasitic); you will be given medicines to prevent 
infections.   
• Decreased red blood cells (anemia), which may make you feel more easily tired, or even 
out of breath when performing simple daily tasks. It may also cause you to feel lightheaded, 
or have a rapid heartbeat. If you become symptomatic, red blood cell transfusion may be 
needed. 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research 
Study 
STUDY NUMBER: 10-C-0011 
CONTINUATION: page 7 of 16 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
• Decreased platelet counts, which may increase the risk of bleeding or bruising. If bleeding 
becomes serious such bleeding from the gastro-intestinal tract, platelet transfusion will be 
warranted. 
• Asymptomatic virus infection, in particular a virus called cytomegalovirus (CMV).  CMV 
is a common virus that infects most people worldwide. It is a member of the herpesvirus 
family. Other members of the herpesvirus family cause chickenpox, infectious 
mononucleosis, fever blisters, and genital herpes. These viruses all share the ability to 
remain alive, but dormant, in the body for life. The virus lives in the body silently without 
causing obvious damage or illness but may reactivate when the immune system weakens. 
Even upon reactivation, there are usually no symptoms produced and is detected only on a 
blood test.  You will be monitored closely with a blood test each time you return to clinic 
for signs of this infection. 
Less likely: These side effects occur in 10-50% of patients: 
These usually occur only with the first dose and are decreased or absent with each following dose. 
• Skin rash 
• itching 
• Nausea 
• Vomiting 
• diarrhea 
• general sick feeling 
• decreased appetite 
• headache 
• fatigue 
• low or high blood pressure 
• shortness of breath  
• cough 
• rapid heart beat 
• sweating 
• muscle pain 
• sepsis - increased risk of bacterial and fungal infections 
Occasional: These side effects occur in <10% of patients: 
• 
dizziness 
• 
dysesthesia or paresthesia (abnormal touch sensation) 
• 
tremors 
• 
insomnia 
• 
sweating 
• 
abnormal taste  
• 
vasodilatation (increased blood flow) 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research 
Study 
STUDY NUMBER: 10-C-0011 
CONTINUATION: page 8 of 16 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
• 
confusion 
• 
anxiety 
• 
constipation  
• 
leg edema 
Unlikely: These side effects occur in <1% of patients.  
• joint pain 
• conjunctivitis 
• deep vein thrombosis 
Unlikely, but serious: These side effects are severe, life threatening, or cause death.   
• Allergic reactions with any of the following symptoms: 
• Marked lowering of the blood pressure, throat tightness, shortness of breath, severe skin rash   
• Development of other cancers or recurrence of a past cancer.   
• Heart rhythm, kidney, and lung problems caused by chemicals released into your blood from 
dead cancer cells; you will receive extra fluids before you start your treatment with campath 
to flush any extra chemicals out of your body, and you will also be given medicine to help 
control the chemical balance of your blood.   
• Serious viral infection 
• Changes in liver enzymes 
• Cardiac arrhythmias 
• Seizure 
• Leukoencephalopathy – Progressive loss of neurological function, the most prominent 
symptoms are clumsiness, progressive weakness, visual, speech and sometimes personality 
changes 
• Abnormal clotting of the blood resulting in serious complications such clotting of blood vessels 
in the lungs. 
Since campath can cause a prolonged lowering of lymphocytes (white blood cells), you may 
develop an increased risk for serious infections, the development of other tumors, or the recurrence 
of a previous cancer.  Also, it is important to know that patients may develop other unexpected 
side effects and these could lead to serious organ damage or even death. 
Side Effects of EPOCH-R: 
Likely: 
• Lowered white blood cell count that may lead to infection. 
• Lowered platelets which may lead to an increase in bruising or bleeding. 
• Lowered red blood cells which may cause anemia, tiredness, or shortness of breath. 
• Should low counts occur, they can be treated with blood products (transfusions), 
antibiotics, and there may be a reduction in the amount of drug given to you. 
• Constipation. 
• Fatigue or tiredness. 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research 
Study 
STUDY NUMBER: 10-C-0011 
CONTINUATION: page 9 of 16 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
• Tingling of fingers and/or toes. 
• Hair loss. 
• Fever and/or chills. 
• Time away from work. 
• Urine colored red for a day or two after the doxorubicin infusion. 
• Fingernail and toenail changes. 
• Tearing or dry eyes. 
• Runny nose. 
• Bony pain. 
Less Likely: 
• Nausea and/or vomiting. 
• Loss of appetite, change in taste and weight loss. 
• Temporary shortness of breath or dizziness while receiving rituximab. 
• Headaches. 
• Muscle aches and muscle weakness. 
• Hoarseness or pain in the jaw. 
• Elevated blood sugar levels. 
• Elevated or decreased blood pressure. 
• Confusion. 
• Mouth & throat sores. Temporary irritation to the mouth may lead to mouth ulcers (similar 
to canker sores). Medications to numb the mouth may ease the mouth discomfort. 
• Stomach ulcers. 
• Skin rashes and/or dry skin. 
• Loss of control of muscles or reflexes. 
• Abnormalities in blood results such as elevated liver enzymes, low blood protein and low 
blood calcium. 
• Mood changes such as agitation or depression. 
• Trouble sleeping. 
Rare, But Serious: 
• Severe constipation may result in abdominal pain and cramping. 
• Bladder irritation with painful and bloody urine. 
• Damage to the heart muscle. 
• Skin rash that may be serious and life-threatening. 
• Allergic reaction that may be severe or life-threatening. Symptoms may include difficulty 
breathing, low blood pressure, fast heart rate, and sweating. 
• Severe hepatitis (liver infection) in those patients who are carriers of the hepatitis virus. 
Patients who may have had prior exposure to the hepatitis B and C virus may be at an 
increased risk of recurrence of the virus that may lead to severe liver damage that can be 
life-threatening. You doctor will screen you for the hepatitis virus before beginning 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research 
Study 
STUDY NUMBER: 10-C-0011 
CONTINUATION: page 10 of 16 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
treatment on this study. If you test positive for the virus, you will be closely monitored 
for signs of the infection, and you will be treated, if appropriate, by your doctor. 
Reproductive risks:  
Many of the drugs used in this treatment program are toxic to the cells in the ovary and testicle 
and may produce sterility.  Recovery of normal fertility is not well studied although we know that 
some patients treated with this combination have remained fertile after the therapy has been 
completed.  For this reason, men who are about to receive this treatment should, if they wish to 
have children in the future, consider sperm banking before start of the treatment.   
Potential Benefits of Participation 
Are there benefits to taking part in this study?  
It is likely that most patients will have at least a temporary improvement from treatment with 
Campath and EPOCH-R chemotherapy.  However, we cannot be certain if you will be cured of 
your lymphoma and it is possible that you may not respond to treatment. 
In addition, your participation in this protocol may contribute to advances in the understanding of 
and treatment for your disease 
Alternative Approaches or Treatments 
What other choices do I have if I do not take part in this study?  
We do not know at this point whether the combination of drugs we are offering to you is more 
effective, less effective or the same as the standard combination chemotherapy for your disease.   
Instead of being in this study, you have these options: 
• Other combination drug regimens and other schedules of the same drugs used in this study.  
For example, a chemotherapy called R-ICE given in the conventional manner would be 
suitable standard therapy for your condition. This is given either by itself or as a bridge to 
stem-cell transplant. 
• Treatment with single drugs.  This is known to produce brief responses of a few months' 
duration in many patients but to have little beneficial effect in long-term control of the 
disease  
• Radiation (X-ray) treatments.  This can stop tumor growth in particular locations, such as 
bone, abdomen, and other sites but is not successful in controlling the disease overall 
unless the disease is very localized at the start of therapy.  
• Surgery.   As with radiation, surgery can be successful in removing tumor from particular 
locations but cannot be used successfully to remove all lymphoma cells from the body, 
since the disease is almost always present in multiple locations.  Also, surgery cannot be 
used against tumor in some of the organs most commonly involved by lymphoma, such 
as the liver or the lungs 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research 
Study 
STUDY NUMBER: 10-C-0011 
CONTINUATION: page 11 of 16 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
• Waiting, without active therapy.  Although a period of watchful waiting is appropriate 
treatment for some kinds of tumors, in lymphomas similar to yours, the disease will often 
grow and spread rapidly if no treatment is administered.  
• Getting treatment or care for your cancer without being in a study 
• Taking part in another study 
• Getting comfort care, also called palliative care.  This type of care helps reduce pain, 
tiredness, appetite problems and other problems caused by the cancer.  It does not treat the 
cancer directly.  Instead, it tries to improve how you feel.  Comfort care tries to keep you 
as active and comfortable as possible. 
Please talk to your doctor about these and other options. 
Stopping Therapy  
Your doctor may decide to stop your therapy for the following reasons: 
• if he/she believes that it is in your best interest 
• if your disease comes back during treatment 
• if you have side effects from the treatment that your doctor thinks are too severe 
• if new information shows that another treatment would be better for you 
In this case, you will be informed of the reason therapy is being stopped. 
You can stop taking part in the study at any time. However, if you decide to stop taking part in the 
study, we would like you to talk to the study doctor and your regular doctor first. 
If you decide at any time to withdraw your consent to participate in the trial, we will not collect 
any additional medical information about you. However, according to FDA guidelines, 
information collected on you up to that point may still be provided to designated representatives. 
If you withdraw your consent and leave the trial, any samples of yours that have been obtained for 
the study and stored at the NCI can be destroyed upon request. However, any samples and data 
generated from the samples that have already been distributed to other researchers or placed in the 
research databases cannot be recalled and destroyed. 
Research Subject’s Rights 
Participation in this investigational treatment protocol is voluntary; you may discontinue your 
participation in the protocol at any time.  You will be given a copy of the consent for your records.  
There are no penalties imposed for withdrawing from the protocol.  Patients may ask questions of 
the staff, and indeed are encouraged to do so.  Any significant new findings that relate to your 
treatment will be discussed with you.  It is possible that participation in this study may make you 
ineligible to participate in other research studies, which limit the type or number of prior treatments 
patients may have received. 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research 
Study 
STUDY NUMBER: 10-C-0011 
CONTINUATION: page 12 of 16 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
What are the costs of taking part in this study?  
If you choose to take part in the study, the following will apply, in keeping with the NIH policy: 
• 
You will receive study treatment at no charge to you. This may include surgery, 
medicines, laboratory testing, x-rays or scans done at the Clinical Center, National 
Institutes of Health (NIH), or arranged for you by the research team to be done outside 
the Clinical Center, NIH if the study related treatment is not available at the NIH.  
• 
There are limited funds available to cover the cost of some tests and procedures 
performed outside the Clinical Center, NIH.  You may have to pay for these costs if 
they are not covered by your insurance company. 
• 
Medicines that are not part of the study treatment will not be provided or paid for by 
the Clinical Center, NIH. 
• 
Once you have completed taking part in the study, medical care will no longer be 
provided by the Clinical Center, NIH. 
Will your medical information be kept private?  
We will do our best to make sure that the personal information in your medical record will be kept 
private.  However, we cannot guarantee total privacy.  Organizations that may look at and/or copy 
your medical records for research, quality assurance, and data analysis include: 
• The National Cancer Institute (NCI) and other government agencies, like the Food and 
Drug Administration (FDA), which are involved in keeping research safe for people. 
• National Cancer Institute Institutional Review Board 
A description of this clinical trial will be available on http://www.Clinicaltrials.gov, as required 
by U.S. Law.  This Web site will not include information that can identify you.  At most the Web 
site will include a summary of the results.  You can search this Web site at any time.  
Certificate of Confidentiality  
To help us protect your privacy, we have obtained a Certificate of Confidentiality. The researchers 
can use this Certificate to legally refuse to disclose information that may identify you in any 
federal, state, or local civil, criminal, administrative, legislative, or other proceedings, for example, 
if there is a court subpoena. The researchers will use the Certificate to resist any demands for 
information that would identify you, except as explained below. 
You should also know that there are several circumstances in which the Certificate does not 
provide coverage. These include when information:  
• will be used for auditing or program evaluation internally by the NIH; or  
• must be disclosed to meet the legal requirements of the federal Food and Drug 
Administration (FDA).  


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research 
Study 
STUDY NUMBER: 10-C-0011 
CONTINUATION: page 13 of 16 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
• is necessary for your medical treatment and you have consented to this disclosure;  
• is for other research.  
In addition, identifiable, sensitive information protected by this Certificate cannot be admissible 
as evidence or used for any purpose in any action, suit, or proceeding without your consent.  
You should understand that a Certificate of Confidentiality does not prevent you or a member of 
your family from voluntarily releasing information about yourself or your involvement in this 
research. If an insurer, employer, or other person obtains your written consent to receive research 
information, then the researchers will not use the Certificate to withhold that information. 
The Certificate of Confidentiality will not protect against the required reporting by hospital staff 
of information on suspected child abuse, reportable communicable diseases, and/or possible threat 
of harm to self or others. 
Conflict of Interest 
The National Institutes of Health (NIH) reviews NIH staff researchers at least yearly for conflicts 
of interest. This process is detailed in a Protocol Review Guide.   You may ask your research team 
for a copy of the Protocol Review Guide or for more information.  Members of the research team 
who do not work for NIH are expected to follow these guidelines but they do not need to report 
their personal finances to the NIH. 
Members of the research team working on this study may have up to $15,000 of stock in the 
companies that make products used in this study.  This is allowed under federal rules and is not a 
conflict of interest.  
Optional Biopsy  
The biopsy to be performed is exclusively for research purposes and will not benefit you.  It might 
help other people in the future.   
If you agree to have the optional biopsy, you will be asked to sign a separate procedure consent 
before you have the procedure. 
Use of Specimens and Data for Future Research   
To advance science, it is helpful for researchers to share information they get from studying human 
samples.  They do this by putting it into one or more scientific databases, where it is stored along 
with information from other studies. A researcher who wants to study the information must apply 
to the database and be approved.  Researchers use specimens and data stored in scientific databases 
to advance science and learn about health and disease.   
We plan to keep some of your specimens and data that we collect, use them for future research 
and share them with other researchers. We will not contact you to ask about each of these future 
uses. These specimens and data will be stripped of identifiers such as name, address or account 
number, so that they may be used for future research on any topic and shared broadly for 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research 
Study 
STUDY NUMBER: 10-C-0011 
CONTINUATION: page 14 of 16 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
research purposes. Your specimens and data will be used for research purposes only and will not 
benefit you. It is also possible that the stored specimens and data may never be used.   
Results of research done on your specimens and data will not be available to you or your doctor.  
It might help people who have cancer and other diseases in the future.  If you do not want your 
stored specimens and data used for future research, please contact us in writing and let us know 
that you do not want us to use your specimens and data. Then any specimens that have not already 
been used or shared will be destroyed and your data will not be used for future research. However, 
it may not be possible to withdraw or delete materials or data once they have been shared with 
other researchers. 


MEDICAL RECORD 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
STUDY NUMBER: 10-C-0011 
CONTINUATION: page 15 of 16 pages 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH 
STUDY (Continuation Sheet) 
• 
Adult Patient or 
• Parent, for Minor Patient 
NIH-2514-1 (07-09) 
P.A.:  09-25-0099 
 
File in Section 4:  Protocol Consent 
 
 
 
OTHER PERTINENT INFORMATION 
1. 
Confidentiality.  When results of an NIH research study are reported in medical journals 
or at scientific meetings, the people who take part are not named and identified.  In most cases, the 
NIH will not release any information about your research involvement without your written 
permission.  However, if you sign a release of information form, for example, for an insurance 
company, the NIH will give the insurance company information from your medical record.  This 
information might affect (either favorably or unfavorably) the willingness of the insurance 
company to sell you insurance. 
The Federal Privacy Act protects the confidentiality of your NIH medical records.  However, you 
should know that the Act allows release of some information from your medical record without 
your permission, for example, if it is required by the Food and Drug Administration (FDA), 
members of Congress, law enforcement officials, or authorized hospital accreditation 
organizations. 
2. 
Policy Regarding Research-Related Injuries.  The Clinical Center will provide short-
term medical care for any injury resulting from your participation in research here.  In general, no 
long-term medical care or financial compensation for research-related injuries will be provided by 
the National Institutes of Health, the Clinical Center, or the Federal Government.  However, you 
have the right to pursue legal remedy if you believe that your injury justifies such action. 
3. 
Payments.  The amount of payment to research volunteers is guided by the National 
Institutes of Health policies.  In general, patients are not paid for taking part in research studies at 
the National Institutes of Health.  Reimbursement of travel and subsistence will be offered 
consistent with NIH guidelines. 
4. 
Problems or Questions.  If you have any problems or questions about this study, or about 
your rights as a research participant, or about any research-related injury, contact the Principal 
Investigator, Wyndham Wilson, M.D., Ph.D.; Building 10, Room 4N115, Telephone:  240-760-
6092. You may also call the Clinical Center Patient Representative at 301-496-2626. If you have 
any questions about the use of your specimens or data for future research studies, you may also 
contact the Office of the Clinical Director, Telephone: 240-760-6070.  
5. 
Consent Document.  Please keep a copy of this document in case you want to read it again. 
 
 


MEDICAL RECORD 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
STUDY NUMBER: 10-C-0011 
CONTINUATION: page 16 of 16 pages 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH 
STUDY (Continuation Sheet) 
• 
Adult Patient or 
• Parent, for Minor Patient 
NIH-2514-1 (07-09) 
P.A.:  09-25-0099 
 
File in Section 4:  Protocol Consent 
 
 
 
 
COMPLETE APPROPRIATE ITEM(S) BELOW: 
A. Adult Patient’s Consent 
B. Parent’s Permission for Minor Patient. 
I have read the explanation about this study 
and have been given the opportunity to 
discuss it and to ask questions.  I hereby 
consent to take part in this study. 
I have read the explanation about this study 
and have been given the opportunity to 
discuss it and to ask questions.  I hereby give 
permission for my child to take part in this 
study.   
(Attach NIH 2514-2, Minor’s Assent, if 
applicable.) 
 
  
  
 
 
 
Signature of Adult Patient/ 
Legal Representative 
Date 
Signature of Parent(s)/ 
Guardian 
Date 
 
 
Print Name 
 
 
Print Name 
C. Child’s Verbal Assent (If Applicable) 
The information in the above consent was described to my child and my child agrees to 
participate in the study. 
 
 
 
 
 
 
 
Signature of Parent(s)/Guardian 
Date 
Print Name 
THIS CONSENT DOCUMENT HAS BEEN APPROVED FOR USE  
FROM SEPTEMBER 24, 2018 THROUGH OCTOBER 15, 2019. 
 
 
  
 
 
  
 
Signature of Investigator 
Date 
Signature of Witness 
Date 
 
 
Print Name 
 
 
Print Name