Clinical trial NCT00069238
Conditions: Lymphoma, T-Cell Lymphoma, Extranodal NK-T-Cell
Keywords: Lymphoma T-Cell Lymphoma NK -Cell Lymphoma
Sponsor: National Cancer Institute (NCI)
Start date: 2003-09-19; Completion date: 2021-03-17
Enrollment: 31 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Background:

The paradigm of combining therapeutic agents with non-overlapping toxicities for the treatment of malignancy produces clinical remissions and cures in a number of tumor types.

A new class of agents, humanized and chimerized monoclonal antibodies, typically have little or no hematopoietic toxicity and can be readily combined with full doses of cytotoxic chemotherapy. It has become clear that in certain lymphomas and breast cancers, the combination of monoclonal antibodies and chemotherapy improves response rate and the quality of the response compared with that achieved by treatment with either agent alone.

The clinical outcome for patients with T-cell non-Hodgkins lymphoma is significantly inferior to the outcome of patients with B-cell non-Hodgkin s lymphoma. In most reports less than 20% of patients with T cell lymphoid malignancies remain free of disease at 5 years.

Objectives:

Determine the toxicity of Alemtuzumab and etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin (EPOCH) chemotherapy in untreated cluster of differentiation 52 (CD52)-expressing T and natural killer (NK) lymphoid malignancies.

Determine the maximum tolerated dose of Alemtuzumab administered in combination with EPOCH chemotherapy.

Determine in a preliminary fashion the anti-tumor activity of the combination of Alemtuzumab and EPOCH chemotherapy.

Eligibility:

CD52-expressing lymphoid malignancy.

Patients with chemotherapy naive aggressive T \& NK lymphomas. Patients with alk-positive anaplastic large cell lymphoma and patients with T cell precursor disease are not eligible.

Age greater than or equal to 17 years.

Adequate organ function, unless impairment due to respective organ involvement by tumor.

No active symptomatic ischemic heart disease, myocardial infarction or congestive heart. failure within the past year.

Human immunodeficiency virus (HIV) negative.

Not pregnant or nursing.

Design:

Three dose levels of Alemtuzumab will be evaluated to determine the toxicity profile and in a preliminary fashion the antitumor activity of the combination with Dose-Adjusted EPOCH.

Three dose levels of Alemtuzumab will be explored, in cohorts of three to six patients each. Patients will receive either 30, 60, or 90 mg of Alemtuzumab on day 1 of therapy, followed by dose-adjusted EPOCH chemotherapy days 1-5.

Detailed description:
Background:

The paradigm of combining therapeutic agents with non-overlapping toxicities for the treatment of malignancy produces clinical remissions and cures in a number of tumor types.

A new class of agents, humanized and chimerized monoclonal antibodies, typically have little or no hematopoietic toxicity and can be readily combined with full doses of cytotoxic chemotherapy. It has become clear that in certain lymphomas and breast cancers, the combination of monoclonal antibodies and chemotherapy improves response rate and the quality of the response compared with that achieved by treatment with either agent alone.

The clinical outcome for patients with T-cell non-Hodgkins lymphoma is significantly inferior to the outcome of patients with B-cell non-Hodgkins lymphoma. In most reports less than 20% of patients with T cell lymphoid malignancies remain free of disease at 5 years.

Objective:

Determine the toxicity and maximum tolerated dose (MTD) of Alemtuzumab and EPOCH chemotherapy in untreated cluster of differentiation 52 (CD52)-expressing T and natural killer (NK) lymphoid malignancies

Eligibility:

* CD52-expressing lymphoid malignancy.
* Patients with chemotherapy naive aggressive T \& NK lymphomas. Patients with alk-positive anaplastic large cell lymphoma and patients with T cell precursor disease are not eligible.
* Age greater than or equal to 17 years.
* Adequate organ function, unless impairment due to respective organ involvement by tumor.
* No active symptomatic ischemic heart disease, myocardial infarction or congestive heart. failure within the past year.
* Human immunodeficiency virus (HIV) negative.
* Not pregnant or nursing.

Design:

Three dose levels of Alemtuzumab will be evaluated to determine the toxicity profile and in a preliminary fashion the antitumor activity of the combination with Dose-Adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin (EPOCH).

Three dose levels of Alemtuzumab will be explored, in cohorts of three to six patients each. Patients will receive either 30, 60, or 90 mg of Alemtuzumab on day 1 of therapy, followed by dose-adjusted EPOCH chemotherapy days 1-5.

Arms: arm 1: Alemtuzumab (Campath) followed by etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin (EPOCH) every 3 weeks for up to 6 cycles. Three cohorts of 3 to 6 patients will be treated. Cohort 1 will receive 30mg of Alemtuzumab, cohort 2 will receive 60mg of Alemtuzumab, and cohort 3 will receive 90mg of Alemtuzumab. If 1 of 3 participants entered at a given dose level experiences dose limiting toxicity (DLT), up to 3 additional participants will be entered at that dose level. If 2 of 6 participants experience DLT at a particular dose level, the maximum tolerated dose (MTD) has been exceeded. The preceding dose level will be the MTD, provided 6 participants have been entered at this level and no more than 1 has experienced DLT.
Interventions: intervention 1: Alemtuzumab (Campath) intervention 2: EPOCH
Intervention descriptions: intervention 1: Alemtuzumab (Campath) followed by etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin (EPOCH) every 3 weeks for up to 6 cycles. intervention 2: Etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin (EPOCH) + Alemtuzumab (Campath) every 3 weeks for up to 6 cycles.

Protocol documents:
Prot_SAP_001.pdf: 
Abbreviated Title:  EPOCH-Campath in T Lymphomas 
Version Date:  05/16/2018 
1 
 Abbreviated Title:  EPOCH-Campath in T Lymphomas 
 
CC Protocol #:   03-C-0304 H 
 
Version Date:  05/16/2018 
 
NCT Number: NCT00069238 
 
 
PHASE 2 TRIAL OF ALEMTUZUMAB AND DOSE-ADJUSTED EPOCH IN 
CHEMOTHERAPY NAÏVE AGGRESSIVE T and NK-CELL LYMPHOMAS  
 
 
 
NCI Principal Investigator: Wyndham H. Wilson, M.D. Ph.D. 
Lymphoid Malignancies Branch (LYMB) 
Center for Cancer Research (CCR) 
National Cancer Institute (NCI) 
Building 10, Room 4N115  
National Institutes of Health 
Bethesda, MD 20892 
Phone:  240-760-6092 
Email:  wilsonw@mail.nih.gov  
 
 
Investigational Agents:  None 
 
Commercial Agents:   
Alemtuzumab, Etoposide, Prednisone, Vincristine, 
Cyclophosphamide, Doxorubicin, Filgrastim 


Abbreviated Title:  EPOCH-Campath in T Lymphomas 
Version Date:  05/16/2018 
2 
PRÉCIS 
Background: 
x The paradigm of combining therapeutic agents with non-overlapping toxicities for the 
treatment of malignancy produces clinical remissions and cures in a number of tumor 
types.   
x A new class of agents, humanized and chimerized monoclonal antibodies, typically have 
little or no hematopoietic toxicity and can be readily combined with full doses of 
cytotoxic chemotherapy.  It has become clear that in certain lymphomas and breast 
cancers, the combination of monoclonal antibodies and chemotherapy improves response 
rate and the quality of the response compared with that achieved by treatment with either 
agent alone.   
x The clinical outcome for patients with T-cell non-Hodgkin’s lymphoma is significantly 
inferior to the outcome of patients with B-cell non-Hodgkin’s lymphoma.  In most reports 
less than 20% of patients with T cell lymphoid malignancies remain free of disease at 5 
years.   
Objective: 
x Determine the toxicity and maximum tolerated dose (MTD) of Alemtuzumab and 
EPOCH chemotherapy in untreated CD52-expressing T and NK lymphoid malignancies 
Eligibility: 
x CD52-expressing lymphoid malignancy. 
x Patients with chemotherapy naïve aggressive T & NK lymphomas. Patients with alk-
positive anaplastic large cell lymphoma and patients with T cell precursor disease are not 
eligible. 
x Age t17 years. 
x Adequate organ function, unless impairment due to respective organ involvement by 
tumor. 
x No active symptomatic ischemic heart disease, myocardial infarction or congestive heart 
failure within the past year 
x HIV negative 
x Not pregnant or nursing 
Design: 
x Three dose levels of Alemtuzumab will be evaluated to determine the toxicity profile and 
in a preliminary fashion the antitumor activity of the combination with Dose-Adjusted 
EPOCH. 
x Three dose levels of Alemtuzumab will be explored, in cohorts of three to six patients 
each.  Patients will receive either 30, 60, or 90 mg of Alemtuzumab on day 1 of therapy, 
followed by dose-adjusted EPOCH chemotherapy days 1-5. 


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TABLE OF CONTENTS 
PRÉCIS ........................................................................................................................................... 2 
TABLE OF CONTENTS ................................................................................................................ 3 
1 INTRODUCTION ...................................................................................................................... 5 
1.1 
Study Objectives............................................................................................................... 5 
1.2 
Background ...................................................................................................................... 5 
1.3 
Therapy of T cell lymphoma ............................................................................................ 6 
1.4 
Rationale for this trial ..................................................................................................... 10 
2 ELIGIBILITY ASSESSMENT AND ENROLLMENT ........................................................... 11 
2.1 
Eligibility Criteria........................................................................................................... 11 
2.2 
Research Eligibility Evaluation ...................................................................................... 11 
2.3 
Registration Procedures .................................................................................................. 12 
3 STUDY IMPLEMENTATION ................................................................................................ 12 
3.1 
Study Design .................................................................................................................. 12 
3.2 
Drug Administration (Via Central Catheter) .................................................................. 13 
3.3 
Treatment Modifications ................................................................................................ 15 
3.4 
On Study Evaluation ...................................................................................................... 17 
3.5 
Concurrent Therapies (continued for 2 months post-treatment) .................................... 17 
3.6 
Post-Study Evaluation .................................................................................................... 17 
3.7 
Criteria for Removal from Protocol Therapy and Off Study Criteria ............................ 18 
4 SUPPORTIVE CARE .............................................................................................................. 18 
4.1 
Pneumocystis carinii Pneumonia.................................................................................... 18 
4.2 
CMV antigenemia .......................................................................................................... 18 
4.3 
Febrile neutropenia ......................................................................................................... 18 
4.4 
Symptomatic anemia ...................................................................................................... 19 
4.5 
Thrombocytopenia .......................................................................................................... 19 
4.6 
Central venous access ..................................................................................................... 19 
5 DATA COLLECTION AND EVALUATION ......................................................................... 19 
5.1 
Data Collection ............................................................................................................... 19 
5.2 
Response Criteria ........................................................................................................... 20 
5.3 
Toxicity Criteria ............................................................................................................. 20 


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6 STATISTICAL CONSIDERATIONS ..................................................................................... 21 
7 HUMAN SUBJECTS PROTECTION ..................................................................................... 21 
7.1 
Rationale for subject selection ....................................................................................... 21 
7.2 
Participation of children ................................................................................................. 22 
7.3 
Participation of Subjects Unable to Give Consent ......................................................... 22 
7.4 
Evaluation of benefits and risks/discomforts ................................................................. 22 
7.5 
Risks/Benefits................................................................................................................. 22 
7.6 
Consent and assent process and documentation ............................................................. 23 
8 SAFETY REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING PLAN 23 
8.1 
Definitions ...................................................................................................................... 23 
8.2 
NCI-IRB and Clinical Director Reporting ..................................................................... 25 
9 PHARMACEUTICAL INFORMATION................................................................................. 26 
9.1 
Etoposide/Doxorubicin/Vincristine Administration ...................................................... 26 
9.2 
Cyclophosphamide Administration ................................................................................ 26 
9.3 
Prednisone ...................................................................................................................... 26 
9.4 
Filgrastim (G-CSF) ........................................................................................................ 27 
9.5 
Alemtuzumab (Campath®) ............................................................................................ 27 
9.6 
Diphenhydramine ........................................................................................................... 29 
9.7 
Acetaminophen ............................................................................................................... 29 
9.8 
Trimethoprim/sulfamethoxazole .................................................................................... 29 
9.9 
Fluconazole .................................................................................................................... 29 
9.10 Methotrexate................................................................................................................... 30 
9.11 Cytarabine ...................................................................................................................... 30 
10 REFERENCES ......................................................................................................................... 31 
11 Appendix 1: EPOCH CHEMOTHERAPY .............................................................................. 32 
12 Appendix 2:  EPOCH ADMIXTURES: PREPARATION AND ADMINISTRATION ......... 33 
 


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1 
INTRODUCTION  
1.1 STUDY OBJECTIVES 
1.1.1 
Primary  
Determine the toxicity and maximum tolerated dose (MTD) of Alemtuzumab and EPOCH 
chemotherapy in untreated CD52-expressing T and NK lymphoid malignancies 
1.1.2 
Secondary 
Determine in a preliminary fashion the anti-tumor activity of the combination of Alemtuzumab 
and EPOCH chemotherapy  
1.2 BACKGROUND  
1.2.1 
Alemtuzumab Background 
Alemtuzumab is a humanized antilymphocyte monoclonal antibody engineered by grafting the 
rodent hypervariable complementarity 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.  It is expressed on lymphocytes and 
monocytes, but monocytes appear to be resistant to Alemtuzumab-mediated lysis.  Monocytes 
disappear from the peripheral circulation but reappear shortly after treatment suggesting a 
sequestration without lysis or regeneration from a precursor pool that is CD52-negative.  It is 
estimated that there are 5 x 105 antibody sites per lymphocyte and the antigen does not modulate 
from the cell surface.  Alemtuzumab is thought to mediate cell lysis through complement or 
antibody-dependent cell-mediated cytotoxicity.  The function of CD52 is not known but it may 
play a role in T-cell activation.  Alemtuzumab has been used in clinical trials to suppress the 
immune system in patients undergoing allogeneic stem cell transplantation and in patients with 
autoimmune disease. 
1.2.1.1 Phase 1 Clinical Trial Experience 
A total of 519 patients have been enrolled in 18 phase I and II studies of Alemtuzumab sponsored 
by Wellcome.  Based on the results of these studies a dose of 30 mg administered intravenously 
three times weekly for 12 weeks was selected for evaluation in phase II studies.  
A total of 174 patients were evaluated in phase I dose-escalation trials in patients with non-
Hodgkin's lymphoma and chronic lymphocytic leukemia.  In study 001, four cohorts of patients 
were evaluated with doses ranging from 2.5 to 80 mg intravenously three times weekly.  In study 
002, four cohorts were evaluated with doses ranging from 7.5 to 240 mg administered 
intravenously once per week.  The administration of Alemtuzumab was associated with acute 
adverse events primarily related to the first dose or the first escalated dose during the period of 
antibody dose-escalation.  The incidence of acute adverse events increased with doses over 3 mg 
but above this dose a dose-effect was less evident.  Common adverse events seen in about half of 
the treated patients included chills/rigors, fever, nausea, and vomiting and skin rash.  
Hypotension occurred in about one third of patients but did not achieve grade 3 or 4 levels and 
dyspnea in about 25% of administrations.  Bronchospasm occurred in about 10% of patients.  In 
vitro data suggest that Fc-receptor crosslinking on NK cells may be responsible for these 
toxicities which are thought to be mediated by cytokine release 1.  Hypertension that achieved 


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grade 3 or 4 toxicity levels occurred in 17% of patients.  Neutropenia emerged during treatment 
in about 24% of patients and was more common in patients treated with higher doses of 
Alemtuzumab (80 mg or higher).  Transient thrombocytopenia occurred in association with early 
infusions in a course of treatment and typically became less pronounced with continued 
treatment.  Thrombocytopenia emerged on treatment in about 15% of patients and was more 
common with higher individual doses.  Thrombocytopenia was attributed to peripheral 
destruction as these patients had normal megakaryocyte numbers and failed to respond to platelet 
transfusions.  Anemia occurred in about 16% of individuals.  Hypoplastic bone marrow findings 
were seen in eight patients during these phase I studies.  In three cases the patients were known to 
have pre-existing bone marrow abnormalities.  In the remaining five cases, the patients were 
treated with 80 mg doses three times weekly.  There were 27 deaths within 28 days of the final 
Alemtuzumab infusion.  Fourteen deaths were attributed to disease progression, 6 were due to 
infectious complications.  Other deaths were attributed to cardiac failure, renal failure in 
association with tumor lysis syndrome, hepatic failure, and respiratory failure.  Two deaths 
occurred after administration of alternative chemotherapy.   
Tumor responses were recorded in 16 patients; 8 occurred in patients with CLL or PLL, 2 in 
patients with small lymphocytic lymphoma, 2 in patients with mycosis fungoides, 2 in patients 
with small-cleaved cell lymphoma and 1 each in follicular and diffuse mixed cell lymphoma.  
The sites of tumor most likely to respond were blood, bone marrow and spleen.  Lymph node 
enlargement, particularly bulky lymph node enlargements were less likely to respond. 
1.2.1.2 Phase II Clinical Trial Experience 
Eight phase II trials, enrolling 190 patients, were conducted by Wellcome (Investigator’s 
brochure).  These studies evaluated the three times weekly intravenous schedule of 
administration with a target dose of 25-30 mg and avoided the higher doses, which were 
associated with increased bone marrow toxicity.  Subcutaneous dosing was evaluated in a subset 
of patients.  An escalating dose regimen was used with attenuated doses of 3 and 10 mg during 
the first week of treatment.  Patients with non-Hodgkin's lymphoma or CLL that was relapsed or 
refractory to initial therapy were eligible for the study.  In one study, 125 patients with NHL or 
CLL were entered and in another study 24 patients with CLL refractory to fludarabine were 
entered.  In the larger trial 8% of patients achieved a CR, 25% a PR and 37% stable disease.  One 
third of fludarabine resistant patients with CLL responded to Alemtuzumab treatment.  The 
investigators brochure indicates that seven patients with ATL have been treated but additional 
information on toxicity and response is not available. 
1.3 THERAPY OF T CELL LYMPHOMA 
The REAL classification has had a significant impact on the management of patients with 
lymphocytic neoplasms 2.  Previous classifications such as the working formulation did not 
account for lymphocyte phenotype in categorizing these disorders.  As a result, B and non-B cell 
neoplasms were treated and categorized similarly.  This has led to controversy with regard to the 
clinical outcome of patients with B and T cell neoplasms.  Early studies evaluating outcome in 
small groups of patients suggested that there were no differences in outcome between the B and 
T cell subgroups.  The REAL classification however makes clear that there are different 
subcategories within the T cell subgroup that have substantially different clinical outcomes and 
this difference combined with early stage disease likely account for the reported findings from 
earlier studies. 


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Table 1 from the Non-Hodgkin’s Lymphoma Classification Project summarizes the results from 
a worldwide survey of nine study sites that examined all newly diagnosed cases of lymphoma 
between 1988 and 1990 3.  A cohort of 1403 cases of lymphoma was evaluated with an intensive 
histologic characterization of the neoplasms and immunologic phenotyping with review by an 
expert panel of five hematopathologists.  Clinical correlations and survival analyses were 
performed.  The report indicates the relative rarity of these malignancies compared with B cell 
lymphomas with only 7% of all diagnoses representing one of several different subgroups of T 
cell neoplasms.  Anaplastic large cell lymphoma, an entity that frequently expresses T cell 
markers represented 2.4% of all lymphoma diagnoses.   
Table 2 shows the survival analysis of these patients and emphasizes the poor outcome of 
patients with peripheral T cell neoplasms compared to that of patients with diffuse large cell 
lymphoma or anaplastic large cell lymphoma, a disease that is sometimes combined with the 
peripheral T cell neoplasms 3.  In the group with peripheral T cell neoplasm of all subtypes, the 
outcome is dependent upon the international prognostic index (IPI) score of the patient although 
the outcome is particularly poor in patients with high IPI scores with only 15% of patients with 
this diagnosis alive at five years and 5% of that group were alive with evidence of disease 
activity.  Patients with low IPI scores fare better but still have only slightly over a fourth of these 
patients are alive with no evidence of disease at five years.  In contrast, patients with anaplastic 
large cell lymphoma have a good outcome without reference to IPI score.  Over 80% of patients 
are alive at 5 years regardless of IPI score.  This emphasizes the potential for inaccuracy in 
comparing outcome between T and B cell lymphoma in older studies where patients with these 
two entities were combined for comparison purposes.   
Three large series have recently been reported evaluating the incidence and clinical outcome of 
patients with T cell neoplasms 4-6.  The series reported from MD Anderson hospital identified 68 
cases of T cell neoplasms among 560 patients (12%) with intermediate grade and immunoblastic 
non-Hodgkin’s lymphoma treated between 1984 and 1995; GELA identified 288 cases of T cell 
neoplasms among 1883 patients (15%) with diffuse aggressive lymphoma treated between 1987 
and 1993; and 174 cases of T cell lymphoma were diagnosed in nine Spanish institutions 
between 1985 and 1996.  Peripheral T cell lymphoma not otherwise specified represented 49-
66% of cases in these series with anaplastic large cell lymphoma representing 15-21% of cases 
and angioimmunoblastic lymphadenopathy 12-24% of cases.  The complete remission rate for all 
patients with T cell neoplasm varied from a low of 49% in the Spanish series to 54% in the 
GELA study and 65% at MD Anderson.  In each of these series the outcome for patients with 
anaplastic large cell lymphoma was significantly better than that of patients with peripheral T cell 
lymphoma otherwise unspecified.  In the Spanish study the median survival of patients with 
anaplastic large cell lymphoma was 65 months versus 20 months for patients with peripheral T 
cell lymphoma and in the GELA study the five year overall survival was 64% for patients with 
anaplastic large cell lymphoma versus 35% for peripheral T cell lymphoma.  The MD Anderson 
study contained only 10 patients with anaplastic large cell lymphoma and although not 
statistically significant, these patients had a better outcome.  These studies and others 7also 
emphasized the importance of the IPI score in outcome for patients with peripheral T cell 
lymphoma.  The IPI score is generated by giving one point for each of five factors including age 
over 60, stage III or IV disease, elevated LDH, more than one extranodal site of disease, and poor 
performance status.  As with other lymphomas, IPI score has an impact on outcome in peripheral 


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8 
T cell lymphoma.  Patients in the low risk group (IPI score 0,1) have a good prognosis with .5-
year survival of 60-80% whereas patients in higher risk groups (IPI score 2, 3, 4, 5) have a bad 
prognosis with about 20% of patients alive at five years with scores of 2-3 and virtually all 
patients with scores of 4 and 5 dead with 5 years of diagnosis.  
We have limited experience with T cell neoplasms treated with EPOCH chemotherapy due to the 
rarity of this disease but in the small number of patients treated the outcome has been poor (Fig. 
1).  In contrast to anaplastic large cell lymphoma, a relatively newly described entity that was 
frequently included as a T cell neoplasm, which has a good prognosis, patients with other T cell 
neoplasms usually do not have durable disease control.  These patients frequently respond to 
chemotherapy but as with low grade B cell neoplasms do not achieve durable complete 
remissions.  A total of 13 patients with T cell neoplasms (2 gamma-delta hepatosplenic, 6 
peripheral T cell not otherwise specified, 1 subcutaneous panniculitis-like T cell, 4 
angioimmunoblastic lymphadenopathy) have been treated with EPOCH at the NCI.  Eight of the 
13 patients have died due to progressive disease.  Five patients are alive (two patients with 
angioimmunoblastic lymphadenopathy and one patient with peripheral T cell not otherwise 
specified).  Two additional patients are alive but both had disease progression on EPOCH 
chemotherapy; one achieved a complete remission with depsipeptide and the other is undergoing 
allogeneic transplantation.  We also treated six patients with adult T cell lymphoma/leukemia 
with EPOCH chemotherapy in combination with Zenapax but all six patients were induction 
failures.  All but one patient showed a transient response to treatment.  Thus, in contrast to the 
good outcome in B cell lymphoma treated with EPOCH chemotherapy alone and the apparent 
improvement in outcome achieved with rituximab and EPOCH chemotherapy due to an 
improvement in outcome for patients with activated B cell phenotypes, progress is desperately 
needed in the treatment of T cell neoplasms.  Potential approaches to the management of these 
patients have included stem cell transplantation with both autologous and allogeneic stem cells at 
the time of disease progression and the incorporation of these methods in patients in complete 
remission represents one avenue of investigation.  Depsipeptide represents another interesting 
approach and has been successful in one patient with EPOCH-refractory disease.  We plan to 
take advantage of the lymphocyte specific monoclonal antibody Alemtuzumab in combination 
with EPOCH chemotherapy in patients with peripheral T cell lymphoma and no prior therapy.  
Three dose levels of Alemtuzumab will be explored, in cohorts of three to six patients each.  
Patients will receive either 30, 60, or 90 mg of Alemtuzumab on day 1 of therapy, followed by 
dose-adjusted EPOCH chemotherapy days 1-5. 
Table 1: Distribution of NHL cases by the Consensus Diagnosis 
Consensus Diagnosis 
No. of Cases % of total cases 
Diffuse large B-cell 
422 
30.6 
Follicular 
304 
22.1 
Grade 1 
131 
9.5 
Grade 2 
85 
6.2 
Grade 3 
88 
6.4 
Marginal zone B-cell, MALT 
105 
7.6 


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9 
Consensus Diagnosis 
No. of Cases % of total cases 
Peripheral T-Cell 
96 
7 
Medium sized, mixed, and large 
51 
3.7 
Angiocentric, nasal 
19 
1.4 
Angioimmunoblastic 
17 
1.2 
Intestinal 
5 
<1 
Lymphoepithelioid 
2 
<1 
Hepatosplenic 
1 
<1 
Adult T-cell leukemia/lymphoma 
1 
<1 
Small B-lymphocytic (CLL) 
93 
6.7 
Mantle cell lymphoma 
83 
6 
Primary mediastinal large B-cell 
33 
2.4 
Anaplastic large T/null-cell 
33 
2.4 
High grade B-cell, Burkitt-like 
29 
2.1 
Marginal zone B-cell, nodal 
25 
1.8 
Precursor T-lymphoblastic 
23 
1.3 
Lymphoplasmacytoid 
16 
1.2 
Marginal zone B-cell, splenic 
11 
<1 
Mycosis fungoides 
11 
<1 
Burkitt's lymphoma 
10 
<1 
All other types 
84 
6.1 
 
Table 2: Survival by Histologic Type and International Prognostic Index 
Consensus 
Diagnosis 
% 5-yr 
OAS 
% 5-yr FFS Index 0/1 Index 4/5 
Follicular, all 
grades 
84 
17 
55 
6 
Mantle cell 
57 
0 
27 
0 
Marginal zone B-
cell, MALT 
89 
40 
83 
0 
Marginal zone B-
cell, nodal 
76 
50 
30 
0 
Small 
76 
38 
35 
13 


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Consensus 
Diagnosis 
% 5-yr 
OAS 
% 5-yr FFS Index 0/1 Index 4/5 
lymphocyctic 
(CLL) 
Diffuse large B-
cell 
73 
22 
63 
19 
Primary 
mediastinal large 
B-cell 
77 
0 
69 
0 
High grade B-cell, 
Burkitt-like 
71 
0 
71 
0 
Precursor T-
lymphoblastic 
29 
40 
29 
40 
Peripheral T-cell, 
all types 
36 
15 
27 
10 
Anaplastic large 
T/null cell 
81 
83 
49 
83 
Abbreviations: IPI: International Prognostic Index; OAS: overall survival; FFS: failure-
free survival; CLL: chronic lymphocytic leukemia 
1.4 RATIONALE FOR THIS TRIAL 
The outcome of treatment of T cell non-Hodgkin’s lymphoma is poor and new approaches to 
management are needed.  The combination of monoclonal antibodies and chemotherapy has 
improved the outcome for patients with B cell NHL and this approach may be beneficial in T cell 
NHL.  This is a pilot study to determine the toxicity of Alemtuzumab in combination with 
EPOCH infusional chemotherapy.  Three dose levels of Alemtuzumab will be evaluated to 
determine the toxicity profile and in a preliminary fashion the antitumor activity of the 
combination.  It is anticipated that the infusional toxicities of Alemtuzumab will be significantly 
reduced by the administration of steroids with dose-adjusted EPOCH.  The plan for 
Alemtuzumab antibody administration will be similar to that used with rituximab with 
administration of the entire dose before chemotherapy is administered.  The only change to this 
will be that steroid administration will begin on the evening before Alemtuzumab is to be given.  
It is our intent to administer a dose of 90 mg of Alemtuzumab in combination with dose-adjusted 
EPOCH at the highest dose level.   


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2 
ELIGIBILITY ASSESSMENT AND ENROLLMENT 
2.1 ELIGIBILITY CRITERIA 
2.1.1 CD52-expressing lymphoid malignancy, confirmed by pathology or flow cytometry staff 
of the Hematopathology Section, Laboratory of Pathology, NCI.  Patients with T & NK 
cell malignancy without accessible tissue for flow cytometry analysis may be treated on 
this study. 
2.1.2 Patients with chemotherapy naïve aggressive T & NK lymphomas, including but not 
limited to peripheral T cell lymphoma (nos), gamma-delta hepatosplenic T cell 
lymphoma, subcutaneous panniculitis-like T cell, NK-T cell lymphoma confirmed by 
pathology or flow cytometry staff of the Hematopathology Section, Laboratory of 
Pathology, NCI. Patients with alk-positive anaplastic large cell lymphoma and patients 
with T cell precursor disease are not eligible. 
2.1.3 Age t17 years. 
2.1.4 Laboratory tests: Creatinine d1.5 mg/dL or creatinine clearance t 60 ml/min; bilirubin < 
2.0 mg/dl unless due to Gilbert’s, AST and ALT d 3x ULN (AST and ALT d 6x ULN for 
patients on hyperalimentation for whom these abnormalities are felt to be due to the 
hyperalimentation) and; ANC t 1000/mm3, platelet t 75,000/mm3; unless impairment 
due to respective organ involvement by tumor. 
2.1.5 No active symptomatic ischemic heart disease, myocardial infarction or congestive heart 
failure within the past year 
2.1.6 HIV negative, because of the unknown effects of combined therapy with chemotherapy 
and an immunosuppressive agent on HIV progression 
2.1.7 Signed informed consent 
2.1.8 Willing to use contraception 
2.1.9 Not pregnant or nursing, because of the unknown effects of Alemtuzumab on the 
developing fetus and infant. 
2.1.10 No serious underlying medical condition or infection that would contraindicate treatment. 
 Patients with CNS involvement are eligible for treatment on this study. 
2.2 RESEARCH ELIGIBILITY EVALUATION 
Tests to be done within 4 weeks before study entry; the laboratory tests in Sections 2.2.2, 2.2.6 
and 2.2.7 must be done within 7 days of starting therapy. 


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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.  Laparotomy, thorachotomy, 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 Serology: HIV; hepatitis B surface and core antigen; hepatitis C; HTLV-1 and HSV 
serologies 
2.2.5 CMV serologies 
2.2.6 Urinalysis 
2.2.7 Serum pregnancy test in women of childbearing potential. 
2.2.8 Imaging Studies: CT chest, abdomen, and pelvis; CT or MRI of head if neurological signs 
or symptoms suggestive of lymphomatous involvement are present. 
2.2.9 Electrocardiogram 
2.2.10 Radionuclide bone and PET scans as clinically indicated. 
2.2.11 Unilateral bone marrow aspiration and biopsy. 
2.2.12 Lumbar puncture for cell count, chemistry, cytology and flow cytometry 
2.3  REGISTRATION PROCEDURES 
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 faxed to 301-
480-0757.  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. 
3 
STUDY IMPLEMENTATION 
3.1 STUDY DESIGN 
This is a pilot trial of Alemtuzumab in combination with dose-adjusted EPOCH.  Three cohorts 
of three to six patients will be treated.  Patients in cohort 1 will receive 30 mg of Alemtuzumab.  
The second cohort, patients will receive 60 mg of Alemtuzumab and the final cohort will receive 
90 mg of Alemtuzumab.  Six to eight 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. For the purposes of dose-escalation of alemtuzumab the 


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13 
toxicity observed during the first cycle will be used to determine escalation.  All patients entered 
at a given dose level must have completed one cycle of treatment before the next dose level can 
begin.  If an eligible patient requires therapy before the next dose level of the protocol is 
available the patient will be entered at the current dose level and will be used in the 
determination of the maximum tolerated dose.  Toxicities observed during subsequent cycles will 
be used to determine the dose of Alemtuzumab that will be used in phase II trials.  
3.2 DRUG ADMINISTRATION (VIA CENTRAL CATHETER)  
3.2.1 
Dose-adjusted EPOCH-Alemtuzumab Chemotherapy (Section 11; Appendix 1): 
Cohort 1 – Alemtuzumab 30 mg  
Cohort 2 – Alemtuzumab 60 mg  
Cohort 3 – Alemtuzumab 90 mg  
3.2.2 
Table for dose-adjusted EPOCH regimen 
Drug  
Dose 
Route 
Treatment Days 
Infused Agents1  
 
 
 
   Alemtuzumab 
30, 60 or 90 mg 
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/bid  
PO 
day 0-54 
 
 
 
 
  Filgrastim 
480 mcg 
SC 
days 6 to ANC recovery 
t 5000/mm3 
Next Cycle  
 
                 
 
 
Day 21  
 
 
 
 
 
 
 
 
 
 
 
 
 
1Begin the infusional agents immediately after Alemtuzumab is administered. 
 
1Infusional agents should be administered through a central venous access device.  
 
2Administer cyclophosphamide immediately after infusions are completed. 
3Begin Prednisone the evening before start of infusional chemotherapy and Alemtuzumab 
with second dose given on the morning of alemtuzumab 
4 The last dose of prednisone is given on the morning of Day 5 (10 total doses of 60 mg/m2 
would be administered over 5 days). 


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14 
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 Alemtuzumab Infusion administration 
Premedicate 30-90 minutes before ALEMTUZUMAB infusion with   
x 650 mg acetaminophen PO 
x 50 mg diphenhydramine PO 
x 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 the 
evening before (evening of day 0) 
Patients will be treated with an escalating dose schedule of Alemtuzumab as detailed above.  
Patients should be premedicated as above.  Alemtuzumab will be administered intravenously 
over twelve hours.  If infusional toxicities are observed the infusion may be stopped for up to 60 
minutes and resumed when toxicity has 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.   
3.2.5 
Definition of Maximum Tolerated Dose (MTD) 
If one of the three patients entered at a given dose-level experiences dose-limiting toxicity, up to 
three additional patients will be entered at that dose level. If 2 of 6 patients experience DLT at a 
particular dose level, the MTD has been exceeded. The preceding dose level will be the MTD, 
provided 6 patients have been entered at this level and no more than one has experienced DLT.  
3.2.6 
Definition of Dose-Limiting Toxicity 
Infusional toxicities such as fever, chills, hypotension, shortness of breath, throat-tightness, or 
abdominal pain are common with monoclonal antibodies.  Dose-limiting toxicity will be defined 
as grade 3 allergic toxicity (bronchospasm with wheezing, hypoxia and/or dyspnea) , any grade 3 
non-hematologic toxicity lasting longer than 6 hours after infusion is completed or any grade 4 
non-hematologic toxicity (except grade 4 dyspnea).  If any grade 5 toxicity occurs the trial will be 
placed on hold to further patient accrual until the toxicity and plan for management for all 
patients is clarified.  Patients who experience grade 3 non-hematologic toxicity may be retreated 
if the toxicity resolves to grade 1 or less before the next scheduled dose of treatment. If the 


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alemtuzumab toxicity does not resolve to grade 1 or less within 28 days from day 1 of treatment, 
the alemtuzumab will be removed from protocol treatment.  Patients who experience infusional 
DLT may be retreated at the next cycle at the next lower dose level.  If a patient experiences DLT 
at the first dose level, alemtuzumab will be discontinued on future cycles. 
3.3 TREATMENT MODIFICATIONS 
3.3.1 
ALEMTUZUMAB (toxicity probably or definitely related) 
Discontinue Alemtuzumab for: 
x Grade 4 non-hematologic toxicity other than easily correctable metabolic 
toxicities or infection  
x Grade 3 infusional dose-limiting toxicity 
Reduce Alemtuzumab one dose level for:  
x Grade 3 non-hematologic toxicity that does not resolve to ≤ grade 1 by the 
time the next administration of alemtuzumab is scheduled, except grade 3 
infectious complications.   
x Grade 4 neutropenia that persists for 3 or more biweekly measurements 
(maximum of approximately 10 days of neutropenia) despite G-CSF 
therapy.  
x Grade 4 thrombocytopenia that persists for 3 or more biweekly measurements 
(maximum of approximately 10 days). 
3.3.2 
EPOCH Dose Adjustments:  
HEMATOLOGICAL TOXICITY 
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. 
Dose-Adjustment Paradigm  
 
 
 
 
 
 
 
 
 
 
 
 
x Dose adjustments above starting dose level (level 1) apply to etoposide, doxorubicin and 
cyclophosphamide 
x Dose adjustments below starting dose level (level 1) apply to cyclophosphamide only.  
x Drug Doses based on previous cycle ANC nadir: 
¾ 
If Nadir ANC t 500/Pl on all measurements:          n 1 dose level  above last cycle  
¾ 
If Nadir ANC  500/Pl on 1 or 2 measurements:        Same dose level as last cycle   
¾ 
If Nadir ANC  500/Pl t 3 measurements:              p 1 dose level below last cycle 
Or 
¾ 
    If nadir platelet  15,000/Pl on 1 measurement:       p 1 dose level below last cycle.  


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x 
If ANC t 1000/Pl and platelets t 75,000/Pl on day 21, begin treatment. 
x 
If ANC < 1000/Pl or platelets < 75,000/Pl on day 21, delay up to 1 week.  G-CSF 480 mcg 
every day may be started for ANC < 1000/Pl and stopped 24 hours before treatment.  If 
counts still low after 1 week delay, p 1 dose level below last cycle 
x 
Important: Measurement of ANC nadir based on twice weekly CBC only (3 days 
apart).  Only use twice weekly CBC for dose-adjustment, even if additional CBC’s are 
obtained.  
NON-HEMATOLOGICAL TOXICITY 
a. Sensory neuropathy  
Grade  
 
 
% Dose of Vincristine 
   
  
2 
 
 
 
 
100 
   
 
3 
 
 
 
 
50 
b. Motor neuropathy 
Grade 
 
 
% Dose of Vincristine 
   
   
1 
 
 
 
 
100 
   
   
2 
 
 
 
 
75 
   
   
3 
 
 
 
 
25 
   
   
4 
 
 
 
 
0 
c. Hepatic dysfunction 
Bilirubin on Day 1 %  Dose of Vincristine 
 
 
1.5-3.0  
 
 
75 
    
       >3.0 
 
 
 
50 
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.  If the patient has severe ileus requiring hospitalization, reduce 
vincristine by 25%.   


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3.4 ON STUDY EVALUATION 
3.4.1 Day 1 all cycles and day 21 last cycle: CBC/differential; electrolytes; mineral panel; AST, 
ALT, Bilirubin and LDH.  
3.4.2 At the beginning of each cycle, and near Day 21 of the last cycle: CMV PCR, CD4, CD8 
and NK cell counts. 
3.4.3 During cycles: CBC/differential BIW.  
3.4.4 Restaging: Day 21, cycles 4 and 6 and 8 (if administered).  Repeat all initially positive 
staging tests. 
3.4.5  Up to 50 cc of blood may optionally be drawn for immunological testing, evaluation of 
hematologic parameters, or other studies that become clinically important during conduct 
of the trial.  (However, this should not be drawn if it brings the total amount of blood 
drawn to more than 450 ml during a 6-week period.)  
3.4.6 16cc of blood in light blue citrate tubes or blue and black cell preservation tube (CPT) for 
polymerase chain reaction to define T cell receptor gene rearrangement 
3.5 CONCURRENT THERAPIES (CONTINUED FOR 2 MONTHS POST-TREATMENT)  
3.5.1 Pneumocystis carinii prophylaxis: Recommend Trimethoprim 160 
mg/sulfamethoxazole 800 mg PO BID 3x/week.  Alternatives include Dapsone 50 - 100 
mg PO qd or 100 mg PO 2x/week; aerosolized pentamidine.  
3.5.2 Herpes Simplex prophylaxis for herpes virus infection will be given (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 therapy. 
3.5.4 Prophylactic Central Nervous System Treatment.   All patients who have bone 
marrow or disseminated bone involvement, or > 1 extranodal site and an elevated LDH 
will receive prophylactic CNS treatment with intrathecal methotrexate on the following 
schedule: methotrexate 12 mg IT on day 1 and 5 of cycles 3, 4, 5 and 6 (total of 8 
treatments). 
3.5.5 Treatment of Meningeal Lymphoma. If the CSF is positive for malignant cells at the 
start of therapy, the CSF should be treated with methotrexate and/or cytarabine as soon as 
possible. Induction- intrathecal methotrexate (6 mg by Ommaya or 12 mg by lumbar 
route) or cytarabine (70 mg by Ommaya or lumbar route). Administer induction treatment 
twice a week for 2 weeks past negative cytology with a minimum of 4 weeks treatment. 
Consolidation-Following induction, change therapy frequency to weekly x 6.  
Maintenance- Following consolidation, change therapy frequency to monthly x 4. Due to 
unforeseeable events, the above therapy may be modified as clinically indicated.  In some 
cases, it may be necessary to administer radiation to the head and/or spine.  
3.6 POST-STUDY EVALUATION 


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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 the next three years, and yearly 
thereafter. 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 All patients will be followed, at restaging visits, with CMV PCR levels until the CD4 
count is greater than 200 
3.7 CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA 
3.7.1 
Criteria for removal from protocol therapy 
x 
Institution of another therapy 
x 
Patient non-compliance. 
x 
Patient voluntary withdrawal.  
x 
Excessive toxicity (as defined in section 3.2.6)  
3.7.2 
Off-Study Criteria 
x 
Participant requests to be withdrawn from study 
x 
Death 
3.7.3 
Off Protocol Therapy and Off Study Procedure 
Authorized staff must notify Central Registration Office (CRO) when a subject is taken off 
protocol therapy and when a subject is taken off-study. A Participant Status Updates Form from 
the web site (http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) main page must be 
completed and sent via encrypted email to:  NCI Central Registration Office 
ncicentralregistration-l@mail.nih.gov. 
4 
SUPPORTIVE CARE 
4.1 PNEUMOCYSTIS CARINII PNEUMONIA   
Patients who develop PCP will receive standard of care including trimethoprim-
sulfamethoxazole, steroids when appropriate and alternative standard agents such as IV 
Pentamidine, atovaquone, or trimetrexate in combination with leucovorin when TMP-sulfa 
cannot be used. 
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. 


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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  
Central venous access is 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. 
5 
DATA COLLECTION AND EVALUATION 
5.1 DATA COLLECTION   
Data will be prospectively collected and entered into the NCI database.  
The principal investigator, associate investigators/research nurses and/or a contracted data 
manager will assist 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 AEs, including clinically significant abnormal findings on laboratory evaluations, regardless 
of severity, will be followed until satisfactory resolution. Patients will be followed for adverse 
events for 30 days following the last dose of study drug or until off-study, whichever comes first.  
An abnormal laboratory value will be considered an AE if the laboratory abnormality is 
characterized by any of the following: 
x 
Results in discontinuation from the study 
x 
Is associated with clinical signs or symptoms  
x 
Requires treatment or any other therapeutic intervention 
x 
Is associated with death or another serious adverse event, including hospitalization.  
x 
Is judged by the Investigator to be of significant clinical impact 
x 
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. 
End of study procedures: Data will be stored according to HHS, FDA regulations, and NIH 
Intramural Records Retention Schedule as applicable.  


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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. 
Exceptions for data collection/recording on case report forms:   
x All adverse events that represent known reactions of grade 1 toxicity will not be recorded 
in the database.   
5.2 RESPONSE CRITERIA  
Response criteria for lymphomas: 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):  t 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 t 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, nonresponders) requires the following: ≥ 50% increase from nadir in the 
SPD of any previously identified abnormal node for PRs or nonresponders. 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. 
5.3 TOXICITY CRITERIA 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 3.0 will be utilized for adverse event reporting.  All 


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21 
appropriate treatment areas should have access to a copy of the CTCAE version 3.0.  A list of 
adverse events that have occurred or might occur (Reported Adverse Events and Potential Risks) 
can be found in Section 9 (Pharmaceutical Information).  A copy of the CTCAE version 3.0 can 
be downloaded from the CTEP web site (http://ctep.cancer.gov/reporting/ctc.html).  
6 
STATISTICAL CONSIDERATIONS   
Determination of sample size: This is pilot study to evaluate the feasibility of administration of 
Alemtuzumab in combination with EPOCH infusional chemotherapy. The primary objective of 
this study is to evaluate the overall and hematologic toxicities of this combination.  Previous 
administration of steroids and/ or other biologic therapy is unlikely to affect these parameters. 
There will be a maximum of 24 patients in this trial, with three to six patients treated in each 
cohort examining different doses of Alemtuzumab with treatment of an additional 6 patients at 
the maximum tolerated dose.  Thus, a total of 12 patients will be treated at the maximum 
tolerated dose. It is assumed that 10 patients per year will be accrued to this trial, and that all 
accrual can be achieved within 2.5 years.  As it is a secondary objective, the small number of 
patients treated at the MTD will have clinical responses reported based on criteria stated in 
section 5.2.  
To date, the patients enrolled on the study have been from three principal histologies: AITL (4), 
PTCL (6) and HTLV-1 ATLL (7). We are interested in obtaining a limited amount of additional 
data on the progression free survival and response durations in patients in each of the three most 
prominent types of histologies enrolled to date. To do so, the study will be amended to allow up 
to 15 additional patients to be enrolled at the 30 mg alemtuzumab dose level, with the goal of 
obtaining approximately 5 more patients from each of the three main categories and thereby 
obtaining an improved estimate of the outcome parameters. These estimates will be useful in 
planning the subsequent study and the additional patients will also allow better information on 
toxicity to be obtained, and to allow patients to continue to be enrolled on a study with these 
agents pending the opening of a subsequent trial.  Thus, the new accrual ceiling is 39 patients. 
At this point there have been no patients among the 18 treated who developed bone marrow 
aplasia at the 30 mg dose level of alemtuzumab.  If two or more cases of bone marrow aplasia 
occur in the remaining cohort of patients treated at this dose level, the study will be placed on 
hold to accrual and future plans discussed with the IRB.  
7 
HUMAN SUBJECTS PROTECTION  
7.1 RATIONALE FOR SUBJECT SELECTION 
All subjects from both genders and all racial/ethnic groups are eligible for this study if they meet 
the eligibility criteria outlined in Section 2.1.  To date, there is no information that suggests that 
differences in drug metabolism or disease response would be expected in one group compared to 
another.  Efforts will be made to extend accrual to a representative population, but in this 
preliminary study, a balance must be struck between patient safety considerations and limitations 
on the number of individuals exposed to potentially toxic and/or ineffective treatments on the one 
hand and the need to explore gender and ethnic aspects of clinical research on the other hand.  If 
differences in outcome that correlate to gender or to ethnic identity are noted, accrual may be 
expanded or a follow-up study may be written to investigate those differences more fully. 


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7.2 PARTICIPATION OF CHILDREN 
Patients of at least 17 years of age will be eligible. T-cell lymphomas are infrequently curable 
with standard treatment.  This study may provide increased clinical benefit compared to standard 
approaches and would be appropriate for a patient of 17 years.  However, younger patients have 
not been included at this time because of the rarity of these diseases in this age group.  Where 
deemed appropriate by the clinician and the child’s parent(s) or guardian, the child will also be 
included in all discussions about the trial and age-appropriate language will be used to describe 
the procedures and tests involved in this study, along with the risks, discomforts and benefits of 
participation.  Written assent will not be obtained from children as the study holds out the 
prospect of direct benefit that is important to the health and well-being of the child and is 
available only in the context of the research. Verbal assent was obtained as appropriate for 
children age 17 and the parent or guardian signed the designated line on the informed consent 
attesting to the fact that the child gave assent.  We request waiver of the two patient signatures 
for consent because both parents may not be able to accompany the patient.   
7.3 PARTICIPATION OF SUBJECTS UNABLE TO GIVE CONSENT 
Adults unable to give consent are 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 a prospect of direct benefit from 
research participation (Section 7.4), all subjects ≥ age 18 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” form so that another person can 
make decisions about their medical care in the event that they become incapacitated or 
cognitively impaired during the course of the study. 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 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. 
7.4 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.  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. 
7.5 RISKS/BENEFITS 
Patients eligible for this protocol will be subject to the toxicity associated with EPOCH 
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 


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that is not seen when either is given alone.  The long-term outcome for T cell lymphoma is 
particularly poor with about 25% of low risk patient surviving at 5 years and virtually all patients 
with advanced disease dying in this interval.  Combining EPOCH with Alemtuzumab may 
produce increased immune suppression and myelosuppression.  The risk/benefit analysis for 
adults with the capacity to consent, as well as for adults who may become unable to provide 
consent, and for children is greater than minimal risk with the prospect of direct benefit based on 
the risks and potential benefits described in Section 7.4. 
7.6 CONSENT AND ASSENT PROCESS AND DOCUMENTATION 
All patients are thoroughly screened for eligibility prior to admission onto this study.  During this 
time the patient, along with family members, will be presented with a detailed description of the 
treatment.  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.  
7.6.1 
Telephone consent for reconsent only 
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 and a copy of the informed consent document and note will be kept in the subject’s 
research record. 
8 
SAFETY REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING 
PLAN 
8.1 DEFINITIONS 
8.1.1 
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. 
8.1.2 
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 


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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. 
8.1.3 
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. 
8.1.4 
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. 
8.1.5 
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: 
x 
Death, 
x 
A life-threatening adverse drug experience 
x 
Inpatient hospitalization or prolongation of existing hospitalization 
x 
Persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
x 
A congenital anomaly/birth defect. 
x 
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. 
8.1.6 
Disability 
A substantial disruption of a person’s ability to conduct normal life functions. 
8.1.7 
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. 
8.1.8 
Protocol Deviation (NIH Definition) 
Any change, divergence, or departure from the IRB-approved research protocol.   


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8.1.9 
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. 
8.1.10 
Unanticipated Problem 
Any incident, experience, or outcome that: 
x 
 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 
x 
Is related or possibly related to participation in the research; AND 
x 
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. 
8.2 NCI-IRB AND CLINICAL DIRECTOR REPORTING 
8.2.1 
NCI-IRB and NCI CD Expedited Reporting of Unanticipated Problems and Deaths 
The Protocol PI will report to the NCI-IRB and NCI Clinical Director: 
x 
All deaths, except deaths due to progressive disease  
x 
All Protocol Deviations 
x 
All Unanticipated Problems 
x 
All non-compliance 
Reports must be received within 7 days of PI awareness via iRIS. 
8.2.2 
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: 
x All Grade 2 unexpected events that are possibly, probably or definitely related to the 
research;  
x All Grade 3 and 4 events that are possibly, probably or definitely related to the 
research;  
x All Grade 5 events regardless of attribution;  
x All Serious Events regardless of attribution.  


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NOTE: Grade 1 events are not required to be reported.  
9 
PHARMACEUTICAL INFORMATION 
EPOCH/Filgrastim 
9.1 ETOPOSIDE/DOXORUBICIN/VINCRISTINE ADMINISTRATION  
These drugs are commercially available.  Stability studies conducted by the Pharmaceutical 
Development Service, Pharmacy Department, NIH Clinical Center, have demonstrated that 
admixtures of vincristine, doxorubicin, and etoposide in 0.9% Sodium Chloride Injection, USP 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 and 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 degrees C. 
Etoposide, doxorubicin, and vincristine will be combined in a single (‘3-in-1’) admixture, diluted 
in a volume of 0.9% Sodium Chloride (NS), Injection, USP, that is based on the amount of 
etoposide needed to complete 24 hours of treatment.  If etoposide < 150 mg per 24 hours, then 
dilute drugs in 500 mL 0.9% sodium chloride; if etoposide > 150 mg per 24 hours, then dilute 
drugs in 1000 mL 0.9% sodium chloride.  Etoposide, doxorubicin and vincristine will be 
administered as a 96 hour continuous IV infusion.  The chemotherapy will be administered with 
a suitable infusion pump via a central venous access device.  Temporary PICC lines or permanent 
lines may be used. Extravasation of these diluted agents has not caused local tissue damage due 
to their low concentrations in the solution. Interruption of the infusions should be avoided expect 
during the time it takes to change the daily cassette.   
Doxorubicin causes myelosuppression. Other toxicities include;  cardiac toxicity which may 
occur at low doses, but significantly increases at total doses  > 550 mg/m2, nausea, vomiting, 
stomatitis , diarrhea and alopecia.  Skin infiltration causes tissue necrosis.  Etoposide  toxicities 
include nausea, vomiting, stomatitis, diarrhea, neutropenia, thrombocytopenia and alopecia. 
Secondary AML has been associated with this drug.  Vincristine causes neurological toxicities 
with paresthesias, jaw pain, ataxia, foot-drop, cranial nerve palsies, paralytic ileus, constipation, 
abdominal pain, and loss of deep tendon reflexes.  It is also a vesicant, and occasionally causes 
alopecia and myelosuppression. 
9.2 CYCLOPHOSPHAMIDE ADMINISTRATION 
Commercially available as a lyophilized powder in  2 gram vials.  Reconstitution with 100 ml 
of sterile water for injection in final concentration of 20 mg/ml.  Cyclophosphamide will be 
diluted in 100 ml of D5W or NS and infused over 15 minutes.  Patients will be instructed to 
drink an adequate amount of fluids and empty their bladders frequently during cyclophosphamide 
administration.  Cyclophosphamide causes myelosuppression, nausea, vomiting, gastrointestinal 
toxicity and hemorrhagic cystitis.  Maintaining good hydration and urinary output during the use 
of this drug may prevent this latter toxicity. Secondary AML has been associated with this drug. 
9.3 PREDNISONE 
Commercially available in a variety of solid and liquid dosage forms.  Tablet strengths include: 
1, 2.5, 5, 20, and 50 mg and the oral solution contained 1 mg/ml.  Prednisone 60 mg/m2 will be 
administered orally on days 0 to 5.  The prednisone starts on the evening of Day 0, with two 


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doses being consumed before the first alemtuzumab dose.  In patients unable to tolerate oral 
medication, methylprednisolone can be substituted at an equivalent dose, diluted in 25 ml of NS, 
and infused over 15 minutes.  Prednisone frequently causes gastritis, immunosuppression, 
muscle wasting, fluid retention and hyperglycemia. To reduce gastrointestinal side effects, 
prednisone should be taken with food  
9.4 FILGRASTIM (G-CSF) 
is a commercially available recombinant human protein produced by Amgen Corp., Thousand 
Oaks, CA, and marketed under the brand name Neupogen.   It is provided in either 1 ml vials 
(300 mcg) or 1.6 ml vials (480 mcg). Intact vials should be stored in the refrigerator (2-8 degrees 
C); do not freeze. Do not dilute with sodium chloride solutions.  Filgrastim is stable for at least 1 
year when refrigerated.  The product is suitable for SC or direct IV injection.  Filgrastim will be 
administered at doses of 300 mcg/day (Pediatric dose 5 mcg/kg/day to a maximum of 300 
mcg/day) as a subcutaneous injection starting on day 6 and continuing until the AGC t 5000.  
Dose adjustments will be allowed as clinically indicated. 
9.5 ALEMTUZUMAB (CAMPATH®)  
Alemtuzumab will be supplied by the clinical center pharmacy.  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, colorless, isotonic 
solution free from visible particulate matter.  Alemtuzumab is available for intravenous or 
subcutaneous use in ampoules containing 30 mg of antibody in 3 ml of sterile phosphate buffered 
saline  
Storage and preparation for injection of Alemtuzumab: Alemtuzumab should be stored at a 
temperature of 2-8qC and protected from light.  Prepare Alemtuzumab for IV infusion within 
four hours of administration.  The required dose should be drawn up into a syringe from the 
ampoule and further diluted in 100 ml of 0.9% sodium chloride or 5% dextrose, USP.  The 
resulting solution should be within the concentration range of 20-4800 Pg/ml.  Alemtuzumab 
must be filtered prior to administration. Note: Alemtuzumab must be filtered with a sterile, low-
protein binding, non-fiber releasing 5 micron filter when removing the dose from the ample. 
Stability:  Alemtuzumab was physically and chemically stable at room temperature for up to 24 
hours after dilutions at concentrations between 20 and 4800 Pg/ml in 0.9% sodium chloride and 
5% dextrose infusion bags.  However, since the product does not contain any preservative it must 
be used within 8 hours of preparation.  In static conditions (no flow) and low concentrations (20 
Pg/ml) of Alemtuzumab in 0.9% sodium chloride, IV administration sets caused a detectable 
reduction in Alemtuzumab concentration that was not demonstrated in the higher concentration 
(4800 Pg/ml) in either sodium chloride or 5% dextrose.  
Method of 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/m2 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 every 15 minutes times 4 or until stable and then 
hourly until the infusion is discontinued.   


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Special handling: No special precautions are warranted.  Empty and partial ampoules should be 
disposed of as biological waste.  
Alemtuzumab 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.  
Main Adverse Events: 
x Infusional reactions occur in most patients.  They commonly consist of rigors, fever, 
headache, nausea, vomiting and diarrhea, rash, pruritis, dyspnea and hypotension. Acute 
infusional reaction may also include chills, abdominal and back pain, Bronchospasm, 
angioedema, tachyarrythmia etc.  These reactions are most prominent during the first week 
of alemtuzumab administration and improve with subsequent treatments.   To reduce the 
frequency and severity of the first dose reaction, a step-up dose escalation schedule and 
proper premedication should be used (see “method of administration” above) 
x Hematologic: Anemia, neutropenia, thrombocytopenia, prolonged and profound 
lymphopenia 
x 
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: 
x Body as a whole: Allergic reaction, rigors, fever, chills, headache, back and abdominal 
pain, infection, fatigue 
x Cardiovascular: Hypertension, hypotension, tachycardia, Atrial arrhythmia, ventricular 
tachycardia, angina and myocardial infarction, peripheral vasoconstriction 
x Digestive: anorexia, nausea, vomiting, diarrhea, constipation, dyspepsia, liver function 
abnormality 
x Hematological: Neutropenia, lymphopenia, thrombocytopenia, anemia, DIC, hemolysis, 
eosinophil disorder, bleeding (GI, gum, ecchymosis) 
x Muscular Skeletal: Myalgia, Arthritis, bone pain, hypotonia, tremor  
x Metabolic and nutritional: Tumor lysis syndrome, acidosis 
x Nervous system: Dizziness, confusion, somnolence, peripheral neuropathy, Cerebral 
hemorrhage, speech disorder, mental status changes, paresthesia, syncope, depression, 
aphasia  
x Pulmonary: Bronchospasm, cough, Pleural effusion, pulmonary edema, interstitial 
pneumonitis   
x Skin/subcutaneous: Angioedema, facial flushing, diaphoresis, pruritis, rash, urticaria, 
injection site reaction (subcutaneous route) 
x Urogenital: Hematuria, oliguria, polyuria, urinary retention, urinary tract infection, 
impotence  


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x Tinnitus 
9.6 DIPHENHYDRAMINE  
Diphenhydramine will be supplied from commercial sources by the clinical center pharmacy.  
Diphenhydramine hydrochloride, is an antihistamine drug having the chemical name 2-
(Diphenylmethoxy)-N,N-dimethylethylamine hydrochloride and has the empirical formula 
C17H21NO·HCl. It occurs as a white, crystalline powder and is freely soluble in water and alcohol 
and has a molecular weight of 291.82.  Each diphenhydramine HCl capsule contains 25 mg or 50 
mg diphenhydramine hydrochloride for oral administration.  The most frequent adverse reactions 
are underscored.  General: Urticaria, drug rash, anaphylactic shock, photosensitivity, excessive 
perspiration, chills, dryness of mouth, nose, and throat.  Cardiovascular System: Hypotension, 
headache, palpitations, tachycardia, extrasystoles.  Hematologic System: Hemolytic anemia, 
thrombocytopenia, agranulocytosis.  Nervous System: Sedation, sleepiness, dizziness, disturbed 
coordination, fatigue, confusion, restlessness, excitation, nervousness, tremor, irritability, 
insomnia, euphoria, paresthesia, blurred vision, diplopia, vertigo, tinnitus, acute labyrinthitis, 
neuritis, convulsions.  GI System: Epigastric distress, anorexia, nausea, vomiting, diarrhea, 
constipation.  GU System: Urinary frequency, difficult urination, urinary retention, and early 
menses.  Respiratory System: Thickening of bronchial secretions, tightness of chest and 
wheezing, nasal stuffiness.  The dose of diphenhydramine is 50 mg, administered orally before 
each infusion of alemtuzumab to help prevent allergic reactions.  
9.7 ACETAMINOPHEN  
Acetaminophen will be supplied from commercial sources by the clinical center pharmacy.  
Acetaminophen, 4'-hydroxyacetanilide, is a non-opiate, non-salicylate analgesic and antipyretic 
which occurs as a white, odorless, crystalline powder, possessing a slightly bitter taste.  It has the 
following molecular formula C8H9NO2  with a molecular weight of 151.16.  No significant 
adverse reactions are expected but patients will be monitored for hepatic toxicity.  The dose of 
acetaminophen is 650 mg, administered orally before each infusion of alemtuzumab to help 
prevent inflammatory responses. 
9.8 TRIMETHOPRIM/SULFAMETHOXAZOLE  
Trimethoprim/sulfamethoxazole will be supplied from commercial sources by the clinical center 
pharmacy.  More common side effects may include: Hives, lack or loss of appetite, nausea, skin 
rash, vomiting.  Less common or rare side effects may include: Abdominal pain, allergic 
reactions, anemia, chills, convulsions, depression, diarrhea, eye irritation, fatigue, fever, 
hallucinations, headache, hepatitis, inability to fall or stay asleep, inability to urinate, increased 
urination, inflammation of heart muscle, inflammation of the mouth and/or tongue, itching, joint 
pain, kidney failure, lack of feeling or concern, lack of muscle coordination, loss of appetite, low 
blood sugar, meningitis (inflammation of the brain or spinal cord), muscle pain, nausea, 
nervousness, red, raised rash, redness and swelling of the tongue, ringing in the ears, scaling of 
dead skin due to inflammation, sensitivity to light, severe skin welts or swelling, skin eruptions, 
skin peeling, vertigo, weakness, yellowing of eyes and skin.  The dose of 
trimethoprim/sulfamethoxazole is one tablet twice daily for three days each week. 
9.9 FLUCONAZOLE  
Fluconazole will be supplied from commercial sources by the clinical center pharmacy.  The 
most common side effect is nausea.  Less common side effects may include: Abdominal pain, 


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diarrhea, headache, skin rash, vomiting.  The dose of fluconazole is 200 mg orally daily.  
Fluconazole should not be given during EPOCH infusional chemotherapy because of 
pharmacologic interactions 
9.10 METHOTREXATE  
Commercially available folic acid antagonist, and only the preservative-free preparation may be 
used for intrathecal injection.  It should be stored at 15-30qC and protected from light. Prior to 
intrathecal or intraventricular injection, the prescribed dose of methotrexate should be 
reconstituted/diluted with preservative-free 0.9% sodium chloride to a total volume of 3 to 5 mL. 
 Prepared methotrexate doses should be utilized within 4 hours of preparation.  Toxicities:  It can 
cause leukopenia, and as such leucovorin may be administered 24 hours after each dose.  It can 
cause headaches, drowsiness, and blurred vision.  It can also cause a transient acute neurologic 
syndrome manifested by confusion, hemiparesis, seizures, and coma. 
9.11 CYTARABINE  
A commercially available pyrimidine nucleoside antimetabolite, and should be stored at –15-
30qC, and used within 2 years of the date of manufacture.  Prior to intrathecal injection it is 
reconstituted with preservative free 0.9% sodium chloride, and should utilized within 4 hours of 
preparation.  Prior to intrathecal or intraventricular injection, the prescribed dose of cytarabine 
should be reconstituted/diluted with preservative-free 0.9% sodium chloride to a total volume of 
3 to 5 mL Toxicities:  It can cause myelosuppression, fever, dizziness, somnolence, and 
arachnoiditis. 


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10 REFERENCES 
1.  Wing MG, Moreau T, Greenwood J, Smith RM, Hale G, Isaacs J, Waldmann H, Lachmann 
PJ, Compston A: Mechanism of first-dose cytokine-release syndrome by CAMPATH 1-H: 
involvement of CD16 (FcgammaRIII) and CD11a/CD18 (LFA-1) on NK cells. J Clin.Invest 
98: 2819-2826, 1996 
2. Harris NL, Jaffe ES, Stein H, Banks PM, Chan JK, Cleary ML, Delsol G, Wolf-Peeters C, 
Falini B, Gatter KC: A revised European-American classification of lymphoid neoplasms: a 
proposal from the International Lymphoma Study Group [see comments]. Blood 84: 1361-
1392, 1994 
3. A clinical evaluation of the International Lymphoma Study Group classification of non-
Hodgkin's lymphoma. The Non-Hodgkin's Lymphoma Classification Project. Blood 89: 
3909-3918, 1997 
4.  Gisselbrecht C, Gaulard P, Lepage E, Coiffier B, Briere J, Haioun C, Cazals-Hatem D, Bosly 
A, Xerri L, Tilly H, Berger F, Bouhabdallah R, Diebold J: Prognostic significance of T-cell 
phenotype in aggressive non-Hodgkin's lymphomas. Groupe d'Etudes des Lymphomes de 
l'Adulte (GELA). Blood 92: 76-82, 1998 
5.  Lopez-Guillermo A, Cid J, Salar A, Lopez A, Montalban C, Castrillo JM, Gonzalez M, 
Ribera JM, Brunet S, Garcia-Conde J, Fernandez dS, Bosch F, Montserrat E: Peripheral T-
cell lymphomas: initial features, natural history, and prognostic factors in a series of 174 
patients diagnosed according to the R.E.A.L. Classification. Ann.Oncol. 9: 849-855, 1998 
6.  Melnyk A, Rodriguez A, Pugh WC, Cabannillas F: Evaluation of the Revised European-
American Lymphoma classification confirms the clinical relevance of immunophenotype in 
560 cases of aggressive non-Hodgkin's lymphoma. Blood 89: 4514-4520, 1997 
7.   Ansell SM, Habermann TM, Kurtin PJ, Witzig TE, Chen MG, Li CY, Inwards DJ, Colgan 
JP: Predictive capacity of the International Prognostic Factor Index in patients with peripheral 
T-cell lymphoma. J.Clin.Oncol. 15: 2296-2301, 1997 
 


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11 Appendix 1: EPOCH CHEMOTHERAPY 
 
Drug 
 
Total dose* 
(mg/m2/d) 
 
Route 
Day 
1  2  3  4     5    6                                                 22 
 
 
 
Alemtuzumab 
 
fixed total dose 
   
    IV 
   x 
 
 
 
30, 60 or 90 mg 
 
 
 
 
 
 
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 3.2 for dose escalations and 3.3.2 for dose modifications 
 
 


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


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ICF_002.pdf: 
MEDICAL RECORD 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
INSTITUTE: 
National Cancer Institute 
STUDY NUMBER: 
03-C-0304 
PRINCIPAL INVESTIGATOR: 
Wyndham H. Wilson, M.D., Ph.D. 
STUDY TITLE:  
Pilot Trial of Alemtuzumab and Dose-Adjusted Epoch in Chemotherapy Naïve 
Aggressive T and NK-Cell Lymphomas 
Continuing Review Approved by the IRB 05/20/20 
Amendment Approved by the IRB on 05/21/20 (I) 
      Date posted to web: 05/29/20 
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.   
Description of Research Study 
Lymphoma and its treatment:  You/your child have a disease called T-cell or NK cell non-
Hodgkin's lymphoma which your/your child’s doctors think would be better treated with 
chemotherapy than surgery or radiation.  For your/your child’s particular kind of non-Hodgkin's 
lymphoma, previous studies have shown that combinations of drugs are much more likely to 
make the disease go away for appreciable periods of time than single drugs, which have only 
very limited effectiveness against this group of lymphomas.  Studies have also shown that more 


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intensive (i.e. higher dose) treatments have a greater chance of success than more gentle 
approaches.   In general, mature T-cell and NK cell lymphomas are less responsive to standard 
therapies than B-cell lymphomas.  This protocol is specifically for people with T-cell and NK 
cell lymphomas, as we are trying to find better treatments for these types of lymphoma.  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.  We therefore plan to test 
this combination in patients who have never received chemotherapy previously.  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, a drug called Alemtuzumab (the trade name is Campath-1H), has been 
manufactured to attach to a protein called CD52 that your/your child’s type of tumor could 
contain.  We will attempt to determine if your/your child’s tumor “expresses” CD52, but 
you/your child will be eligible for treatment even if the results are unknown.  Up to 30 patients 
will be treated on this study. 
Objectives and design of this study:   
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 
alemtuzumab in combination with continuous infusion EPOCH chemotherapy with filgrastim is 
safe and if it improves the outcome of therapy of your/your child’s lymphoma.  In this study five 
chemotherapy drugs are given together in an intensive combination called EPOCH.  Each series 
of treatments is called a cycle; a cycle is repeated every three weeks and drugs are administered 
during the first five days of every cycle.  EPOCH consists of prednisone by mouth on days 1-5, 
and etoposide, doxorubicin, and vincristine as a continuous infusion on days 1 through 5 (total of 
96 hours).  In addition, cyclophosphamide is given by intravenous injection over about 15 
minutes on day 5.  You/your child will also receive a dose of alemtuzumab on day 1, 
immediately before the chemotherapy begins.  Each cycle lasts 3 weeks: 5 days of chemotherapy 
followed by 16 days of no chemotherapy.  You/your child will receive repeated cycles of 
Alemtuzumab and EPOCH until remission (disappearance of tumor) is achieved or until the 
tumor shows no further evidence of shrinkage.  Between cycles of treatment we give another 
drug, filgrastim, whose purpose is to help your/your child’s normal bone marrow cells recover 
from the chemotherapy and produce normal white cells.  The use of filgrastim in this way may 
help us increase the total amount of chemotherapy you/your child can receive. 
Treatment consists of the following drugs: 
1. 
Doxorubicin, etoposide, and vincristine - These three drugs are given by continuous IV 
infusion over four days, beginning on day 1 and ending on day 5 of each cycle.  We 
deliver these drugs with the aid of one lightweight, portable infusion pump, each about 
the size of a portable tape recorder; this permits treatment on an outpatient basis.  The 


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pumps deliver the therapy through an intravenous catheter, which is placed in your/your 
child’s vein beforehand.  You/your child will be taught about the use and care of the 
pump and what to do if it stops working.  
2. 
Cyclophosphamide - This is given over about 15 minutes on day 5 of each treatment 
cycle. 
3. 
Prednisone - These are pills given by mouth twice a day for the first 5 days of every 
cycle. 
4. 
Alemtuzumab – Administered by vein over approximately twelve hours on the first day 
of therapy, immediately before the chemotherapy infusion begins. 
5. 
Filgrastim - This is given by injection under the skin once a day starting on day 6 of each 
cycle and continuing until recovery of the white blood cell count or until day 19 of each 
cycle.  If your/your child’s white blood cell count is still very low on the day treatment is 
due to begin again, the chemotherapy may be deferred and the filgrastim will be given 
until you/your child have a fuller recovery of the white count. This drug is given to 
stimulate your/your child’s bone marrow to produce neutrophils, one of your/your child’s 
white blood cells.  You/your child will be taught how to administer the filgrastim to 
yourself/your child during the first treatment cycle. 
We expect that treatment will be given for 6 cycles (18 weeks), depending on how you/your 
child’s respond to the therapy.  In general you/your child will receive two cycles past the point of 
maximum response.  Since several of these drugs can lower your/your child’s resistance to 
infection, we also require that you/your child take a combination antibiotic, 
trimethoprim/sulfamethoxazole (SeptraR or BactrimR) for three days each week while you/your 
child are on chemotherapy, acyclovir (or an alternative drug) daily and fluconazole in an attempt 
to prevent infections.  If allergic to these preparations, you/your child will be given other drugs 
with similar activities in their place.   
What happens after treatment is completed: 
This depends on how you/your child have responded to the therapy.  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 gets worse while receiving therapy, does not disappear 
entirely or if it should recur after having disappeared for a period of time, then you/your child 
may need further therapy.  At that time you/your child will be given the opportunity of 
participating in additional research protocols that may be appropriate for you/your child.  If no 
such protocols are available, you/your child will be returned to the care of your/your child’s local 
physician.  It is important to stress that participation in this protocol does not constitute a 
promise of long-term medical care here at the Clinical Center.  It is conceivable that participation 
in this study may make you/your child ineligible to participate in certain other research protocols 
because the requirements for entry onto these protocols may not allow patients who have already 
been treated with certain drugs or who have had certain side effects from previous treatment.  


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You/your child may decide now not to receive treatment on this protocol, or you/your child may 
choose at any point in time to stop the treatment and withdraw from the protocol; in either case 
you/your child will be returned to the care of your/your child’s referring physician. 
Treatment of disease in the nervous system:   
It occasionally happens that lymphomas spread to the coverings of the brain (the meninges) at 
some point during the illness. We will test to see whether there is any evidence of lymphoma in 
your brain or spinal fluid before you receive any treatment.   If this should happen, the treatment 
usually includes the instillation of one of two chemotherapy drugs (methotrexate and cytarabine) 
directly into the fluid (the cerebrospinal fluid, or CSF) surrounding the brain.  This is usually 
done by first placing a small reservoir (an Ommaya reservoir) under the skin of the scalp; this 
reservoir is connected to a catheter that is placed through the brain itself into the fluid.  This 
procedure is performed by a neurosurgeon under general anesthesia.  These drugs may also be 
administered through a spinal tap (also called a lumbar puncture).  Depending on how you/your 
child responds to this therapy, it may be necessary to modify it and to also administer radiation to 
your/your child’s brain and spinal cord.  Each of these therapies will be discussed with you/your 
child if they are needed.  Patients who have lymphoma in their bone marrow are at higher risk of 
developing lymphoma in the brain areas.  To reduce this risk, patients at higher risk will receive 
methotrexate by a spinal tap on days 1 and 5 of cycles 3-6 of their EPOCH chemotherapy.  
Your/your child’s treating physicians will discuss this with you/your child. 
Risks or Discomforts of Participation 
In order to determine whether this study is suitable for you/your child, a number of tests will 
have to be done.  This period of evaluation may take up to two weeks and is usually done on an 
outpatient basis.  Depending on the tests you/your child have already had before coming here, 
these may include blood and urine tests, studies of lung function, CAT or MRI scans, 
radioisotope scans, and biopsies of tumor tissue, bone marrow, liver, or other sites.  As reviewed 
in the section above, you will undergo a lumbar puncture to remove a small amount of spinal 
fluid (about 1-2 teaspoons) that 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.   
Biopsies will, when possible, be done under local anesthesia.  The risks associated with blood 
draws include pain, blood clots, bruises, infection and nerve damage.  The risks associated with 
bone marrow biopsies include pain, bleeding, and infection.  Risks of biopsies include pain, 
bleeding, infection, and the risks to the particular area undergoing surgery.  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/your child in more detail at 
the time of surgery, if this is needed. 


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In order to receive this therapy you/your child will need to have an intravenous catheter placed.  
This catheter is usually placed in the arm, chest or neck area into a major vein inside your/your 
child’s chest.  We usually remove the catheter after each cycle but on occasion it can be left in 
for several cycles.  The catheter is necessary for infusion of chemotherapy and for the drawing of 
blood.  It is usually inserted under local anesthesia.  The risks associated with the procedure 
include pain, bleeding, infection, and puncture of the underlying lung. Lung puncture can result 
in lung collapse, which might require that a chest tube be placed into the chest cavity (usually for 
a day or two) to help the lung reinflate.  The long-term risks of the catheter include infection and 
clotting of the vein in which the catheter sits.  If these occur, it may be necessary to remove the 
catheter.  These risks will be explained to you/your child in more detail at the time of the 
insertion.  
Side effects that have been observed with the drugs in this program when they are used 
individually include the following: 
a. 
Doxorubicin may cause sore mouth, loss of hair, a fall in blood counts with increased risk 
of serious infection or bleeding, tissue damage if the drug contacts the skin, heart damage 
and, rarely, death due to heart failure.  However, the infusion method used in this study 
has been shown to reduce the risk of heart damage compared to the standard rapid 
infusion method. 
b. 
Cyclophosphamide may cause a fall in blood counts with increased risk of serious 
infection or bleeding, loss of hair, damage to the lining of the urinary bladder with 
painful and bloody urination, loss of function of the ovaries or testes, and nausea and 
vomiting.  The bladder irritation can be minimized by drinking at least two quarts of fluid 
each day. Fluid retention with lowering of blood salt levels (known as SIADH) can rarely 
occur.  
c. 
Vincristine often causes numbness of the hands and feet after several cycles.  Patients 
also may have constipation and medications will be given to reduce this.  In most 
instances, these symptoms resolve when the drug is stopped, but resolution of the 
numbness in the hands and feet may sometimes take months or even years.  The drug can 
also cause tissue damage if it contacts the skin, low or high blood pressure, frequent or 
burning on urination, weight loss, rash, fever, headache, jaw pain and eye problems. 
Fluid retention with lowering of blood salt levels (known as SIADH) can rarely occur. 
d. 
Etoposide may cause nausea and vomiting, diarrhea, loss of hair, lowering of blood 
pressure during administration, rash, itching, liver abnormalities, allergic reactions, 
mouth ulcers, and lowering of blood counts. 
e. 
Alemtuzumab has a spectrum of side effects that can be divided into infusional reactions, 
immune suppression, bone marrow toxicity, and other side effects.  These reactions are 
detailed below. 
 


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Acute infusion reactions  
Some patients have reactions during the first few treatments that do not occur with later infusions 
of Alemtuzumab.  The administration of Alemtuzumab can cause allergic reactions which may 
appear as shortness of breath or wheezing.  If the shortness of breath becomes severe, you/your 
child may be required to have a tube placed in your/your child’s throat to help you/your child 
breath.  Other types of allergic-like possibilities include severe lowering of blood pressure, fever, 
chills, rash, hives, itching, or abdominal pain and throat swelling.  Lowering of the blood 
pressure may cause damage to the heart or brain and this damage may be permanent.  These 
reactions can be severe and some patients have died as a result of such reactions.  You/your child 
will be given acetaminophen and diphenhydramine to reduce the severity of these side effects.  
Your/your child’s doctors or nurses will closely monitor you/your child closely throughout the 
treatment for these side effects.   
Immune suppression  
The normal cells that fight infection in your/your child’s body are killed by this treatment.  
Without these cells you/your child may develop infections that occur in patients whose immune 
system does not function.  Patients treated with this drug can develop infection with viruses, 
fungi, parasites and bacteria.  You/your child will be treated with oral medications to prevent 
certain infections and they will be continued until your/your child’s doctors have determined that 
it is safe to discontinue them.   
Bone marrow toxicities 
Many patients have had low blood counts when Alemtuzumab is given at the doses used in this 
trial.  These effects are even more severe when Alemtuzumab is given to patients with bone 
marrow abnormalities.  Anemia or a low red blood cell count, which causes weakness or fatigue 
has occurred and may require blood transfusion.  Low platelet counts, which may cause a 
tendency to bleed, may require platelet transfusions and low white blood cell counts may make 
you/your child susceptible to infection.  If the infection fighting white blood cells fall to low 
levels we may give you/your child G-CSF to stimulate the production of these cells.  Occasional 
patients have had severe depression of all of the normal blood elements, a condition called 
aplasia.   
Miscellaneous toxicities 
Other common side effects include loss of appetite, nausea, vomiting, fatigue, headache, 
diarrhea, muscle or joint pain, ringing in the ears, difficulty with thinking, and damage to the 
liver.  Blood pressure has been seen to increase following administration of Alemtuzumab and 
may require treatment.  Your/your child body may react to the Alemtuzumab by making 
antibodies to it.  These antibodies may rapidly inactivate the injected Alemtuzumab making it 
ineffective. Infections caused by organisms that normally inhabit your/your child body and cause 
no disease may become evident as a result of the treatment with Alemtuzumab.  You/your child 


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may also be more susceptible to viral and bacterial infection.  In addition the combination of 
Alemtuzumab and EPOCH chemotherapy may produce toxicities that are unknown. 
f. 
Prednisone may cause ulceration in the stomach or bowel, increased blood pressure, high 
blood sugar (diabetes), increased risk of infection, a round appearance of your/your 
child’s face, weight gain, change in mood, thinning of your/your child’s bones with 
increase in the risk of fracture, increased pressure in the eye (known as glaucoma) and 
clouding of the eye (called cataracts).  It can also cause or worsen acne. 
g. 
Filgrastim can occasionally cause bone pain by stimulating normal bone marrow.  This 
stops when drug administration stops.  It has also been reported sometimes to cause skin 
rash, skin reddening around the injection site, muscle cramps, decreased platelets (not 
clinically significant), pain or numbness and tingling around the chin, worsening of 
certain pre-existing inflammatory conditions (such as psoriasis eczema, or vasculitis), 
fever, body aches, and alterations in certain laboratory tests.  With prolonged 
administration filgrastim has been associated with hair thinning and enlargement of the 
spleen. These side effects do not necessarily stop when drug treatment stops. 
h. 
Trimethoprim/sulfamethoxazole can cause a skin rash that goes away when the drug is 
stopped. It is possible that the rash may not resolve and could indicate a severe reaction 
(i.e. Stevens-Johnson syndrome). If you/your child are allergic to this drug, you/your 
child will receive inhaled pentamidine instead. Inhaled pentamidine can cause coughing, 
wheezing, and burning pain in the throat.  All of these symptoms usually go away shortly 
after the inhalation treatment is finished 
i. 
Acyclovir can cause nausea/vomiting, diarrhea, headache, vertigo, insomina, irritability, 
depression, skin rash, acne. accelerated hair loss, arthralgia, fever, palpitations, sore 
throat, muscle cramps, menstrual abnormalities, and lymphadenopathy. 
j. 
Fluconazole can cause nausea.  Less common side effects may include: Abdominal pain, 
diarrhea, headache, skin rash, vomiting and elevated liver enzymes. 
k. 
Methotrexate, when administered into the spinal fluid, may cause low blood counts and 
ulcerations in the mouth, stomach, and intestines.  It can cause acute headache, back pain, 
stiff neck, and /or fever; it can also cause weakness or paralysis of certain muscles.  It can 
cause seizures and coma.  Other side effects it can cause are usually associated with 
intravenous administration rather than intrathecal (lumbar puncture administration), but 
these include liver function abnormalities, inflammation and scarring of the lungs, 
inflammation of the tissue covering the heart, and severe skin reactions.   
l. 
Cytarabine given by lumber puncture can cause nausea, vomiting, fever, and headaches.  
Rarely, it can cause weakness and seizures.  When given into the spinal fluid, it does not 
usually cause systemic toxicity, but we will monitor you/your child for low blood counts, 
and liver function abnormalities, which can occur with cytarabine when given by vein. 


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It is important to emphasize that when you/your child have a decreased white blood cell count, 
you/your child are at risk of infection.  Such infections can be very serious and can even cause 
death if not quickly and properly treated.  Therefore, if you/your child have a temperature greater 
than 38.3° C (101° F), you/your child must call your doctor immediately.  Chemotherapy may 
also cause your platelets to fall; since platelets are the blood elements that permit blood to clot, 
this may place you/your child at increased risk of serious bleeding.  It may be necessary to give 
you/your child transfusions of platelets if your/your child’s platelet counts reach very low levels.  
You/your child may also need red blood cell transfusions if your/your child’s hemoglobin level 
drops very low. There is a small chance that damage to the normal bone marrow may eventually 
result in bone marrow failure, leading to a serious shortage of one or more kinds of cells in the 
blood, or to leukemia.  Because this is a relatively new combination of drugs, it is always 
possible that unanticipated side effects may occur. 
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.  These drugs 
may also be very toxic to an unborn child.  Therefore, adequate birth control measures (such as 
the contraceptive pill, condoms, diaphragm with contraceptive foam or ointment, contraceptive 
sponge, etc.) should be used by participants or their sexual partners while receiving treatment on 
this study.  Women of childbearing age will have a pregnancy test, which must be negative at the 
time of study entry.  This test requires that blood be drawn from a vein one or two days prior to 
the study.  The results of the pregnancy test will be made available to you/your child prior to the 
initiation of the study.  Your/your child’s physicians will watch you/your child closely for side 
effects and will stop treatment if any side effects become a serious threat to your/your child’s life 
or well-being.  Your/your child’s physicians will also stop the treatments if it becomes clear that 
the treatment is not successfully controlling your/your child’s disease.  Complications of 
Ommaya insertion are uncommon when done by an experienced group but could include 
infection and bleeding at the operative site or in the brain itself.  Complications of lumbar 
puncture may include pain or bleeding at the site of needle insertion (the low back), infection, 
and headache.  Most patients tolerate this treatment without serious side effects, although drugs 
placed into the brain fluid (CSF) may cause headache, stiff neck, and confusion that resolve 
when they are stopped.  With long-term treatment, confusion and a slowing of thought processes 
may occur.  If this treatment becomes necessary for you/your child, the complications of the 
lumbar puncture or Ommaya insertion and methotrexate instillation will be discussed in more 
detail. 
Potential Benefits of Participation 
It is likely that most patients will have at least a temporary improvement from treatment with 
Alemtuzumab and EPOCH chemotherapy.  However, we cannot be certain if you/your child will 


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be cured of your/your child’s lymphoma and it is possible that you/your child may not respond to 
treatment. 
Alternative Approaches or Treatments  
It should be emphasized that we do not know at this point whether the combination of drugs we 
propose to give you/your child is superior, inferior, or equivalent to standard combination 
chemotherapy for your/your child’s disease.  Alternative procedures that could be used to treat 
your/your child’s disease include: 
1.  
Other combination drug regimens and other schedules of the same drugs used in this 
study.  For example, a chemotherapy called CHOP given in the conventional manner 
would be suitable standard therapy for your/your child’s condition. 
2.  
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. 
3.  
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.  
4.  
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. 
5. 
Waiting, without active therapy.  Although a period of watchful waiting is appropriate 
treatment for some kinds of tumors, in lymphomas similar to yours/your child’s, the 
disease will often grow and spread rapidly if no treatment is administered.  
6.  
No treatment.  You/your child can choose not to receive any therapy for your/your child’s 
lymphoma.  In this case, your/your child’s doctor can give you/your child’s medications 
that will make you/your child feel comfortable.   
Research Subject's Rights 
What are the costs of taking part in this study?  
x 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.  


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x 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. 
x Medicines that are not part of the study treatment will not be provided or paid for by the 
Clinical Center, NIH. 
x 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: 
x 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. 
x 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:  
x will be used for auditing or program evaluation internally by the NIH; or  
x must be disclosed to meet the legal requirements of the federal Food and Drug 
Administration (FDA).  
x is necessary for your medical treatment and you have consented to this disclosure;  
x 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 


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: 03-C-0304 
CONTINUATION: page 11 of 13 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. 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.  
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 and 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 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/or 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: 03-C-0304 
CONTINUATION: page 12 of 13 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 
Wyndham H. 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: 03-C-0304 
CONTINUATION: page 13 of 13 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 MAY 20, 2020 THROUGH MAY 19, 2021.  
 
 
 
 
 
 
 
 
Signature of Investigator 
Date 
Signature of Witness 
Date 
 
 
Print Name 
 
 
Print Name