Clinical trial NCT01445535
Conditions: T-Cell Peripheral Lymphoma Gamma Delta Hepatosplenic T-Cell Lymphoma Subcutaneous Panniculitis-Like T-Cell Lymphoma NK T-Cell Lymphoma
Keywords: CD2 Positive Toxicity EBV Lymphoma Chemotherapy Naive Maximum Tolerated Dose Lymphoma T-Cell Lymphoma NK T-Cell Lymphoma
Sponsor: National Cancer Institute (NCI)
Start date: 2009-01-13; Completion date: 2020-10-22
Enrollment: 15 participants; Allocation: NA; Intervention model: SEQUENTIAL

Brief summary:
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 of six chemotherapy drugs, known as Etoposide, Prednisone, Vincristine, Cyclophosphamide, Doxorubicin, Rituximab (EPOCH-R), has had a high degree of effectiveness in people with certain kinds of cancer. Recent evidence also indicates that the effects of chemotherapy may be improved by combining the treatment with monoclonal antibodies, which are purified proteins that are specially made to attach to foreign substances such as cancer cells. This protocol is specifically for adults with the types of cancer known as T-cell and Naturel Killer (NK)-cell lymphomas, who have never received chemotherapy previously. The additional monoclonal antibody in the study, called siplizumab, has been manufactured to attach to the cluster of differentiation 2 (CD2) protein contained in these types of tumors.

Study volunteers will need to undergo an initial period of evaluation that may take up to 3 weeks and may be done on an outpatient basis. Evaluation may include some or all of the following tests: blood and urine tests, tests of lung and heart function, lumbar punctures to take samples of cerebrospinal fluid, magnetic resonance imaging (MRI) or computerized tomography (CT) scans, full-body positron emission tomography (PET) scans, bone marrow biopsies, and biopsies of suspected tumor areas.

During the study, patients will receive EPOCH-R chemotherapy, which includes the following drugs: etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab. The additional drug, siplizumab, will be given by IV infusion on the first day of treatment over several hours. When the siplizumab intravenous (IV) infusion is complete, the drugs doxorubicin, etoposide, and vincristine will each be given by continuous IV infusion over the next 4 days (that is, continuously for a total of 96 hours). When this infusion is completed, the drugs rituximab and cyclophosphamide will be given by IV infusion over several hours on Day 5. Prednisone will be given by mouth twice each day for 5 days. Patients may be given other drugs to treat the side effects of chemotherapy and to prevent possible infections.

The siplizumab-EPOCH-R therapy will be repeated every 21 days, which is known as a cycle of therapy, for a total of 6 cycles. Following the fourth and sixth treatment cycles (approximately weeks 12 and 18) of siplizumab-EPOCH-R, study researchers will perform blood tests and CT/MRI scans on all patients to assess their response to the treatment.

Detailed description:
Background:

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.

The combination of alemtuzumab and Etoposide, Prednisone, Vincristine, Cyclophosphamide and Doxorubicin (EPOCH) chemotherapy was evaluated in patients with chemotherapy naive aggressive T and natural killer (NK) cell lymphoid malignancy. Dose-limiting bone marrow toxicity prevented escalation of the alemtuzumab dose.

Siplizumab is a humanized monoclonal antibody directed at cluster of differentiation 2 (CD2) that demonstrated activity in the treatment of relapsed/refractory T cell lymphoma, suggesting further development by combining with chemotherapy for untreated patients. Siplizumab caused Epstein-Barr Virus (EBV) lymphoproliferative disease in patients treated with a weekly schedule of administration.

Rituximab prevents the development of EBV lymphoproliferative disease in the allogeneic transplant setting and may be active in preventing EBV-related B cell lymphoma in other settings.

Objectives:

Determine the toxicity and maximum tolerated dose of siplizumab and dose-adjusted EPOCH rituximab chemotherapy in chemotherapy naïve CD2- expressing T and NK lymphoid malignancies.

Eligibility:

CD2-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.

Design:

Four dose levels of siplizumab will be evaluated to determine the toxicity profile and in a preliminary fashion, and its activity in combination with dose-adjusted EPOCH with rituximab.

Four dose levels of siplizumab will be explored, in cohorts of three to six patients each. Patients will receive 3.4, 4.8, 8.5, or 15 mg/kg of siplizumab on day 1 of therapy, followed by dose-adjusted EPOCH-rituximab chemotherapy days 1-5 every 3 weeks for a total of 6 cycles.

Arms: arm 1: siplizumab will be given with EPOCH (combo chemo) and rituximab every 21 days
Interventions: intervention 1: Rituximab intervention 2: Etoposide intervention 3: Siplizumab intervention 4: Prednisone intervention 5: Vincristine intervention 6: Cyclophosphamide intervention 7: Doxorubicin
Intervention descriptions: intervention 1: Rituximab will be given with siplizumab and etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin every 21 days intervention 2: Etoposide will be given with siplizumab and prednisone, vincristine, cyclophosphamide, doxorubicin and rituximab every 21 days intervention 3: Siplizumab will be given with etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin and rituximab every 21 days intervention 4: Prednisone will be given with siplizumab and etoposide, vincristine, cyclophosphamide, doxorubicin and rituximab every 21 days intervention 5: Vincristine will be given with siplizumab and etoposide, prednisone, cyclophosphamide, doxorubicin and rituximab every 21 days intervention 6: Cyclophosphamide will be given with siplizumab and etoposide, prednisone, vincristine, doxorubicin and rituximab every 21 days intervention 7: Doxorubicin will be given with siplizumab and etoposide, prednisone, cyclophosphamide and rituximab every 21 days

Protocol documents:
Prot_SAP_000.pdf: 
Abbreviated Title: Siplizumab/EPOCH-R in T/NK NHL 
NCI Version Date: 11/21/2018 
 
 
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 Abbreviated Title: Siplizumab/EPOCH-R in T/NK NHL 
 
NCI Protocol #: 09C0065 H 
 
Version Date:  11/21/2018 
 
NCT Number: NCT01445535 
 
 
Phase I Trial of Siplizumab and Dose-Adjusted EPOCH-Rituximab (DA-EPOCH-R)  
in T and NK-Cell Lymphomas 
 
 
NCI Principal Investigator:  Wyndham H. Wilson, M.D., Ph.D. A-F 
Lymphoid Malignancies Branch (LYMB) 
Center for Cancer Research (CCR) 
National Cancer Institute (NCI) 
National Institutes of Health (NIH) 
Building 10, Room 4N115 
Bethesda, MD 20892 
Phone:  240-760-6092 
Email: wilsonw@mail.nih.gov 
 
 
Investigational Agent: 
Drug Name: 
Siplizumab 
IND Number: 
103970 – IND withdrawn 01-22-2013 
Sponsor: 
Dr. Thomas Waldmann 
Manufacturer: MedImmune  
 
Commercial Agents: 
Etoposide, Prednisone, Vincristine, Cyclophosphamide, Doxorubicin, Rituximab 
   


Abbreviated Title: Siplizumab/EPOCH-R in T/NK NHL 
NCI Version Date: 11/21/2018 
 
 
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PRÉCIS 
Background:  
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. 
x The combination of alemtuzumab and EPOCH chemotherapy was evaluated in patients 
with chemotherapy naïve aggressive T and NK cell lymphoid malignancy. Dose-limiting 
bone marrow toxicity prevented escalation of the alemtuzumab dose.  
x Siplizumab is a humanized monoclonal antibody directed at CD2 that demonstrated 
activity in the treatment of relapsed/refractory T cell lymphoma, suggesting further 
development by combining with chemotherapy for untreated patients. Siplizumab caused 
EBV lymphoproliferative disease in patients treated with a weekly schedule of 
administration. 
x Rituximab prevents the development of EBV lymphoproliferative disease in the 
allogeneic transplant setting and may be active in preventing EBV-related B cell 
lymphoma in other settings  
Objective:  
x Determine the toxicity and maximum tolerated dose of siplizumab and dose-adjusted 
EPOCH rituximab chemotherapy in chemotherapy naïve CD2-expressing T and NK 
lymphoid malignancies.  
Eligibility:  
x CD2-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.  
Design:  
x Four dose levels of siplizumab will be evaluated to determine the toxicity profile in a 
preliminary fashion and its activity in combination with dose-adjusted EPOCH with 
rituximab.  
x Four dose levels of siplizumab will be explored in cohorts of three to six patients each. 
Patients will receive 3.4, 4.8, 8.5, or 15 mg/kg of siplizumab on day 1 of therapy, 
followed by dose-adjusted EPOCH-rituximab chemotherapy days 1-5 every 3 weeks for a 
total of 6 cycles.  


Abbreviated Title: Siplizumab/EPOCH-R in T/NK NHL 
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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 
Rationale for this trial ..................................................................................................... 11 
2. 
ELIGIBILITY ASSESSMENT AND ENROLLMENT ....................................................... 13 
2.1 
Eligibility Criteria .......................................................................................................... 13 
2.2 
Screening Evaluation...................................................................................................... 13 
2.3 
Registration Procedures.................................................................................................. 14 
3. 
STUDY IMPLEMENTATION ............................................................................................. 14 
3.1 
Study Design .................................................................................................................. 14 
3.2 
Drug Administration (Via Central Catheter) .................................................................. 15 
3.3 
Treatment Modifications ................................................................................................ 19 
3.4 
Pharmacokinetics and Immunogenicity ......................................................................... 21 
3.5 
On Study Evaluation ...................................................................................................... 22 
3.6 
Concurrent Therapies ..................................................................................................... 24 
3.7 
Criteria for Removal from Protocol Therapy and Off Study Criteria ............................ 24 
3.8 
Post-Treatment Evaluation ............................................................................................. 25 
4. 
CONCOMITANT/SUPPORTIVE CARE ............................................................................. 25 
4.1 
Pneumocystis Jiroveci Pneumonia ................................................................................. 25 
4.2 
CMV Antigenemia ......................................................................................................... 25 
4.3 
Febrile Neutropenia ........................................................................................................ 25 
4.4 
Symptomatic Anemia ..................................................................................................... 25 
4.5 
Thrombocytopenia ......................................................................................................... 25 
4.6 
Central Venous Access................................................................................................... 25 
5. 
CORRELATIVE STUDIES FOR RESEARCH ................................................................... 26 
5.1 
Sample Storage, Tracking and Disposition .................................................................... 26 
6. 
DATA COLLECTION AND EVALUATION ..................................................................... 27 
6.1 
Data Collection ............................................................................................................... 27 
6.2 
Response Criteria ........................................................................................................... 28 
6.3 
Toxicity Criteria ............................................................................................................. 29 
7. 
SAFETY REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING PLAN
 
29 
7.1 
Definitions ...................................................................................................................... 29 


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7.2 
NIH Intramural IRB IRB and Clinical Director Reporting ............................................ 31 
7.3 
Expedited Adverse Event Reporting Criteria to the IND Manufacturer ........................ 32 
7.4 
Data and Safety Monitoring Plan ................................................................................... 32 
8. 
STATISTICAL CONSIDERATIONS .................................................................................. 32 
9. 
COLLABORATIVE AGREEMENTS .................................................................................. 33 
9.1 
Cooperative Research and Development Agreement (CRADA) ................................... 33 
10. 
HUMAN SUBJECTS PROTECTIONS ............................................................................ 34 
10.1 
Rationale for Subject Selection .................................................................................... 34 
10.2 
Participation of Children .............................................................................................. 34 
10.3 
For Adults who may be become Unable to Consent .................................................... 34 
10.4 
Evaluation of Benefits and Risks/Discomforts ............................................................ 35 
10.5 
Risks/Benefits Analysis................................................................................................ 35 
10.6 
Consent Process and Documentation ........................................................................... 35 
11. 
PHARMACEUTICAL INFORMATION .......................................................................... 35 
11.1 
Doxorubicin HCL (Adriamycin PFS™, Adriamycin RFS™, Rubex®) ...................... 36 
11.2 
Etoposide (VePesid®, Epidophyllotoxin, VP-16) ....................................................... 37 
11.3 
Etoposide Phosphate .................................................................................................... 38 
11.4 
Vincristine sulfate (VCR, Leurocristine sulfate, Oncovin®, Vincasar PFS) ................ 39 
11.5 
Cyclophosphamide (Cytoxan®; Neosar®) .................................................................... 40 
11.6 
Prednisone (Deltasone, miscellaneous) ........................................................................ 41 
11.7 
Rituximab ..................................................................................................................... 41 
11.8 
Filgrastim ..................................................................................................................... 42 
11.9 
Siplizumab (IND #103970 – withdrawn 1/22/13) ....................................................... 43 
11.10 
Methotrexate ........................................................................................................... 44 
11.11 
Cytarabine ............................................................................................................... 45 
12. 
REFERENCES .................................................................................................................. 46 
13. 
APPENDICES ................................................................................................................... 48 
13.1 
APPENDIX 1: EPOCH-RS Chemotherapy ................................................................. 48 
13.2 
APPENDIX 2:  EPOCH Admixtures ........................................................................... 49 
13.3 
APPENDIX 3: Performance Status Criteria................................................................. 50 
 
 
 


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1. INTRODUCTION 
1.1 STUDY OBJECTIVES 
1.1.1 Primary Objective 
x Determine the toxicity and maximum tolerated dose of siplizumab and DA-EPOCH-
R chemotherapy in untreated CD2-expressing T and NK lymphoid malignancies 
1.1.2 Secondary Objectives 
x Determine in a preliminary fashion the anti-tumor activity of the combination of 
siplizumab and DA-EPOCH-R chemotherapy 
x Determine the time course of B, T, and NK cell depletion  
x Determine the time course of B, T and NK cell recovery  
x Monitor EBV reactivation and its association with the development of EBV 
lymphoproliferative disease    
1.2 BACKGROUND  
1.2.1 Siplizumab Background 
Siplizumab (MEDI-507) is a humanized IgG1N class monoclonal antibody that binds to the CD2 
receptor found on human T-lymphocytes (T-cells), natural killer (NK) cells, and thymocytes.  
The functional protein is composed of two approximately 50 kDa heavy chains (J1) and two 
approximately 25 kDa light chains (N) for a combined molecular weight of approximately 150 
kDa. Siplizumab was constructed using molecular techniques to insert the CD2 binding region 
(complementary determining regions: CDRs) from a characterized CD2 specific rat monoclonal 
antibody, BTI-322, developed by Bazin et al 1.  In an effort to reduce the potential for 
immunogenicity in humans, changes to the human framework of siplizumab have been kept at a 
minimum consistent with preservation of activity. Siplizumab has a binding coefficient 
determined by Scatchard analysis of 1-1.1 x 10-9 M. The number of CD2 binding sites varies; 
Jurkat cells have about 25,000 sites/cell and peripheral blood cells have about 7,500 sites/cell.   
In vitro studies have shown that siplizumab induces alloantigen hyporesponsiveness and causes 
deletion of T- and NK-cells in mixed lymphocyte reaction (MLR).  These properties have led 
siplizumab to be considered as an immuno-modulator in clinical settings where the suppression 
of T-cell reactivity may have clinical benefits such as psoriasis and other autoimmune diseases, 
graft-versus-host disease (GvHD), T-cell lymphoproliferative disorders, and in solid organ 
transplantation.  
1.2.2 Phase 1 Clinical Trial Experience 
The main therapeutic area of investigation in the siplizumab clinical program is cancer. 
Siplizumab has also been investigated in graft-versus-host disease (GvHD), renal transplantation, 
and psoriasis.  In the GvHD and renal transplantation programs, high-dose, short duration 
regimens (1-2 weeks) of siplizumab were evaluated in four Phase 1 studies for treatment of T-
cell mediated pathophysiology in GvHD following hematopoietic stem cell transplantation and 
graft rejection in renal transplantation.  In the autoimmune disease program, extended dosing 
regimens (1-4 months) of siplizumab have been evaluated in four Phase 1 studies and in three 
Phase 2 studies for immune modulation of chronic inflammatory diseases, such as psoriasis; a 
follow-up observational study (MI-CP085) in psoriasis patients is ongoing.  Results of Phase 1/2 


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studies in patients with GvHD and psoriasis did not warrant further development of siplizumab 
for these diseases. 
In the cancer program, siplizumab has been investigated in two Phase 1 studies of similar design 
(MI-CP099 [NCI study] and MI-CP107 [multi-institutional study]) in patients with CD2-positive 
lymphoproliferative disorders. In these studies, patients have been treated with IV siplizumab at 
doses ranging from 0.4 to 8.5 mg/kg per treatment week using a variety of treatment schedules.   
In MI-CP099 22 patients received siplizumab at doses ranging from 0.4 to 4.8 mg/kg/week 
administered on an every other week schedule and 7 patients received siplizumab at doses 
ranging from 0.8 to 4.8 mg/kg/week on a weekly schedule of administration (O’Mahony et al., 
manuscript submitted).  The majority of the patients treated on the study had ATLL (15 pts) and 
LGL leukemia (7 pts).  Responses were observed in nine patients with two complete responses 
and seven partial remissions.   This change to a weekly schedule was made in order to increase 
the dose intensity because of evidence of tumor growth during the week off therapy.  In addition, 
toxicity was minimal consisting of grade 1/2 infusion reactions, primarily manifested as fever 
and chills, usually confined to the first dose of treatment and CMV reactivation without 
clinically apparent organ involvement. With the switch to the weekly schedule of siplizumab 
three of six patients treated with multiple doses of siplizumab developed Epstein-Barr virus 
(EBV) lymphproliferative disease (LPD), including two cases of EBV related lymphoma.  The 
initial 22 patient cases were reviewed and one case of EBV LPD was noted.  This case occurred 
nine months after completion of siplizumab therapy and was attributed to the agent that the 
patient was being treated with at that time, depsipeptide, which has also been associated with 
other cases of EBV LPD (Bates S, personal communication).   
MI-CP107 had an identical trial design to MI-CP099 and 22 patients were treated primarily with 
the biweekly schedule.  The majority of the patients treated on this study had PTCL and CTCL 
and again responses were observed.  The predominant toxicity has been Grade 1/2 infusion 
reactions.  One case of EBV LPD was observed on that study.  This occurred several months 
after discontinuation of siplizumab for progressive disease and at the time of development of 
EBV LPD the patient was receiving treatment for his underlying lymphoma.  Of these five 
patients who developed EBV related complications, three had EBV lymphoma; one responded to 
EPOCH-rituximab therapy but two died of complications related to lymphoma although both 
also had progressive T cell lymphoma.   Two patients had polymorphous EBV LPD; one 
responded to withdrawal of the siplizumab therapy and one responded to rituximab.  The risk of 
EBV LPD in MI-CP099 was increased with the weekly schedule of siplizumab administration 
with only one case among the 22 patients treated every other week whereas three of seven 
patients treated with the weekly schedule developed EBV LPD.  Although T cell depletion was 
similar with both schedules, two features differentiated the patients who developed EBV LPD 
from those that did not.  First, CD2 is downregulated by exposure to siplizumab and recovery of 
its expression requires about 7-10 days.  With chronic CD2 downregulation T cells may not be as 
reactive to EBV positive B cells that are reactivated.  Lymphocytes from mice deficient in CD2 
expression exhibit a profound defect in interferon gamma production and T cell proliferation in 
response to antigen stimulation although cytolytic T cell and NK cell function is not affected 2.   
Second, a more severe depletion of NK cells was observed in patients who developed EBV LPD.  
Based on these findings, the trials of siplizumab alone in T cell lymphoproliferative disease were 
discontinued because of safety concerns.        


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1.2.3 Use of rituximab to control EBV LPD  
The development of EBV LPD is a known complication of congenital or acquired 
immunodeficiency.  Patients undergoing solid organ or stem cell transplants, individuals with 
HIV infection and patients treated with immunosuppressive chemotherapies particularly patients 
with rheumatoid arthritis following treatment with methotrexate or patients with lymphoma 
treated with fludarabine, deoxycoformycin and cladrabine are candidates to develop this 
complication3-6.  Interestingly although alemtuzumab severely depletes T cells it is not generally 
associated with EBV LPD presumably because it simultaneously depletes B cells although a case 
of EBV LPD has recently been reported 7.  Transient EBV reactivation can be detected at early 
times after alemtuzumab administration but the level of EBV DNA  detected in the serum is  
relatively low and can be detected for about two weeks in most patients 8.  This observation 
suggests that a strategy to eliminate B cells in conjunction with T cell depletion may prevent the 
emergence of EBV LPD.  Rituximab has demonstrated activity in the treatment of EBV LPD 
particularly in patients whose disease is of recent onset where overall response rates of 44–75% 
and complete response rates of 35–69% are observed.9,10  In addition rituximab has been tested in 
a preemptive fashion in patients undergoing T cell depleted stem cell transplantation.  In this 
study patients who exhibited evidence of EBV reactivation as detected by monitoring plasma for 
EBV DNA at levels of greater than 1000 genome equivalents per milliliter of blood were treated 
with one infusion of rituximab11.   In this study of 49 patients, 17 developed EBV reactivation as 
described including two patients who had EBV LPD at the time the blood EBV DNA level 
reached the treatment threshold.  Treatment was effective in all but one patient who required 
additional rituximab and donor lymphocyte infusions to control the EBV LPD.  These 
observations suggest that EBV LPD can be prevented by early administration of rituximab and 
that its use prior to T cell depletion may improve this outcome. 
1.2.4 Therapy of T cell lymphoma 
The REAL classification has had a significant impact on the management of patients with 
lymphocytic neoplasms12.  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. 
 
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 199013.  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.   


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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.  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 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 14-16.  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 also emphasized the importance of the IPI score in outcome for patients with 
peripheral T cell lymphoma 17.  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 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 within 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.  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 


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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.   
Our first study to combine monoclonal antibodies with chemotherapy for T cell lymphoma used 
alemtuzumab and dose-adjusted EPOCH (DA-EPOCH) infusional chemotherapy to assess the 
maximum tolerated dose and safety in patients with CD52-positive aggressive NHL. A single 
infusion of alemtuzumab-1H (30, 60, or 90 mg) was given over 12 hours before each cycle of 
chemotherapy; patients were premedicated with prednisone 12 hours before the alemtuzumab 
infusion was initiated. DA-EPOCH was initiated immediately following completion of the 
alemtuzumab infusion. Toxicity during the first cycle of treatment was used to determine 
alemtuzumab dose escalation. Most patients experienced grade 1–2 allergic and infusional 
reactions manifested as fever, chills, and urticaria. Although not originally incorporated into the 
definition of dose-limiting toxicity, bone marrow suppression with reversible bone marrow 
aplasia prevented the administration of further treatment in 2 patients at the 60 mg dose level 
(cycle 3 and 5) and 2 pts at the 90 mg dose level (cycle 4 and 5) of alemtuzumab. Three of these 
four patients were CMV antigen positive and were treated with oral or intravenous gangcyclovir. 
Myelosuppression was common with this regimen but with the 30 mg dose of alemtuzumab 
myelosuppression was equivalent to that observed with EPOCH alone or in combination with 
rituximab.  We evaluated the ability to dose escalate EPOCH chemotherapy in patients treated 
with alemtuzumab and found that there was no significant difference in dose escalation or 
reduction with the regimen.  All but one patient developed grade 4 lymphopenia. Documented 
infections were common and included bacterial, fungal and viral pathogens. CMV antigen 
positivity during treatment was common and when detected inevitably required treatment.  
Another viral pathogen not commonly seen with EPOCH alone or with rituximab was 
hemorrhagic cystitis associated with BK virus infection in the urine that resolved despite 
continued treatment.  In addition, there was one death due to disseminated toxoplasmosis in a 
patient who developed an allergy to trimethoprim sulfamethoxazole and a second sudden death 
during EPOCH infusion that was thought to be related to a cardiac arrthymia.  The 30 mg dose 
level of alemtuzumab appears safe to administer in combination with DA-EPOCH and there has 
been no bone marrow suppression that prevented completion of therapy in any patient treated at 
the 30 mg dose of alemtuzumab.  Our preliminary results do not appear to be significantly better 
than chemotherapy alone and the inability to escalate the dose of alemtuzumab suggests that 
other antibodies that target T cells should be tested.  Siplizumab is of interest because of its 
limited infusional toxicity and its single agent activity in T cell malignancies.  Two recent studies 
have been published combining alemtuzumab with CHOP chemotherapy for the treatment of 
newly diagnosed T cell lymphoma.18,19  In the study conducted by Gallimini et al.20 24 patients 


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10 
(21 with PTCL-U, 6 angioimmunoblastic T cell lymphoma, 3 Alk negative anaplastic large cell 
lymphoma and 1 enteropathy-associated T cell lymphoma) were entered in a phase I study.  The 
initial four patients received four 30 mg doses of alemtuzumab with cycles 1-4 of therapy and the 
remaining patients received eight doses of alemtuzumab with each cycle of CHOP 
chemotherapy.  Complete remission was obtained in 17 patients (71%) and one had a partial 
remission.  The most frequent side effects were grade 4 neutropenia and cytomegalovirus 
reactivation.  Major infections included Jacob-Creutzfeldt reactivation, aspergillosis, and 
bacterial infections.  In the second study conducted by Kim et al.21, 20 patients were treated with 
alemtuzumab (30 mg per cycle) and CHOP chemotherapy for six cycles.  This study was 
terminated early due to two treatment-related deaths and a high incidence of adverse infectious 
and hematologic toxicities.  Similar to the Gallimini study, a high response rate was observed 
(80% overall response rate, 65% complete remission and 15% partial response).  Grade 4 
neutropenia occurred in 90% of patients and febrile neutropenia in over half of the subjects.  
CMV reactivation occurred in 5 patients and was associated with retinitis and pneumonia.          
In this study, we plan to use the lymphocyte specific monoclonal antibody siplizumab in 
combination with DA-EPOCH-rituximab chemotherapy in patients with peripheral T cell and 
NK cell lymphoma and no prior therapy.  Four dose levels of siplizumab will be explored, in 
cohorts of three to six patients each.  Patients will receive doses of 3.4, 4.8, 8.5 or 15 mg/kg of 
siplizumab on day 1 of therapy, followed by DA-EPOCH-R 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 
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 


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Consensus Diagnosis 
No. of Cases 
% of total cases 
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 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 lymphocyctic (CLL) 
76 
38 
35 
13 
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 
 
1.3 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.  Our phase I/II trial of dose-adjusted EPOCH chemotherapy with alemtuzumab showed 
that we were unable to increase the dose of alemtuzumab beyond 30 mg as a single infusion with 


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12 
each cycle of EPOCH and there were significant infectious complications.  This limited dose of 
alemtuzumab administered may be inadequate to penetrate lymph nodes whereas siplizumab 
which will be given at higher doses may permit administration of higher doses of antibody.  The 
major safety concern associated with administration of siplizumab is the development of EBV 
LPD.  We postulate that administration of rituximab in combination with siplizumab will prevent 
the development of EBV LPD and there will be a conservative stopping rule.  We will place the 
trial on hold if there is more than one case of EBV LPD in patients treated with this combination. 
This is a phase I study to determine the toxicity of siplizumab in combination with DA-EPOCH-
R infusional chemotherapy.  Four dose levels of siplizumab 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 siplizumab will be significantly reduced by the 
administration of steroids with dose-adjusted EPOCH.  The plan for siplizumab 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 siplizumab is to be given.  It is our intent to administer a 
maximum dose of 15 mg/kg of siplizumab in combination with dose-adjusted EPOCH-R at the 
highest dose level.   
 


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2. ELIGIBILITY ASSESSMENT AND ENROLLMENT 
2.1 ELIGIBILITY CRITERIA 
2.1.1 CD2-expressing lymphoid malignancy, confirmed by pathology or flow cytometry staff 
of the Hematopathology Section, Laboratory of Pathology, NCI.  At least 30% of the 
malignant cells must be CD2 positive for inclusion in this study.   
2.1.2 Patients with chemotherapy naïve 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 t18 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 (unconjugated hyperbilirubinemia without other known 
cause), 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 impairment by tumor. 
2.1.5 No active symptomatic ischemic heart disease, myocardial infarction or congestive heart 
failure within the past year. 
2.1.6 Patients must not have a marked baseline prolongation of QT/QTc interval (e.g., 
demonstration of a QTc interval >500 milliseconds (ms)). 
2.1.7 HIV negative, because of the unknown effects of combined therapy with chemotherapy 
and an immunosuppressive agent on HIV progression 
2.1.8 Signed informed consent by the patient or patient’s representative. 
2.1.9 Willing to use contraception 
2.1.10 Not pregnant or nursing, because of the unknown effects of DA-EPOCH-R or siplizumab 
on the developing fetus and infant. 
2.1.11 No serious underlying medical condition or infection that would contraindicate treatment.  
Patients with CNS involvement are eligible for treatment on this study. 
2.2 SCREENING EVALUATION  
Tests to be done within 4 weeks before study entry (prior to receiving any intervention); the 
laboratory tests in Sections 2.2.2, 2.2.7and 2.2.8 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 CD2 staining if 
accessible tissue is available. Where possible, tumor biopsies will be obtained by core 
needle biopsy or surgery pre-treatment.  Laparotomy, thoracotomy, or biopsy of 
relatively inaccessible lymph nodes (i.e. high axillary nodes) will only be performed if 
needed for definitive diagnosis and not for research purposes alone. 
2.2.4 Serology: HIV; hepatitis B surface and core antigen; hepatitis C; HTLV-1 and HSV 
serologies 
2.2.5 CMV, EBV and toxoplasmosis serologies 
2.2.6 CMV antigen by PCR, serum BK virus by PCR, EBV viral load 
2.2.7 Urinalysis and urine for BK virus by PCR 
2.2.8 Serum pregnancy test in women of childbearing potential. 
2.2.9 Imaging Studies: CT chest, abdomen, and pelvis; CT or MRI of head if neurological 
signs or symptoms suggestive of lymphomatous involvement are present. 
2.2.10 Electrocardiogram 
2.2.11 Radionuclide bone and PET scans as clinically indicated. 
2.2.12 Unilateral bone marrow aspiration and biopsy. 
2.2.13 Lumbar puncture for cell count, chemistry, cytology, 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 sent via 
encrypted email to:  NCI Central Registration Office ncicentralregistration-l@mail.nih.gov. 
After confirmation of eligibility at Central Registration Office, CRO staff will call pharmacy to 
advise them of the acceptance of the patient on the protocol prior to the release of any 
investigational agents. Verification of Registration will be forwarded electronically via e-mail to 
the research team. A recorder is available during non-working hours. 
3. STUDY IMPLEMENTATION 
3.1 STUDY DESIGN 
This is a phase I trial of siplizumab in combination with DA-EPOCH-R given every 21 days for 
a total of 6 cycles of treatment.  Four cohorts of three to six patients will be treated.  Patients in 
cohort 1 will receive 3.4 mg/kg of siplizumab.  Subsequent cohorts will receive 4.8, 8.5 and 15 
mg/kg of siplizumab. Six cycles of therapy will be administered based on clinical response 
evaluation.  If a patient has progressive disease at any point during therapy, he/she will be 
removed from protocol treatment. The toxicity observed during the first cycle of treatment will 


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15 
be used to determine the dose escalation of siplizumab.  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 lowest dose level that has been successfully completed without dose limiting 
toxicity in three or six patients.  If three patients have been entered and dose limiting toxicity 
occurs in this patient, two additional patients will be added to bring the total number of patients 
evaluated at the dose level to six, and accrual to the current dose level will be suspended.  If six 
patients have been entered and dose limiting toxicity occurs in this patient, accrual to the 
currently accruing dose level will be allowed to continue.  A delay in protocol accrual will thus 
be necessary only following the first dose level. Toxicities observed during subsequent cycles 
will be used to determine the dose of siplizumab that will be used in phase II trials.  
3.2 DRUG ADMINISTRATION (VIA CENTRAL CATHETER)  
3.2.1 Siplizumab DA-EPOCH-R Chemotherapy (Appendix 1): 
Siplizumab will be given on day 1 of each treatment cycle.  The volume of siplizumab to be 
infused and the minimum duration of infusion are given in Section 11.9.3. 
Cohort 1 – Siplizumab 3.4 mg/kg 
Cohort 2 – Siplizumab 4.8 mg/kg 
Cohort 3 – Siplizumab 8.5 mg/kg 
Cohort 4 – Siplizumab 15 mg/kg 
The patients’ baseline weight will be used to determine all doses of siplizumab.  Dosing will be 
adjusted if there is a change in weight greater than or equal to 10% during one cycle.  Patients 
will receive each treatment cycle until unacceptable toxicity, documentation of disease 
progression, completion of six cycles of therapy or other reasons for patient withdrawal, 
whichever comes first.   
Patients will be treated with an escalating dose schedule of siplizumab as detailed above.  
Patients should be premedicated as described in Section 3.2.4.  Siplizumab will be administered 
as described in Section 11.9.3. an IV infusion..   
If anaphylaxis (Grade 4) hypersensitivity reactions occur, further treatment with siplizumab will 
be discontinued.  Infusional reactions should be managed according to procedures outlined in 
Table 3. Meperidine 25 mg IV should be administered for treatment of patients with rigors. It is 
recommended that infusions should not exceed 24 hours in duration and administration should be 
controlled by a volumetric pump.   
Table 3:  Treatment Guidelines for Management of Siplizumab Infusion Reactions 
 
Treatment Guidelines 
Severity of Symptoms 
Siplizumab 
Mild  
x Stop siplizumab infusion until the patient is evaluated. 
x Following evaluation, the infusion may be restarted under observation and monitor 
subject; complete siplizumab infusion at the initial planned rate. 
x Additional diphenhydramine 25-50 mg oral may be administered at the discretion of the 
treating physician. Chills without rigors can be managed with warm blankets.  
Localized cutaneous reactions 
such as mild pruritus, flushing, 
rash and chills 
Moderate  
x Stop siplizumab infusion 


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Treatment Guidelines 
Severity of Symptoms 
Siplizumab 
Generalized pruritus, flushing, 
rash, dyspnea, fever, chills, 
rigors, and hypotension with 
systolic blood pressure >80 
mmHg  
x Administer diphenhydramine 50 mg IV and monitor patient until symptoms resolve. 
Resume siplizumab at one-half the initial infusion rate after recovery of symptoms; if 
symptoms develop after restarting the infusion, the infusion should be stopped and no 
additional siplizumab should be administered at that time. 
x Additional oral or IV antihistamine may be administered. A maximum dose of 
diphenhydramine of 100 mg in a 6 hour period should not be exceeded.  Rigors should 
be managed with IV meperidine 25 mg every 5-10 minutes to a maximum of 100 mg.  
x Give oral diphenhydramine, 50 mg and acetaminophen 650 mg 30 minutes prior to the 
next scheduled dose of siplizumab. 
 
Severe  
x Immediately stop siplizumab infusion 
x Bronchospasm, hypotension unresponsive to intravenous fluids, or angioedema may 
require administration of epinephrine 1 mg subcutaneously and/or diphenhydramine 50 
mg IV with methylprednisolone 100 mg IV or dexamethasone 20 mg IV, as needed, as 
well as supplemental oxygen. 
x Hypotension should be managed with intravenous fluids but if unresponsive may 
require more aggressive intervention such as phenylephrine infusion. 
x Monitor patient until resolution of symptoms.   
x Give oral diphenhydramine, 50 mg and acetaminophen 650 mg 30 minutes prior to the 
next scheduled dose of siplizumab 
 
Any reaction such as 
bronchospasm, generalized 
urticaria, angioedema, or systolic 
BP d80 mmHg) 
 
 
Anaphylaxis  
Defined as a reaction that is life 
threatening and requires pressor 
and/or ventilator support or 
shock associated with acidemia 
and impairing vital organ 
function due to tissue 
hypoperfusion 
x Manage as described above for severe reaction and discontinue further treatment with 
siplizumab 
 
3.2.2 Dose-Adjusted EPOCH-R regimen 
All patients initiate therapy at Dose Level 1 of DA-EPOCH-R shown below. Subsequent 
treatment doses are determined by hematological toxicity experienced on the previous cycle 
according to the dose-adjustment paradigm in Section 3.3.2. Dose adjustment is based on 
measurements of twice weekly CBC only (e.g., Monday and Thursday, or Tuesday and 
Friday), even if additional CBCs are obtained. 
Cycle 1 Doses 
Drug  
Dose 
Route 
Treatment Days 
Infused Agents1  
 
 
 
Siplizumab 
3.4, 4.8, 8.5 or 15 mg/kg 
IV 
day 1 
Rituximab5 
375 mg/m2 
IV 
day 5 
   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 


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1 Begin the rituximab immediately after EPOCH infusion has completed. For the first cycle of treatment, the 
EPOCH infusion may be infused on days 2-6 if the Siplizumab infusion is prolonged due to infusion reaction. 
Begin the infusional agents immediately after siplizumab infusion has completed. Infusional agents should be 
administered through a central venous access device.  
2 Administer cyclophosphamide immediately after infusions are completed over 30 minutes. 
3 Begin Prednisone the 8-12 hours before start of siplizumab with second dose given just prior to siplizumab. 
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). 
5 Rituximab is given as outlined in Section 11.7.4. 
3.2.3 Table of doses per level for adjusted agents:   
Drugs 
Drug Doses per Dose Levels 
-2 
-1 
1 
2 
3 
4 
5 
6 
Doxorubicin (mg/m2/day) 
10 
10 
10 
12 
14.4 
17.3 
20.7 
24.8 
Etoposide (mg/m2/day) 
50 
50 
50 
60 
72 
86.4 
103.7 124.4 
Cyclophosphamide (mg/m2/day) 
480 
600 
750 
900 
1080 
1296 
1555 
1866 
3.2.4 Premedication for Monoclonal Antibody Infusions  
Premedicate 30-90 minutes before Siplizumab infusion with   
x 650 mg acetaminophen PO 
x 25 mg diphenhydramine PO 
x 25 mg IV meperidine IV– first cycle required, subsequent cycles at PI discretion 
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 8-12 hours 
before siplizumab. 
For prevention of rigors, patients will receive 25 mg IV meperidine at the start of the first 
siplizumab infusion and thereafter only if medically necessary, unless the patient is allergic to 
meperidine.  If the patient tolerated the first dose of siplizumab with grade 2 or less adverse 
events associated with the infusion, siplizumab can be given 1 hour after initiating the 
prednisone on subsequent cycles. 
Prophylaxis for tumor lysis syndrome will be administered at the discretion of the Principal 
Investigator according to institutional practice.  Hydration and urine alkalinization will be 
administered according to the discretion of the Principal Investigator. 
Premedicate 30-60 minutes before rituximab infusion with  
x 650 mg acetaminophen PO 
x 25 mg diphenhydramine PO 
Rituximab infusion should begin immediately after the EPOCH infusion has completed and 
infuse over 4-5 hours as per Section 11.7.4.  There will be no dose adjustments for rituximab. 


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3.2.5 CNS Prophylaxis and Treatment 
3.2.5.1 CNS Prophylaxis 
Patients with (1) t 2 extranodal sites and elevated LDH, or (2) bone marrow involvement by 
lymphoma will receive CNS prophylaxis consisting of intrathecal methotrexate 12 mg on day 1 
(or day 2) of Cycles 3, 4, 5, and 6. 
3.2.5.2 Treatment of CNS Disease 
x Treatment of CNS Disease 
If the CSF is positive at the time of enrollment the patient should receive active 
treatment of the CSF with methotrexate (see below). If this treatment either is not 
tolerated or found to be not effective, then cytarabine alone or in combination with 
methotrexate may be used. Additionally, a brain MRI should be obtained and radiation 
consolidation administered at the end of chemotherapy if there are parenchymal lesions. 
x CNS Induction Treatment 
CNS induction treatment will be administered twice per week for two weeks beyond 
negative cytology with a minimum of 4 weeks of treatment. CNS induction may consist 
of one of the following: 
x Intrathecal methotrexate 12 mg or intraventricular (via Ommaya) methotrexate 
6 mg  
OR 
x Intrathecal or intraventricular (via Ommaya) cytarabine 70 mg 
OR 
x Intrathecal methotrexate 12 mg + cytarabine 30 mg or intraventricular (via 
Ommaya) methotrexate 6 mg + cytarabine 30 mg 
x CNS Consolidation Treatment 
CNS consolidation will consist of the same treatment as induction, but administered 
weekly x 6. 
x CNS Maintenance Treatment 
CNS maintenance will consist of the same treatment as induction, but administered 
monthly x 4. 
3.2.6 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.  
3.2.7 Definition of Dose-Limiting Toxicity 
Expected toxicities due to the DA-EPOCH-R chemotherapy regimen or support medication 
administration (as listed in the protocol or in the package inserts for commercial agents) will not 
be considered DLTs. Infusional toxicities such as fever, chills, hypotension, shortness of breath, 
throat-tightness, or abdominal pain are common with monoclonal antibodies and will not be 
considered DLTs unless the criteria below is met.  Grade 3 laboratory events will not be 


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19 
considered a DLT. Dose-limiting toxicity will be defined as at least possibly related to 
siplizumab and as:  
x any grade 3 non-hematologic toxicity lasting longer than 6 hours after infusion is 
completed  
x any grade 4 non-hematologic toxicity (except grade 3 or 4 dyspnea (unless intubation is 
required) and grade 4 uric acid).   
x development of an EBV LPD. 
Patients with rising EBV DNA levels should be evaluated for evidence of EBV LPD (CT and 
PET scan) but rising EBV DNA levels alone will not be considered a dose limiting toxicity.  
If any grade 5 toxicity related to siplizumab administration occurs the trial will be placed on hold 
to further patient accrual until the toxicity and plan for management for all patients is clarified.  
If more than one patient develops EBV-LPD the trial will be placed on hold until discussed with 
the FDA and IRB and a plan to permit additional accrual is formulated.   
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 excluding neurologic 
toxicity attributed to vincristine which will be handled as described in Section 3.3.2.2. If the 
siplizumab toxicity does not resolve to grade 1 or less within 28 days from day 1 of treatment, 
the siplizumab 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 reduced dose of siplizumab from Section 3.3.1, siplizumab will be discontinued on 
future cycles, but treatment with EPOCH-R will continue. 
3.3 TREATMENT MODIFICATIONS 
3.3.1 Siplizumab Dose Adjustments 
3.3.1.1 DLT 
If a patient experiences a DLT (defined in Section 3.2.7) while on treatment, subsequent doses 
will be modified as shown below.   
Siplizumab Dose Modifications 
Siplizumab Doses (mg/kg)a,b 
Original Doses 
Modified Doses 
Cohort 1 
3.4 
2.6 
Cohort 2 
4.8 
3.4 
Cohort 3 
8.5 
4.8 
Cohort 4 
15 
8.5 
a. Patients in Cohorts 1 through 4 will receive siplizumab 1 day of each cycle until unacceptable toxicity, 
documentation of disease progression, or other reasons for patient withdrawal, whichever comes first. 
b. See Section 11.9 for calculated volume of siplizumab.  
3.3.1.2 QTc Prolongation 
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siplizumab must be discontinued. ECGs and electrolytes should be followed 3 times per week 
post QTc prolongation until QTc falls below 460 msec. 


Abbreviated Title: Siplizumab/EPOCH-R in T/NK NHL 
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20 
,IWKH47FYDOXHLVPVHFDQGPVHFRUWKHUHLVDQLQFUHDVHIURPEDVHOLQHRI
PVHFEXWPVHFWRD47FYDOXHPVHFWKen a repeat ECG should be performed 
within 48 hours to confirm the QTc prolongation. If the repeat ECG meets the criteria again, then 
siplizumab must be discontinued. ECGs and electrolytes should be followed 3 times per week 
post QTc prolongation until QTc falls below 460 msec. 
3.3.2 EPOCH Dose Adjustments 
3.3.2.1 Hematological Toxicity 
No dose adjustments at cycle 1 will be made for patients that have low neutrophil count or 
platelet count due to bone marrow involvement of disease. Drug doses may be modified from the 
following algorithm at the discretion of the investigator for severe life-threatening toxicity such 
as ICU admissions for sepsis. When two different rules give different answers for a particular 
dose decision, use the lower of the two dose options. 
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  25,000/Pl on 1 measurement:   p 1 dose level below last cycle  
x If ANC t 1000/Pl and platelets t 75,000/Pl on day 21, and filgrastim was stopped 24 
hours before begin treatment. 
x If ANC < 1000/Pl or platelets < 75,000/Pl on day 21, delay up to 1 week.  Filgrastim 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.  
3.3.2.2 Non-Hematological Toxicity 
a. Sensory neuropathy  
 Grade  
% Dose of Vincristine 
2 
100 
   
3 
50 
b. Motor neuropathy 
 Grade 
% Dose of Vincristine 


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21 
 
1 
100 
 
2 
75 
 
3 
25 
 
4 
0 
c. Bilirubin 
Vincristine dose will be decreased for elevated bilirubin only secondary to 
lymphoma as follows: 
Bilirubin (mg/dL) 
Vincristine Dose 
> 1.5- < 3 
decrease by 25%* 
 
decrease by 50%* 
Vincristine dose will be re-escalated as hyperbilirubinemia improves.  
d. Ileus 
Constipation commonly occurs in patients receiving vincristine so patients should 
receive stool softeners as indicated.  Occasionally, symptomatic ileus may occur 
and this should be treated with a vincristine dose reduction.  Because the severity of 
ileus is dose related, it is usually unnecessary to stop the vincristine altogether.  
Furthermore, because the therapy administered in this study is potentially curative, 
every effort should be made to not unnecessarily reduce vincristine doses.  If the 
patient has severe ileus requiring hospitalization, reduce vincristine by 25%.   
e. Dose Modifications Based on Creatinine Clearance Secondary to Lymphoma 
No etoposide dose modifications will be made for decreased creatinine clearance or 
increase creatinine. It is anticipated that decreased clearance or increased creatinine 
will improve after the first treatment cycle.  
3.3.3 Dose Modification for Obese Patients 
All dosing is based on the patient’s BSA as calculated from actual weight. There is no clearly 
documented adverse impact of treatment of obese patients when dosing is performed according 
to actual body weight.  Failure to use actual body weight in the calculation of drug dosages will 
be considered a major protocol deviation. 
3.4 PHARMACOKINETICS AND IMMUNOGENICITY  
Venous blood samples will be collected and stored for future pharmacokinetic analysis at the 
following timepoints during the first treatment cycle: 
Cycle 1 Day 1:  
x Pretreatment 
x End of siplizumab infusion (prior to starting EPOCH infusion)  
x 2 hours post siplizumab infusion 
x 6 hours post siplizumab infusion 
Cycle 1 Day 2: 
x 24 hours post siplizumab infusion  


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Cycle 1 Day 3: 
x 48 hours post siplizumab infusion 
Cycle 1 Day 4: 
x 72 hours post siplizumab infusion 
Cycle 1 Day 5: 
x End of EPOCH infusion but before start of rituximab 
x End of Rituximab infusion but before start of cyclophosphamide 
x End of cyclophosphamide infusion 
Three additional samples of blood will be drawn in all subsequent cycles: 
x Prior to starting the siplizumab infusion  
x End of siplizumab infusion  
x End of EPOCH infusion 
In the event of unexpected toxicity occurring, suggestive of a drug-drug interaction, samples will 
be analyzed for pharmacokinetics of the combination agents, using validated LC-MS-MS or 
ELISA assays. 
An additional sample will be collected pre-treatment each cycle, for evaluation of 
immunogenicity with a human anti-humanized antibody (HAHA) assay.  
Samples cannot be drawn from the same site as study drug administration. They must be 
obtained from a separate peripheral IV site or central line. Venous blood samples should be 
collected in a 8.5-ml Serum Separator Tube (SST). Immediately invert 5 times, keep specimens 
at room temperature for 30 minutes (to allow for clotting) and then refrigerate. The date and 
exact time of each blood draw should be recorded on the sample tube and the PK sheet. Please e-
mail NCIBloodcore@mail.nih.gov at least 24 hours before transporting samples (the Friday 
before is preferred). Page 102-11964  for sample pick-up. For immediate help, call 240-760-6180 
(main blood processing core number) or, if no answer, 240-760-6190 (main clinical 
pharmacology lab number).  
A PK sheet with specific instructions will be provided to the nurses caring for each patient. 
Please record infusion start and end times for all infusions. 
Upon arrival in the CPP, blood samples will be centrifuged for 10 minutes at 1000-1300 x g. The 
serum will be transferred into two cryovials and immediately frozen. All samples will be stored 
at -80qC until the time of analysis.  
3.5 ON STUDY EVALUATION 
3.5.1 Day 1 all cycles and day 21 last cycle: CBC/differential; electrolytes; mineral panel; 
AST, ALT, Bilirubin and LDH.  
3.5.2 At the beginning of each cycle, and near Day 21 of the last cycle: CMV PCR, BK 
antigenemia, EBV viral load, urine BK, CD4, CD8, B and NK cell counts.  
3.5.3 Electrocardiograms (ECGs) will be conducted for a formal assessment of QTc. During 
cycle 1 only, 2 ECGs will be performed at each of the following time points: 1) prior to 
siplizumab dose 1 and 2) within 1 hour following of the completion of the siplizumab 


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23 
infusion. Data regarding the effect of siplizumab on QTc interval in humans is required 
during evaluation of new drugs by the FDA. Guidance for management of prolonged QTc 
interval is provided in Section 3.3.1.2. 
3.5.4 Each cycle: Samples for pharmacokinetics and immunogenicity (HAHA) will be obtained 
as per Section 3.4.  
3.5.5 During cycles: CBC/differential BIW.  
3.5.6 Restaging: Day 21, cycles 4 and 6.  Repeat all initially positive staging tests, including 
peripheral blood flow cytometry. 
3.5.7 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.)  
3.5.8 9cc of blood in light blue sodium citrate tube for polymerase chain reaction to define T 
cell receptor gene rearrangement at baseline, post cycle 4, and post cycle 6. 
3.5.9 A fresh tissue biopsy of accessible lymph node or a core needle biopsy will be obtained if 
possible without major surgery or requirement for general anesthesia. Lymphapheresis 
may be performed pre-treatment in patients with leukemic PTCL. The pretreatment 
lymph node biopsy or apheresis (in the case of leukemic disease) will be used to perform 
all standard diagnostic tests. In addition we will extract RNA and protein for research 
studies such as microarray, proteomic analysis, and identification of mutations in target 
genes in tumor tissues.  Analysis of mutations in germline tissue will not be performed 
without patient consent.  If patient consent is obtained, tumor tissue may be stored for 
future research assays which are related to this study and do not pose an increase in 
patient risk.  
 
Studies 
Pre-
therapyA 
Day -1 or 
day 1 of 
each cycle 
Bi-weekly 
during 
therapy 
Post 
cycles 
4 & 6 
Follow-
upB 
Hx; PE; VS; PS   
x 
x 
 
 
x 
Tumor Measurement 
x 
 
 
x 
x 
CBC/diff 
xF 
x 
x 
 
x 
Electrolytes, Creatinine/BUN, ALT, 
AST, Bilirubin, LDH, Ca++, Phos, Mg 
xF 
x 
 
 
x 
CMV PCR, BK antigenemia, EBV 
Viral load, urine BK, T-cell subsets 
x 
x 
 
 
 
Pharmacokinetics 
 
x 
 
 
 
HAHA assay 
 
x 
 
 
 
T cell gene rearrangement 
x 
 
 
x 
 
Clinical PET scan D 
x 
 
 
 
 
ECG 
x 
 
 
 
 
CT chest/abdomen/pelvis C 
x 
 
 
x 
x 
Bone marrow biopsy & aspirate E and 
x 
 
 
xE 
 


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peripheral blood for flow cytometry 
where indicated  
Lumbar puncture 
x 
 
 
 
 
Tumor biopsy and/or apheresis G 
x 
 
 
 
 
A. Initial assessment performed within 1-4 weeks prior to starting treatment as per Section 2.2.  
B. Follow-up to occur as per Section 3.8. 
C. Extent of CT scans may be limited to assess sites of prior disease.   
D. PET scans will be performed pre-therapy if clinically indicated. PET may be obtained at the 
first post-treatment restaging in patients in CRu.   
E. Obtain pre-treatment and after patients achieve CR by other staging.  
F. These laboratory tests must be obtained within one week of initial treatment.   
G. Where possible, tumor biopsies will be obtained by core needle biopsy or surgery pre-
treatment. Snap freeze and store tissue biopsies at -80°C. Lymphapheresis may be 
performed pre-treatment in patients with leukemic PTCL. 
3.6 CONCURRENT THERAPIES  
(continue until CD4 count greater to/equal to 200) 
3.6.1 Pneumocystis jiroveci 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 or atovaquone.  Patients with 
positive serologies for toxoplasmosis should receive atovaquone.   
3.6.2 Herpes Simplex prophylaxis for herpes virus infection will be given (acyclovir 400 mg 
twice daily or famciclovir 500 mg twice daily). 
3.6.3 Fungal prophylaxis: Fluconazole will be administered as prophylaxis for fungal 
infections (200 mg daily).  Fluconazole should be held during EPOCH infusion. 
3.7 CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA 
Prior to removal from study, effort must be made to have all subjects complete a safety visit 
approximately 30 days following the last dose of study therapy. 
3.7.1 Criteria for Removal from Protocol Therapy 
x Excessive toxicity (as defined in Section 3.2.6)  
x Progressive disease  
x Intercurrent illness that prevents further administration of treatment 
x General or specific changes in a patient’s condition that render the patient 
unacceptable for further treatment as determined by that principal investigator 
3.7.2 Off Study Criteria 
x Death 
x Patient non-compliance 
x Patient voluntary withdrawal 
x Patient becomes decisionally impaired  
3.7.3 Off Protocol Therapy and Off Study Procedure 


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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 Update 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. 
3.8 POST-TREATMENT EVALUATION 
3.8.1 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, T/B/NK cell quantitation, mineral panel, 
electrolytes, AST, ALT, Bilirubin, and LDH.  The timing for these visits may be adjusted 
+ 2 months.   
3.8.2 All patients will be followed at restaging visits with CMV antigen levels until the CD4 
count is greater than 200. 
3.8.3 All patients will have a monthly CBC with differential every month for six months post 
treatment. 
4. CONCOMITANT/SUPPORTIVE CARE 
4.1 PNEUMOCYSTIS JIROVECI 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. 
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 


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supervision to include patient self-care and cleaning/flushing of the devices. 
5. CORRELATIVE STUDIES FOR RESEARCH 
5.1 SAMPLE STORAGE, TRACKING AND DISPOSITION 
Samples will be ordered in CRIS and tracked through a Clinical Trial Data Management system. 
Should a CRIS screen not be available, the CRIS downtime procedures will be followed. 
Samples will not be sent outside NIH without IRB notification and an executed MTA. 
5.1.1 Procedures for PK and HAHA samples 
All samples will be barcoded, with data entered and stored in Labrador, the Patient Sample Data 
Management (PSDM) System utilized by the CPP. This is a secure program, with access to the 
PSDM System limited to defined CPP personnel, who are issued individual user accounts. The 
program creates a unique barcode ID for every sample and sample box, which cannot be traced 
back to patients without PSDMS access. The data recorded for each sample includes the patient 
ID, name, trial name/protocol number, time drawn, cycle time point, dose, material type, as well 
as box and freezer location. Patient demographics associated with the clinical center patient 
number are provided in the system. For each sample, there are notes associated with the 
processing method (delay in sample processing, storage conditions on the ward, etc.). 
Barcoded samples are stored in barcoded boxes in a locked freezer at or below -20°C.  These 
freezers are located onsite in the CPP and offsite at NCI Frederick Central Repository Services in 
Frederick, MD. Samples will be stored until requested by a researcher named on the protocol. All 
requests are monitored and tracked in the PSDM System. All researchers are required to sign a 
form stating that the samples are only to be used for research purposes associated with this trial 
(as per the IRB approved protocol) and that any unused samples must be returned to the CPP. 
Following completion of this study, samples will remain in storage as detailed above. Access to 
these samples will only be granted following IRB approval of an additional protocol, granting 
the rights to use the material.  
If, at any time, a patient withdraws from the study and does not wish for their existing samples to 
be utilized, the individual must provide a written request. Following receipt of this request, the 
samples will be destroyed (or returned to the patient, if so requested), and reported as such to the 
IRB. Any samples lost (in transit or by a researcher) or destroyed due to unknown sample 
integrity (i.e. broken freezer allows for extensive sample thawing, etc.) will be reported as such 
to the IRB. 
Sample barcodes are linked to patient demographics and limited clinical information. This 
information will only be provided to investigators listed on this protocol, via registered use of the 
PSDMS. It is critical that the sample remains linked to patient information such as race, age, 
dates of diagnosis and death, and histological information about the tumor, in order to correlate 
genotype with these variables. 
5.1.2 Procedures for Collecting, Processing, and Storing of Tumor Biopsies and/or Peripheral 
Blood Cells 
x Orders for tumor biopsies, research blood samples and lymphapheresis collections should 
be placed in CRIS (Clinical Research Information System, Clinical Research Center, 
NIH, Bethesda, MD) 


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


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with the data management efforts. All data obtained during the conduct of the protocol will be 
kept in secure network drives or in approved alternative sites that comply with NIH security 
standards. Primary and final analyzed data will have identifiers so that research data can be 
attributed to an individual human subject participant. 
All adverse events, including clinically significant abnormal findings on laboratory evaluations, 
regardless of severity, will be followed until return to baseline or stabilization of event. Patients 
will be followed for adverse events for 30 days after removal from study treatment or until off-
study, whichever comes first.  
An abnormal laboratory value will be recorded in the database as an AE only if the laboratory 
abnormality is characterized by any of the following: 
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.  
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. 
6.1.1 Exceptions for data collection/recording on case report forms, include: 
x The results of physical exams do not need to be recorded in the database. 
x Since the patient is receiving multiple agents which include commercially available 
agents (EPOCH-R and supportive medications) in combination with the investigational 
agent, all grade 1 adverse events do not require reporting/ recording in the database.  
x Only concomitant medications used for treatment of or prophylaxis for infections will be 
recorded in the database. Other concomitant medications will not be recorded in the 
database.  
x As patients will potentially remain on protocol until the time they die, subsequent 
regimens received after completing treatment on this protocol will be recorded in the 
database. 
6.2 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 


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29 
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 
LQWKHVL]HRIWKHSUHYLRXVO\LQYROYHGVLWHV*UHDWHUWKDQRUHTXDOWRLQFUHDVHLQ
greatest diameter of any previously identified node > 1 cm in its shortest axis or in the SPD of 
more than one node.  
Progressive disease (PR, non-responders) requires the following: LQFUHDVHIURPQDGLULQ
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. 
6.3 TOXICITY CRITERIA 
The following adverse event management guidelines are intended to ensure the safety of each 
patient while on the study. The descriptions and grading scales found in the revised NCI 
Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 will be utilized for AE 
reporting.  All appropriate treatment areas should have access to a copy of the CTCAE version 
3.0. A copy of the CTCAE version 3.0 can be downloaded from the CTEP web site 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm).  
7. SAFETY REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING 
PLAN 
7.1 DEFINITIONS 
7.1.1 Adverse Event  
Any untoward medical occurrence in a human subject, including any abnormal sign (for 
example, abnormal physical exam or laboratory finding), symptom, or disease, temporally 


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associated with the subject’s participation in research, whether or not considered related to the 
subject’s participation in the research.  
7.1.2 Suspected adverse reaction 
Suspected adverse reaction means any adverse event for which there is a reasonable possibility 
that the drug caused the adverse event. For the purposes of IND safety reporting, ‘reasonable 
possibility’ means there is evidence to suggest a causal relationship between the drug and the 
adverse event. A suspected adverse reaction implies a lesser degree of certainty about causality 
than adverse reaction, which means any adverse event caused by a drug. 
7.1.3 Unexpected adverse reaction 
An adverse event or suspected adverse reaction is considered “unexpected” if it is not listed in 
the investigator brochure or is not listed at the specificity or severity that has been observed; or, 
if an investigator brochure is not required or available, is not consistent with the risk information 
described in the general investigational plan or elsewhere in the current application. 
"Unexpected”, also refers to adverse events or suspected adverse reactions that are mentioned in 
the investigator brochure as occurring with a class of drugs or as anticipated from the 
pharmacological properties of the drug, but are not specifically mentioned as occurring with the 
particular drug under investigation. 
7.1.4 Serious 
An Unanticipated Problem or Protocol Deviation is serious if it meets the definition of a Serious 
Adverse Event or if it compromises the safety, welfare or rights of subjects or others. 
7.1.5 Serious Adverse Event 
An adverse event or suspected adverse reaction is considered serious if in the view of the 
investigator or the sponsor, it results in any of the following: 
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. 
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events: 
If a woman becomes pregnant or suspects she is pregnant while participating in this study, she 
must inform her treating physician immediately and permanently discontinue drug. 
7.1.6 Disability 
A substantial disruption of a person’s ability to conduct normal life functions. 
7.1.7 Life-threatening adverse drug experience 
Any adverse event or suspected adverse reaction that places the patient or subject, in the view of 


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31 
the investigator or sponsor, at immediate risk of death from the reaction as it occurred, i.e., it 
does not include a reaction that had it occurred in a more severe form, might have caused death. 
7.1.8 Protocol Deviation (NIH Definition) 
Any change, divergence, or departure from the IRB-approved research protocol.   
7.1.9 Non-compliance (NIH Definition) 
The failure to comply with applicable NIH Human Research Protections Program (HRPP) 
policies, IRB requirements, or regulatory requirements for the protection of human research 
subjects. 
7.1.10 Unanticipated Problem 
Any incident, experience, or outcome that: 
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. 
7.2 NIH INTRAMURAL IRB IRB AND CLINICAL DIRECTOR REPORTING 
7.2.1 NIH Intramural IRB and NCI CD Expedited Reporting of Unanticipated Problems and 
Deaths 
The Protocol PI will report in the NIH Problem Form to the NIH Intramural IRB and NCI 
Clinical Director (NCI CD): 
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. 
7.2.2 NIH Intramural IRB Requirements for PI Reporting at Continuing Review 
The protocol PI will report to the NIH Intramural 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 


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research;  
x All Grade 5 events regardless of attribution;  
x All Serious Events regardless of attribution.  
NOTE: Grade 1 events are not required to be reported. 
7.3 EXPEDITED ADVERSE EVENT REPORTING CRITERIA TO THE IND MANUFACTURER  
All serious adverse events that are reported to the IRB will also be faxed to MedImmune Product 
Safety at: 301.398.4205. 
7.4 DATA AND SAFETY MONITORING PLAN 
All data will be collected in a timely manner and reviewed by the PI and/or lead associate 
investigator for toxicity.  In the event that unacceptable toxicity occurs, the IRB will be informed 
and appropriate measures as outlined in the protocol will be taken  
This trial will be monitored by a CCR Contractor to the NCI, NIH. Monitors are qualified by 
training and experience to monitor the progress of clinical trials. Personnel monitoring this study 
will not be affiliated in any way with the trial conduct. 
At least 25% of enrolled patients’ will be randomly selected and monitored at least quarterly, 
based on accrual rate. The patients selected will have 100% source document verification done. 
Additional monitoring activities will include: adherence to protocol specified study eligibility, 
treatment plans, data collection for safety and efficacy, reporting and time frames of adverse 
events to the NCI IRB and FDA, and informed consent requirements. Written reports will be 
generated in response to the monitoring activities and submitted to the Principal investigator and 
Clinical Director or Deputy Clinical Director, CCR, NCI. 
NOTE:  It may be noted that this trial is no longer monitored as all subjects are off treatment and 
the IND is withdrawn.   
7.4.1 Principal Investigator/Research Team  
The clinical research team will meet on a regular basis (i.e., approximately weekly) when 
patients are being actively treated on the trial to discuss each patient. Decisions about dose level 
enrollment and dose escalation if applicable will be made based on the toxicity data from prior 
patients.  
All data will be collected in a timely manner and reviewed by the principal investigator or a lead 
associate investigator. Adverse events will be reported as required above. Any safety concerns, 
new information that might affect either the ethical and or scientific conduct of the trial, or 
protocol deviations will be immediately reported to the IRB using iRIS. 
The principal investigator will review adverse event and response data on each patient to ensure 
safety and data accuracy. The principal investigator will personally conduct or supervise the 
investigation and provide appropriate delegation of responsibilities to other members of the 
research staff.  
8. STATISTICAL CONSIDERATIONS 
Determination of sample size: This is a phase I study to evaluate the feasibility of administration 
of siplizumab in combination with dose adjusted EPOCH-rituximab infusional chemotherapy. 
The primary objective of this study is to evaluate the overall and hematologic toxicities of this 


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combination.  Previous administration of steroids and/ or other biologic therapy is unlikely to 
affect these parameters. There will be a maximum of 30 patients in this trial, with three to six 
patients treated in each cohort examining different doses of siplizumab 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 3 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 6.2. Since there will be only 12 patients at the MTD, this information will be 
considered as an early estimate of the response rate to the combination.  Responses at the MTD 
will be identified and reported with a 95% confidence interval; since the number of patients will 
be limited, this will be considered preliminary and may be useful information to guide parameter 
estimation for a subsequent trial. The more definitive estimate will be obtained in a subsequent 
trial enrolling a greater number of patients at a single dose level.  
B, T, and NK cell depletion and recovery will primarily be evaluated in a descriptive manner, but 
also by comparing the results after each cycle to those obtained at baseline. The differences will 
be tested for potential statistical significance using a Wilcoxon signed rank test, focusing on the 
findings in patients treated in a consistent manner at the MTD. As  an illustration, for a given 
parameter and a particular time point, with 12 patients, a difference equal to one standard 
deviation of the difference can be detected with a two-tailed 0.05 alpha level test and >80 % 
power.  The fact that multiple parameters and multiple time point comparisons may be 
undertaken will be used when the findings are being interpreted.   
EBV reactivation and development of EBV lymphoproliferative disease are expected to occur 
rarely, but the presence and absence of the two conditions will be described by a 2 x 2 table and 
evaluated with appropriate epidemiologic measures if either occurs in more than a single patient. 
9. COLLABORATIVE AGREEMENTS 
9.1 COOPERATIVE RESEARCH AND DEVELOPMENT AGREEMENT (CRADA) 
The agent(s) supplied by MedImmune used in this protocol is/are provided to the NCI under a 
Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical Company(ies) 
(hereinafter referred to as “Collaborator(s)”) and the NCI Lymphoid Malignancies Branch.  
Therefore, the following obligations/guidelines, in addition to the provisions in the “Intellectual 
Property Option to Collaborator” (http:// ctep.cancer.gov/industry) contained within the terms of 
award, apply to the use of the Agent(s) in this study: 
9.1.1 Agent(s) may not be used for any purpose outside the scope of this protocol, nor can 
Agent(s) be transferred or licensed to any party not participating in the clinical study.  
Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) and 
shall be maintained as such by the investigators. The protocol documents for studies 
utilizing investigational Agents contain confidential information and should not be shared 
or distributed without the permission of the NCI.  If a copy of this protocol is requested 
by a patient or patient’s family member participating on the study, the individual should 
sign a confidentiality agreement. A suitable model agreement can be downloaded from: 
http://ctep.cancer.gov. 
9.1.2 For a clinical protocol where there is an investigational Agent used in combination with 
(an)other investigational Agent(s), each the subject of different collaborative agreements , 


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the access to and use of data by each Collaborator shall be as follows (data pertaining to 
such combination use shall hereinafter be referred to as "Multi-Party Data”.): 
a. NCI will provide all Collaborators with prior written notice regarding the existence 
and nature of any agreements governing their collaboration with NIH, the design of 
the proposed combination protocol, and the existence of any obligations that would 
tend to restrict NCI's participation in the proposed combination protocol. 
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical 
trial by any other Collaborator solely to the extent necessary to allow said other 
Collaborator to develop, obtain regulatory approval or commercialize its own 
investigational Agent. 
c. Any Collaborator having the right to use the Multi-Party Data from these trials must 
agree in writing prior to the commencement of the trials that it will use the Multi-
Party Data solely for development, regulatory approval, and commercialization of its 
own investigational Agent. 
9.1.3 Clinical Trial Data and Results and Raw Data developed under a Collaborative 
Agreement will be made available exclusively to Collaborator(s), the NCI, and the FDA, 
as appropriate and unless additional disclosure is required by law or court order. 
Additionally, all Clinical Data and Results and Raw Data will be collected , used and 
disclosed consistent with all applicable federal statutes and regulations for the protection 
of human subjects, including, if applicable, the Standards for Privacy of Individually 
Identifiable Health Information set forth in 45 C.F.R. Part 164. 
9.1.4 When a Collaborator wishes to initiate a data request, the request should be sent to the 
Sponsor of the protocol, Dr. Thomas Waldmann. 
10. HUMAN SUBJECTS PROTECTIONS 
10.1 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 2.0.  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. 
10.2 PARTICIPATION OF CHILDREN 
Patients less than 18 years of age will be excluded because siplizumab has not been given to 
minors in combination with chemotherapy. 
10.3 FOR ADULTS WHO MAY BE BECOME UNABLE TO CONSENT 
Adults unable to give consent were excluded from enrolling in the protocol.  Re-consent may be 
necessary and there is a possibility, though unlikely, that subjects could become decisionally 
impaired. Because all patients are in follow-up, there is no longer a prospect of direct benefit. 
Therefore, if a patient becomes decisionally impaired, he/she will be removed from the study. 


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10.4 EVALUATION OF BENEFITS AND RISKS/DISCOMFORTS 
The potential benefits to the subject are that the patient may achieve a partial or complete 
remission.  The benefits of combinations of chemotherapy and monoclonal antibodies may 
produce remissions that cannot be achieved with either approach alone.  Chemotherapy may 
produce bleeding or infectious complications as a result of chemotherapy-induced 
myelosuppression. Siplizumab causes immunosuppression which may be made more severe as a 
result of combining it with chemotherapy. 
10.5 RISKS/BENEFITS ANALYSIS 
Patients eligible for this protocol will be subject to the toxicity associated with EPOCH-
rituximab infusional chemotherapy, which include myelosuppression, stomatitis, numbness or 
tingling in the extremities, motor weakness, and the need for transfusion or hospitalization due to 
complications of treatment noted.  There may be adverse effects due to the combination of agents 
that is not seen when either is given alone. 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-R with siplizumab may 
produce increased immune suppression and myelosuppression.  The development of EBV LPD 
is a risk in patients treated on this study and will result in discontinuation of accrual to the 
protocol if more than one patient develops this complication. 
10.6 CONSENT 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 or friends, 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. The patient will receive a copy of the signed consent. 
10.6.1 Telephone Re-consent 
Re-consent on this study may be obtained via telephone according to the following procedure: 
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 signature will sign 
and date the consent. 
The original informed consent document will be sent back to the consenting investigator who 
will sign and date the consent form with the date the consent was obtained via telephone.   
A fully executed copy will be returned via mail for the subject’s records. 
The informed consent process will be documented on a progress note by the consenting 
investigator. 
11. PHARMACEUTICAL INFORMATION 
Qualified personnel who are familiar with procedures that minimize undue exposure to 
themselves and to the environment should undertake the preparation, handling, and safe disposal 


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of chemotherapeutic agents in a self-contained, protective environment. Discard unused portions 
of injectable chemotherapeutic agents that do not contain a bacteriostatic agent or are prepared 
with unpreserved diluents (i.e., Sterile Water for Injection USP or 0.9% Sodium Chloride for 
Injection USP) within eight hours of vial entry to minimize the risk of bacterial contamination.  
The total administered dose of chemotherapy may be rounded up or down within a range of 5% 
of the actual calculated dose.  The weight at Cycle 1 should be used for dose calculations for all 
F\FOHVXQOHVVWKHUHLVDFKDQJHRYHUDSHULRGRIRQHF\FOH,IDZHLJKWFKDQJH
occurs within one cycle, then doses should be recalculated and the new dose used from that time 
forward. 
11.1 DOXORUBICIN HCL (ADRIAMYCIN PFS™, ADRIAMYCIN RFS™, RUBEX®) 
11.1.1 Availability 
Doxorubicin is commercially available as a lyophilized powder for reconstitution in 10, 20, 50, 
and 100 mg vials. Also available are 2 mg/mL solutions for injection in 10, 20, 50, and 200 mg 
vials. Please refer to the FDA-approved package insert for doxorubicin for product information, 
extensive preparation instructions, and a comprehensive list of adverse events. 
11.1.2 Storage & Stability 
Intact vials of doxorubicin solution should be stored in the refrigerator. Intact vials of powder for 
reconstitution should be stored at room temperature. Reconstituted solutions are stable for 7 days 
at room temperature and 15 days under refrigeration when protected from light. Commercially 
available solutions labeled as such are intended to be multidose vials. 
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, 350 mcg/mL are 
stable for at least 36 hours at room temperature when protected from light. Also, admixtures 
containing vincristine, doxorubicin, etoposide concentrations of 1.6, 40, and 200 mcg/mL are 
stable for at least 30 hours at 32°C. 
11.1.3 Preparation 
Reconstitute the vials of doxorubicin powder with 5, 10, 25, or 50 mL, respectively, of sodium 
chloride for injection, USP, resulting in a concentration of 2 mg/mL. 
The daily dose (i.e., 24-hour supply) of doxorubicin will be admixed in 0.9% sodium chloride, 
along with vincristine and etoposide. Infusion solutions should be changed every 24 hours. The 
volume of the infusion solution will be determined by the 24 hour etopoVLGHGRVH,IHWRSRVLGH
150 mg per 24 hours, then dilute drugs in 500 mL; if etoposide > 150 mg per 24 hours, then 
dilute drugs in 1000 mL 0.9% sodium chloride. Infusion solutions should be protected from 
light. 
11.1.4 Administration 
Doxorubicin will be administered as a 96-hour continuous IV infusion, along with vincristine 
and etoposide in the same infusion solution (see “Storage and Stability” above). 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. 
11.1.5 Toxicities 


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x Hematologic: Leukopenia (dose-limiting), thrombocytopenia, anemia. Nadir in 10-14 
days with recovery usually in 21 days. 
x Dermatologic: alopecia (usually complete; reversible) radiation recall reactions; 
increased sensitivity to sunlight. 
x Gastrointestinal: nausea and vomiting (doxorubicin is generally considered 
moderately to highly emetogenic), anorexia, diarrhea, mucositis (stomatitis, 
esophagitis). 
x Cardiovascular: cardiomyopathy may occur and is related to total cumulative lifetime 
dose. The risk for cardiomyopathy increases with total doses > 450 mg/m2. ECG 
changes and less often, arrhythmias, are seen. Rarely, sudden death has occurred. 
x Other: Red discoloration of urine for 24-48 hours after drug administration. 
Doxorubicin is a vesicant and can cause tissue necrosis if extravasated, especially at 
the concentration usually employed for bolus injections (i.e., 2 mg/mL). 
x Fluconazole should not be given during EPOCH infusional chemotherapy because of 
pharmacologic interactions 
11.2 ETOPOSIDE (VEPESID®, EPIDOPHYLLOTOXIN, VP-16) 
11.2.1 Availability 
Etoposide is commercially available as a solution for injection in 5 mL, 7.5 mL, 25 mL, and 50 
mL vials containing 20 mg/mL. Please refer to the FDA-approved package insert for etoposide 
for product information, extensive preparation instructions, and a comprehensive list of adverse 
events. 
11.2.2 Storage & Stability 
Intact vials of etoposide for injection should be stored at room temperature and protected from 
light. 
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, 350 mcg/mL are 
stable for at least 36 hours at room temperature when protected from light. Also, admixtures 
containing vincristine, doxorubicin, etoposide concentrations of 1.6, 40, and 200 mcg/mL are 
stable for at least 30 hours at 32°. 
11.2.3 Preparation 
The daily dose (i.e., 24-hour supply) of etoposide will be admixed in 0.9% sodium chloride, 
along with vincristine and doxorubicin. Infusion solutions should be changed every 24 hours. 
The volume of the infusion solution will be determined by the 24 hour etoposide dose. If 
HWRSRVLGHPJSHUKRXUVWKHQGLOXWHGUXJVLQP/VRGLXPFKORULGHLI
etoposide > 150 mg per 24 hours, then dilute drugs in 1000 mL 0.9% sodium chloride. 
11.2.4 Administration 
Etoposide will be administered as a 96-hour continuous IV infusion, along with vincristine and 
doxorubicin in the same infusion solution (see “Storage & Stability” above). The chemotherapy 
will be administered with a suitable infusion pump via a central venous access device. 


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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. 
11.2.5 Toxicity 
Myelosuppression, predominantly neutropenia and thrombocytopenia, is the most common 
toxicity associated with etoposide. Nausea and vomiting range from mild to severe in severity, 
depending on the dose. Mucositis is also more common at the dose used in this study. Alopecia 
is likely. Hypotension is associated with too rapid administration of etoposide. This would be 
unlikely to occur in this trial. 
Fluconazole should not be given during EPOCH infusional chemotherapy because of 
pharmacologic interactions 
11.3 ETOPOSIDE PHOSPHATE  
11.3.1 Source 
ETOPOPHOS® (etoposide phosphate) for Injection will be purchased by the NIH Clinical 
Center Pharmacy Dept. from commercial vendors. 
11.3.2 Formulation 
ETOPOPHOS® is commercially marketed as a sterile lyophilized product in individually 
cartoned, single-dose vials with white flip-off seals containing etoposide phosphate equivalent to 
100 mg etoposide, 32.7 mg sodium citrate, USP, and 300 mg dextran 40.  
Etoposide phosphate is a water soluble ester of etoposide, with an advantage over the latter drug 
of a decreased potential for precipitation following dilution and during intravenous 
administration.  
11.3.3 Preparation 
The contents of each vial of ETOPOPHOS® must be reconstituted prior to use with one of the 
following solutions: 
x Sterile Water for Injection, USP (SWFI); 
x 5% Dextrose Injection, USP (D5W); 
x 0.9% Sodium Chloride Injection, USP (0.9%NS); 
x Bacteriostatic Water for Injection with Benzyl Alcohol (BWFI); or 
x Bacteriostatic Sodium Chloride for Injection with Benzyl Alcohol (B0.9%NS) 
Use the quantity of diluent shown below to reconstitute each vial of ETOPOPHOS® containing 
100 mg etoposide equivalents 
Volume of Diluent 
Resulting Concentrations 
Etoposide Equivalents 
Etoposide phosphate 
5 mL 
20 mg/mL 
22.7 mg/mL 
10 mL 
10 mg/mL 
11.4 mg/mL 
Following reconstitution, etoposide phosphate may be further diluted to concentrations as low as 
0.1 mg/mL etoposide with either 0.9%NS or D5W. 


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11.3.4 Dosage and Administration 
Etoposide and etoposide phosphate (ETOPOPHOS®) may be used interchangeably.  Etoposide 
phosphate dosages and calculated doses are expressed as etoposide equivalents.  Administration 
routes, rates, durations, intervals, and schedules are the same for either etoposide or etoposide 
phosphate. 
11.3.5 Storage  
Store unopened vials under refrigeration 2°–8°C (35.6°–46.4°F) in the original packaging to 
protect the drug product from light. 
11.3.6 Stability 
Unopened vials of ETOPOPHOS® for Injection are stable until the date indicated on the 
package when stored in the original packaging under refrigeration 2°–8°C (35.6°–46.4°F). 
After reconstitution, etoposide phosphate solutions can be stored in glass or plastic containers 
under refrigeration for up to 7 days; at controlled room temperature 20°–25°C (68°–77°F) for 24 
hours following reconstitution with SWFI, D5W, or 0.9%NS; or at controlled room temperature 
for 48 hours following reconstitution with BWFI or B0.9%NS. 
After further dilution, etoposide phosphate solutions may be stored under refrigeration or at 
controlled room temperature for up to 24 hours. 
Etoposide phosphate is not less stable than etoposide base when prepared as an admixture with 
doxorubicin and vincristine in the proportions used in the EPOCH chemotherapy regimen; i.e., 5 
parts etoposide to 1 part doxorubicin to 0.04 parts vincristine (initial dose level). [reference: 
Yuan P, et al. Am J Health Syst Pharm 2001;58:594-8].  Consequently, the same strategies and 
procedures for preparation, stability, and expiration dating that apply to admixtures containing 
etoposide + doxorubicin + vincristine will apply to admixtures in which etoposide is replaced by 
etoposide phosphate. 
11.4 VINCRISTINE SULFATE (VCR, LEUROCRISTINE SULFATE, ONCOVIN®, VINCASAR PFS) 
11.4.1 Availability 
Vincristine is commercially available in 1 mL, 2 mL, and 5 mL vials in a concentration of 1 
mg/mL. Please refer to the FDA-approved package insert for vincristine sulfate for product 
information, extensive preparation instructions, and a comprehensive list of adverse events. 
11.4.2 Storage & Stability 
Unopened vials should be stored under refrigeration and protected from light. Commercially 
available solutions labeled as such are intended to be multidose vials. 
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, 350 mcg/mL are 
stable for at least 36 hours at room temperature when protected from light. Also, admixtures 
containing vincristine, doxorubicin, etoposide concentrations of 1.6, 40, and 200 mcg/mL are 
stable for at least 30 hours at 32°. 
11.4.3 Preparation 
The daily dose (i.e., 24-hour supply) of vincristine will be admixed in 0.9% sodium chloride. 
Infusion solutions should be changed every 24 hours. The volume of the infusion solution will be 


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determined by thHKRXUHWRSRVLGHGRVH,IHWRSRVLGHPJSHUKRXUVWKHQGLOXWHGUXJV
in 500 mL 0.9% sodium chloride; if etoposide > 150 mg per 24 hours, then dilute drugs in 1000 
mL 0.9% sodium chloride. Infusion solutions should be protected from light. 
11.4.4 Administration 
Vincristine will be administered as a 96-hour continuous IV infusion, along with etoposide and 
doxorubicin. These three agents should be admixed in the same infusion solution (see “Storage 
& Stability” above). The chemotherapy will then 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. 
11.4.5 Toxicity 
The most common toxicity associated with vincristine is neurotoxicity. Peripheral manifestations 
of neurotoxicity include: numbness of extremities, paresthesias, loss of deep tendon reflexes, 
neuropathic pain and muscle weakness. GI manifestations of neurotoxicity include constipation, 
and adynamic ileus. Cranial nerve manifestations include: diplopia, hoarseness, tinnitus, jaw pain 
(the latter usually occurring with the first dose of vincristine). Orthostatic hypotension & SIADH 
may also be seen. Vincristine is a vesicant and may cause tissue necrosis upon extravasation. 
This is more likely with bolus injections as opposed to dilute infusions. 
Fluconazole should not be given during EPOCH infusional chemotherapy because of 
pharmacologic interactions 
11.5 CYCLOPHOSPHAMIDE (CYTOXAN®; NEOSAR®) 
11.5.1 Availability 
Commercially available as a powder for reconstitution in 100 mg, 200 mg, 500 mg, 1 gram, and 
2 gram vials. Please refer to the FDA-approved package insert for cyclophosphamide for product 
information, extensive preparation instructions, and a comprehensive list of adverse events. 
11.5.2 Preparation 
Reconstitute 100 mg, 200 mg, 500 mg, 1 gram and 2 gram vials with 5, 10, 25, 50, or 100 mL of 
sterile water for injection or 0.9% sodium chloride to give a final concentration of 20 mg/mL.  
The appropriate dose should be added to 100 mL of 0.9% sodium chloride for infusion. Vigorous 
shaking and/or gentle warming may be necessary for non–lyophilized preparations. 
Bacteriostatic water for injection (paraben preserved only) may be used; benzyl alcohol 
derivatives may NOT be used. 
11.5.3 Storage & Stability 
Intact vials should be stored at room temperature. Reconstituted and diluted solutions are stable 
for 24 hours at room temperature and 6 days if refrigerated. 
11.5.4 Administration 
The total dose of cyclophosphamide will be administered by IV bolus injection over 30 minutes. 
All patients should receive hydration with 0.9% sodium chloride at the following volumes (based 
on cyclophosphamide dose levels) and rates with half administered before and half administered 
after cyclophosphamide. 
DA-EPOCH-R Levels 1-2: 
1  liter NS @ 300-500 cc/hr 
DA-EPOCH-R Levels 3-5: 
2  liter NS @ 300-500 cc/hr 


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DA-EPOCH-R Level  6 : 
2.5 liter NS @ 300-500 cc/hr 
11.5.5 Toxicity 
Myelosuppression, hemorrhagic cystitis (patients must be well-hydrated before, during, and after 
treatment and have adequate renal function). Syndrome of inappropriate antidiuretic hormone 
(SIADH), fatigue, alopecia, anorexia, nausea, vomiting, hyperuricemia, azospermia, amenorrhea, 
cardiotoxicity (myocardial necrosis) usually at doses higher than those used in this study. 
11.5.6 Drug Interactions 
Cyclophosphamide undergoes metabolic activation via cytochrome P450 3A4 in the liver and 
may potentially interact with any drug affecting the same isoenzyme. Inhibitors of 3A4 (e.g., 
itraconazole) could theoretically inhibit activation and inducers of 3A4 (e.g., phenytoin) could 
theoretically enhance activation of cyclophosphamide to active akylating species. For the most 
part, such interactions have not yet been documented clinically. 
11.6 PREDNISONE (DELTASONE, MISCELLANEOUS) 
11.6.1 Availability 
Commercially available in 1, 2.5, 5, 10, 20, 25, and 50 mg tablets, or as an oral solution or syrup 
- 5 mg/5 ml (in 5% alcohol); solution concentrate - 5 mg/ml (with 30% alcohol). Please refer to 
the FDA-approved package insert for prednisone for product information, and a comprehensive 
list of adverse events. 
11.6.2 Storage & Stability 
Store tablets, solutions and syrup in tightly closed containers at room temperature. 
11.6.3 Administration 
Oral. 
11.6.4 Toxicity 
Side effects likely to be encountered with intermittent high doses include: GI (dyspepsia, 
ulceration), insomnia, and hyperglycemia. Occasionally a “withdrawal syndrome” after short-
term high doses, such as in this study, manifest muscle aches and pains. Immunosuppression 
with risk of infection is also seen. 
11.7 RITUXIMAB 
11.7.1 Availability 
Rituximab is commercially available in 10 mL and 50 mL single-use vials containing 100 mg or 
500 mg rituximab solution, respectively, at a concentration of 10 mg/mL. Please refer to the 
FDA-approved package insert for rituximab for product information, extensive preparation 
instructions, and a comprehensive list of adverse events. 
11.7.2 Storage & Stability 
Intact vials should be stored under refrigeration. Dilute solutions for infusion (1-4 mg/mL) are 
stable for 24 hours under refrigeration, and for an additional 24 hours at room temperature. 
11.7.3 Preparation 
The desired dose of rituximab should be diluted in 0.9% NaCl or D5W to a final concentration of 
1-4 mg/mL. The solution should be mixed by gently inverting the bag. 
11.7.4 Administration 
Oral pre-medication 650 mg of acetaminophen and 25 mg diphenhydramine hydrochloride will 


Abbreviated Title: Siplizumab/EPOCH-R in T/NK NHL 
NCI Version Date: 11/21/2018 
 
 
42 
be administered 30 to 60 minutes prior to starting each infusion of rituximab. Rituximab will be 
administered as an intravenous infusion at 375 mg/m2 on day 5 of each cycle of DA-EPOCH-R, 
just after the EPOCH infusion has completed. The first rituximab infusion should be started at 50 
mg/hr, and increased in 50-mg/hr increments every 30 minutes to a maximum rate of 400 mg/hr. 
If this rate of escalation is well tolerated the second and subsequent infusions can begin at a rate 
of 100 mg/hr and increase in 100 mg/hr increments every 30 minutes to a maximum of 400 
mg/hr. CAUTION: DO NOT ADMINISTER AS AN INTRAVENOUS PUSH OR BOLUS. 
11.7.5 Toxicity 
The most severe serious adverse events associated with rituximab include severe infusion 
reactions, tumor lysis syndrome, and severe mucocutaneous reactions. Severe infusion reactions 
consisting of hypoxia, pulmonary infiltrates, acute respiratory distress syndrome, myocardial 
infarction, ventricular fibrillation or cardiogenic shock may be fatal. Most reported fatal 
reactions occurred within 24 hours of the first dose of rituximab. 
Tumor lysis syndrome resulting in renal failure has been described, and occasional fatalities 
noted. Tumor lysis syndrome is more likely in patients with high numbers of circulating 
PDOLJQDQWFHOOV/ 
Severe mucocutaneous reactions associated with rituximab include Stevens-Johnson syndrome 
and toxic epidermal necrolysis. The onset of these reactions has been from 1-3 weeks. 
Less severe infusion reactions are common with rituximab. These include fever, chills, and 
dyspnea. The mechanism of rituximab infusion reactions is thought to be secondary to release of 
cytokines. If a reaction occurs, then the infusion should be stopped until the symptoms resolve, 
and then restarted at a 50% slower rate. 
Recent reports describe hepatitis B reactivation with fulminant hepatitis, hepatic failure and 
death in some patients with hematologic malignancies treated with rituximab. The majority of 
these patients received rituximab in combination with chemotherapy. The median time to 
diagnosis of hepatitis was approximately 4 months after starting rituximab and approximately 1 
month after the last dose. 
11.8 FILGRASTIM  
(G-CSF; r-met HuG-CSF; Granulocyte Colony Stimulating Factor; Neupogen®) 
11.8.1 Availability  
Commercial filgrastim is available in 1 mL and 1.6 mL vials containing 300 mcg and 480 mcg 
filgrastim, and in prefilled syringes containing 300 mcg/0.5 mL or 480mcg/0.8 mL. Please refer 
to the FDA-approved package insert for filgrastim for product information, extensive preparation 
instructions, and a comprehensive list of adverse events. 
11.8.2 Storage & Stability 
Intact vials and prefilled syringes should be stored in the refrigerator at 2-8° Centigrade (36-46° 
Fahrenheit). Do not freeze.  
11.8.3 Administration 
Filgrastim will be administered as a subcutaneous injection. The daily dose will be 480 mcg 
administered daily starting day 6 and continued until ANC is >5000 post nadir. 
11.8.4 Toxicity 
The most common side effect associated with filgrastim is medullary bone pain. Bone pain is 


Abbreviated Title: Siplizumab/EPOCH-R in T/NK NHL 
NCI Version Date: 11/21/2018 
 
 
43 
usually reported as mild or moderate and, if necessary, may be treated with non-opioid or opioid 
analgesics. 
11.9 SIPLIZUMAB (IND #103970 – WITHDRAWN 1/22/13) 
Supplies of siplizumab will be requested from MedImmune as specified in the Clinical Trial 
Material Manual provided to investigators. Shipments are sent out via FedEx and are performed 
Monday thru Wednesday.  Thursday shipment for Friday delivery is available if there is an 
urgent need.    
Accountability of the supplies received may be done through NIH Clinical Center standard 
procedures with pre-approval by a staff member of MedImmune Clinical Research Pharmacy 
Services.  Otherwise, accountability must be maintained utilizing a MedImmune accountability 
record. 
11.9.1 Formulation 
Siplizumab is a humanized IgG1k class monoclonal antibody and will be supplied by 
MedImmune.  The functional protein is composed of two approximately 50 kDa heavy chains 
(g1) and two approximately 25 kDa light chains (k) for a combined molecular weight of 
approximately 150 kDa.  Siplizumab was constructed using molecular techniques to insert the 
CD2 binding region (complementary determining regions:  CDRs) from a characterized CD2 
specific rat monoclonal antibody, BTI-322, developed by Bazin et al.  This antibody binds to the 
human CD2 receptor that is involved in the T-cell costimulatory signal.  In an effort to reduce the 
potential for immunogenicity in humans, changes to the human framework of siplizumab have 
been kept at a minimum consistent with preservation of activity. 
Siplizumab is supplied as a clear colorless solution.  The bulk solution was sterilized by filtration 
and aseptically filled into prewashed, presterilized, depyrogenized vials.  Siplizumab is available 
in one of two formulations, 5 mg/mL or 10 mg/mL.  These formulations are described in Table 
below. 
Table of Siplizumab Formulations 
Formulation 
10 mg/mL 
5 mg/mL 
Active Ingredient 
siplizumab 
siplizumab 
Amount per mL 
10 r 1.0 mg 
5 r 0.5 mg 
PH 
6.0 r 0.5 
6.0 r 0.5 
Volume 
 1 mL  
1 mL 
Inactive 
Ingredients 
(per mL) 
1.552 mg Histidine, USP 
6.14 mg Sodium chloride, USP 
 
1.552 mg Histidine, USP 
6.14 mg 
Sodium chloride, USP 
11.9.2 Storage & Stability 
The appropriate amount of siplizumab should be mixed with 0.9% Sodium Chloride for 
Injection, USP and infused within 24 hours of preparation.  The calculated volume of siplizumab 
should be mixed with 0.9% Sodium Chloride for Injection as follows: 
 
 
 
 
 
 
Table of Calculated Volume of Siplizumab 
 
Dose Level 
Dilute with 0.9 % 
sodium chloride to 
total volume 
3.4 mg/kg 
350 mL 


Abbreviated Title: Siplizumab/EPOCH-R in T/NK NHL 
NCI Version Date: 11/21/2018 
 
 
44 
4.8 mg/kg 
450 mL 
8.5 mg/kg 
800 mL 
15 mg/kg 
  1250 mL 
Siplizumab drug product at 10 mg/mL has been placed on stability testing.  It is stable at 2qC to 
8qC.  Stability testing of drug product is ongoing.  As siplizumab contains no preservatives, the 
product should be used immediately after dilution for use and within 24 hours of preparation.  If 
the prepared infusion is not used immediately it should be stored at 2 to 8qC.  Opened vials must 
not be used after 6 hours.  
11.9.3 Administration 
Siplizumab will be administered as an IV infusion. Siplizumab must not be administered via IV 
push or bolus Siplizumab must not be administered via IV push or bolus. The prepared 
Siplizumab diluted solution must be used within 24 hours of preparation The initial infusion of 
antibody should be given over 2-24 hours.  The infusion rate for the first 30 minutes should be 
25 mL/hr and if well tolerated may be increased to 50 mL/hr.  If this is well tolerated after 30 
minutes the rate of infusion may be increased to 75 mL/hr.  If this is well tolerated after 30 
minutes the rate of infusion may be increased to 100 mL/hr. After the first course of siplizumab 
therapy, the rate of infusion may be increased to a maximum of 200 ml/hr at the discretion of the 
investigator.  After the first two courses of siplizumab therapy, the rate and duration of 
siplizumab infusions will be adjusted by the treating physician, provided that previous infusions 
were well tolerated with no more than a Grade 1 toxicity. It is anticipated that the first infusion 
will be the longest due to infusional toxicity but that subsequent infusions should be better 
tolerated and the infusion duration will be shortened.   The infusion should be held for 
hypotension requiring fluid resuscitation, hypoxia requiring oxygen supplementation, chills 
requiring meperidine or other untoward clinical events at the discretion of the investigator.  The 
infusion should be restarted at the infusion rate that was tolerated prior to the development of 
toxicity. 
Special handling: No special precautions are warranted.  Empty and partial vials should be 
disposed of as biological waste. 
11.9.4 Toxicity 
Siplizumab is a foreign protein that binds to specific immune cells and therefore allergic 
reactions, including anaphylaxis, or cytokine release syndrome may be observed after 
administration of siplizumab. 
Based upon the clinical experience to date, the most common clinical symptoms reported are 
chills, headache, myalgia, changes in vital signs, and (SC administration only) injection site 
reaction.  These events generally have been temporally associated with dosing, brief in duration, 
and resolved without sequelae.  Changes in hematological parameters, including decreased 
absolute lymphocyte count (ALC), have also been observed.  Dose-level-dependent reductions in 
ALC occur after treatment with siplizumab administered SC or IV.  Sustained reduction of ALC 
has been observed.  Doses as high as 4.8 mg/kg have been administered.  These events are not 
unexpected given the mechanism of action of the molecule. 
11.10 METHOTREXATE 
11.10.1Availability 


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NCI Version Date: 11/21/2018 
 
 
45 
Methotrexate is commercially available in 2 mL (25 mg/mL) vials or 20 mg, 25, mg, 50 mg, or 
100 mg vials for reconstitution.  Only the preservative free methotrexate formulation should be 
used for intrathecal dosing. Read the manufacturer’s package labeling carefully for solution 
concentrations. Please refer to the agent’s package insert for additional information. 
11.10.2Storage & Stability 
Unopened vials of methotrexate should be stored at room temperature, and protected from light. 
11.10.3Preparation 
For intrathecal/intraventricular injection: reconstitute to a concentration of 1-5 mg/mL with 
an appropriate sterile, preservative free medium such as Sodium Chloride Injection, USP. 
11.10.4Administration 
In this study, methotrexate will be administered as an intrathecal injection of 12 mg or 
intraventricular injection of 6 mg. Methotrexate will be given to select patients as described in 
Section 3.2.5.2. 
11.10.5Toxicity 
Toxicities associated with intrathecal administration: arachnoiditis, ataxia, coma, confusion, 
dementia, encephalopathy, headache, paresis, seizures. 
11.10.6Drug interactions 
The use of NSAIDs, probenecid, salicylates, sulfonamides may prolong methotrexate levels and 
enhance toxicity. 
11.11 CYTARABINE 
11.11.1Availability 
A commercially available pyrimidine nucleoside antimetabolite.  Read the manufacturer’s 
package labeling carefully for solution concentrations. Please refer to the agent’s package insert 
for additional information. 
11.11.2Storage & Stability 
Unopened vials 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.   
11.11.3Preparation 
For intrathecal/ intraventricular injection: reconstitute to a total volume of 3 to 5 mL with an 
appropriate sterile, preservative free medium such as Sodium Chloride Injection, USP. 
11.11.4Administration 
In this study, cytarabine will be administered as an intraventricular or intrathecal  injection of 30 
or 70 mg. Cytarabine will be given to select patients as described in Section 3.2.5.2. 
11.11.5Toxicity 
Toxicities associated with intrathecal administration: myelosuppression, fever, dizziness, 
somnolence, and arachnoiditis 


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12. REFERENCES 
 
 
(1)  de la Parra B., van den Branden, Smyej I, Bazin H. Inhibition of T-cell activation by LO-
CD2-1, a rat monoclonal antibody against the human CD2 glycoprotein. Belg J Zool. 
1991;13. 
 
(2)  Teh SJ, Killeen N, Tarakhovsky A, Littman DR, Teh HS. CD2 regulates the positive 
selection and function of antigen-specific CD4- CD8+ T cells. Blood. 1997;89:1308-
1318. 
 
(3)  Abruzzo LV, Rosales CM, Medeiros LJ et al. Epstein-Barr virus-positive B-cell 
lymphoproliferative disorders arising in immunodeficient patients previously treated with 
fludarabine for low-grade B-cell neoplasms. Am J Surg Pathol. 2002;26:630-636. 
 
(4)  Bird AG, McLachlan SM. Cyclosporin A and Epstein-Barr virus. Lancet. 1980;2:418. 
 
(5)  Bhargava R, Barbashina V, Filippa DA, Teruya-Feldstein J. Epstein-Barr virus positive 
large B-cell lymphoma arising in a patient previously treated with Cladribine for hairy 
cell leukemia. Leuk Lymphoma. 2004;45:1043-1048. 
 
(6)  Birkeland SA, Hamilton-Dutoit S. Is posttransplant lymphoproliferative disorder (PTLD) 
caused by any specific immunosuppressive drug or by the transplantation per se? 
Transplantation. 2003;76:984-988. 
 
(7)  Roch N, Salameire D, Gressin R et al. Fatal adenoviral and enteroviral infections and an 
Epstein-Barr virus positive large B-cell lymphoma after alemtuzumab treatment in a 
patient with refractory Sezary syndrome. Scand J Infect Dis. 2007;1-4. 
 
(8)  Scheinberg P, Fischer SH, Li L et al. Distinct EBV and CMV reactivation patterns 
following antibody-based immunosuppressive regimens in patients with severe aplastic 
anemia. Blood. 2007;109:3219-3224. 
 
(9)  Choquet S, Leblond V, Herbrecht R et al. Efficacy and safety of rituximab in B-cell post-
transplantation lymphoproliferative disorders: results of a prospective multicenter phase 2 
study. Blood. 2006;107:3053-3057. 
 (10)  Milpied N, Vasseur B, Parquet N et al. Humanized anti-CD20 monoclonal antibody 
(Rituximab) in post transplant B-lymphoproliferative disorder: a retrospective analysis on 
32 patients. Ann Oncol. 2000;11 Suppl 1:113-116. 
 (11)  van Esser JW, Niesters HG, van der HB et al. Prevention of Epstein-Barr virus-
lymphoproliferative disease by molecular monitoring and preemptive rituximab in high-
risk patients after allogeneic stem cell transplantation. Blood. 2002;99:4364-4369. 
 (12)  Harris NL, Jaffe ES, Diebold J et al. World Health Organization classification of 
neoplastic diseases of the hematopoietic and lymphoid tissues: report of the Clinical 


Abbreviated Title: Siplizumab/EPOCH-R in T/NK NHL 
NCI Version Date: 11/21/2018 
 
 
47 
Advisory Committee meeting-Airlie House, Virginia, November 1997. J Clin Oncol. 
1999;17:3835-3849. 
 (13)  A clinical evaluation of the International Lymphoma Study Group classification of non-
Hodgkin's lymphoma. The Non-Hodgkin's Lymphoma Classification Project. Blood. 
1997;89:3909-3918. 
 (14)  Gisselbrecht C, Gaulard P, Lepage E et al. Prognostic significance of T-cell phenotype in 
aggressive non-Hodgkin's lymphomas. Groupe d'Etudes des Lymphomes de l'Adulte 
(GELA). Blood. 1998;92:76-82. 
 (15)  Lopez-Guillermo A, Cid J, Salar A et al. 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. 1998;9:849-855. 
 (16)  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. 1997;89:4514-4520. 
 (17)  Ansell SM, Habermann TM, Kurtin PJ et al. Predictive capacity of the International 
Prognostic Factor Index in patients with peripheral T-cell lymphoma. J Clin Oncol. 
1997;15:2296-2301. 
 (18)  Gallamini A, Zaja F, Patti C et al. Alemtuzumab (Campath-1H) and CHOP 
chemotherapy as first-line treatment of peripheral T-cell lymphoma: results of a GITIL 
(Gruppo Italiano Terapie Innovative nei Linfomi) prospective multicenter trial. Blood. 
2007;110:2316-2323. 
 (19)  Kim JG, Sohn SK, Chae YS et al. Alemtuzumab plus CHOP as front-line chemotherapy 
for patients with peripheral T-cell lymphomas: a phase II study. Cancer Chemother 
Pharmacol. 2007;60:129-134. 
 (20)  Gallamini A, Zaja F, Patti C et al. Alemtuzumab (Campath-1H) and CHOP 
chemotherapy as first-line treatment of peripheral T-cell lymphoma: results of a GITIL 
(Gruppo Italiano Terapie Innovative nei Linfomi) prospective multicenter trial. Blood. 
2007;110:2316-2323. 
 (21)  Kim JG, Sohn SK, Chae YS et al. Alemtuzumab plus CHOP as front-line chemotherapy 
for patients with peripheral T-cell lymphomas: a phase II study. Cancer Chemother 
Pharmacol. 2007;60:129-134. 
 
 
 


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48 
13. APPENDICES 
13.1 APPENDIX 1: EPOCH-RS CHEMOTHERAPY 
 
 
 
 
EPOCH-RS CHEMOTHERAPY 
 
Drug 
 
Total dose* 
(mg/m2/d) 
 
Route 
Day 
1  2  3  4    5    6                                                 22 
 
 
 
Siplizumab 
 
fixed total dose 
   
  IV 
   x 
 
 
 
3.4, 4.8, 8.5 or 15 mg/kg 
Rituximab  
 
 
375 mg/m2  
 
 
 IV  
                x 
 
 
 
 
 
 
Etoposide          
 50 mg/m2/day 
 
  CIV 
    x-x-x-x- 
Vincristine 
          
0.4 mg/m2/day 
 
  CIV 
    x-x-x-x- 
Doxorubicin 
           
10 mg/m2/day 
 
  CIV 
    x-x-x-x- 
Cyclophosphamide  
750 mg/m2 
 
  IV 
                  x 
Prednisone 
 
60 mg/m2/day BID  
  PO 
    x-x-x-x-x 
Filgrastim  
   
 
480 mcg QD 
 
 
  SC  
                      x until ANC recovery > 5000/mm3 
New cycle begins 
 
 
 
 
 
 
 
                                           
 
 
 
 
  x 
 
*First cycle doses, refer to 3.2 for dose escalations and 3.3.2 for dose modifications 
For the first cycle of treatment, the EPOCH infusion may be infused on days 2-6 if the Siplizumab infusion is prolonged due to 
infusion reactions. 


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NCI Version Date: 11/21/2018 
 
 
49 
13.2 APPENDIX 2:  EPOCH ADMIXTURES 
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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NCI Version Date: 11/21/2018 
 
 
50 
13.3 APPENDIX 3: PERFORMANCE STATUS CRITERIA 
 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able to 
carry on all pre-disease performance 
without restriction. 
100 
Normal, no complaints, no evidence of 
disease. 
90 
Able to carry on normal activity; minor 
signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able to 
carry out work of a light or sedentary 
nature (e.g., light housework, office 
work). 
80 
Normal activity with effort; some signs 
or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time.  Ambulatory 
and capable of all self-care, but 
unable to carry out any work 
activities.  Up and about more than 
50% of waking hours. 
60 
Requires occasional assistance, but is 
able to care for most of his/her needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable of 
only limited self-care, confined to bed 
or chair more than 50% of waking 
hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any self-
care.  Totally confined to bed or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes progressing 
rapidly. 
5 
Dead. 
0 
Dead. 

ICF_001.pdf: 
MEDICAL RECORD 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
INSTITUTE: 
National Cancer Institute 
STUDY NUMBER: 
09-C-0065 
PRINCIPAL INVESTIGATOR: 
Wyndham Wilson, M.D., Ph.D 
STUDY TITLE:  
Phase 1 Trial of Siplizumab and Dose-Adjusted EPOCH-Rituximab in T and NK-Cell 
Lymphomas 
Continuing Review Approved by the IRB on 02/05/18 
Amendment Approved by the IRB on 12/18/18 (H) 
Date posted to web:  12/28/18 
Standard 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• Adult Patient or 
• Parent, for Minor Patient 
NIH-2514-1 (07-09) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent (1) 
 
 
INTRODUCTION 
We invite you to take part in a research study at the National Institutes of Health (NIH). 
First, we want you to know that: 
 
Taking part in NIH research is entirely voluntary. 
 
You may choose not to take part, or you may withdraw from the study at any time.  In 
either case, you will not lose any benefits to which you are otherwise entitled.  However, 
to receive care at the NIH, you must be taking part in a study or be under evaluation for 
study participation. 
 
You may receive no benefit from taking part.  The research may give us knowledge that 
may help people in the future. 
Second, some people have personal, religious or ethical beliefs that may limit the kinds of 
medical or research treatments they would want to receive (such as blood transfusions).  If you 
have such beliefs, please discuss them with your NIH doctors or research team before you agree 
to the study. 
Now we will describe this research study.  Before you decide to take part, please take as much 
time as you need to ask any questions and discuss this study with anyone at NIH, or with family, 
friends or your personal physician or other health professional. 
Why are you being asked to take part in this study? 
Lymphoma and its treatment:  You have a disease called T-cell or NK cell non-Hodgkin's 
lymphoma which your doctors think would be best treated with chemotherapy.  In general, 
mature T-cell and NK cell lymphomas are generally responsive to chemotherapy but less likely 
to be cured 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.   


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:  09-C-0065 
CONTINUATION: page 2 of 17 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
. 
Why is this study being done? 
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-R (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, called siplizumab, has been manufactured to 
attach to a protein called CD2 that your type of tumor contains.   
How many people will take part in this study? 
Up to 30 patients will be treated on this study. 
Description of Research 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 
siplizumab in combination with continuous infusion EPOCH chemotherapy with filgrastim is 
safe and if it improves the outcome of therapy of your lymphoma.  In this study five 
chemotherapy drugs are given together in an intensive combination called EPOCH. In addition, 
you will receive a drug called rituximab. Rituximab is another monoclonal antibody which binds 
to a specific molecule (called CD20) present on most B-cells. This drug is being given to help 
prevent a potential side effect of the siplizumab.  EPOCH-R contains drugs which are standard 
for the treatment of lymphomas.  Because higher doses of chemotherapy may increase the 
benefit, the doses of several drugs in EPOCH-R may be increased on each cycle if you tolerated 
them on the previous cycle.    
Siplizumab-EPOCH-R chemotherapy treatment:  
The chemotherapy regimen known as Siplizumab-EPOCH-R will be given by intravenous (IV) 
infusion through a “central line,” an IV catheter (or tube) placed in a large vein in your arm or 
chest.  You will be admitted to the hospital for the infusion of the monoclonal antibody therapy 
on this protocol but may receive the chemotherapy infusion as an outpatient. Patients will receive 
dose adjusted (DA) EPOCH-R chemotherapy which includes the following drugs: etoposide (E), 
prednisone (P), vincristine (O), cyclophosphamide (C), doxorubicin (H), and rituximab (R). The 
drug siplizumab will be given by IV infusion on the first day of treatment over several hours. 
When the siplizumab IV infusion is complete, the drugs doxorubicin, etoposide, and vincristine 
will each be given by continuous IV infusion over the next 4 days (that is, continuously for a 
total of 96 hours). When this infusion is completed, the drug rituximab will be given by IV 
infusion over several hours on Day 5. Cyclophosphamide will be given by IV infusion on Day 5 


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:  09-C-0065 
CONTINUATION: page 3 of 17 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
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. 
after you have received the previous chemotherapy drugs. Prednisone will be given by mouth 
(orally) twice each day for 5 days. You will take the first dose of prednisone 8-12 hours before 
starting the siplizumab. 
You will receive the drug filgrastim by subcutaneous (under the skin) injection starting on Day 6 
to increase white blood cell counts. Filgrastim will be continued until your white blood counts 
have reached acceptable levels. The dose of doxorubicin, etoposide, and/or cyclophosphamide 
may be “adjusted” up or down depending on your white blood cell count. You will be given a 
drug commonly known as Bactrim to be taken by mouth (orally) three times a week (for 
example, on a Monday-Wednesday-Friday schedule) to guard against possible infections. You 
will receive a drug called fluconazole to prevent fungal infections, and a drug called acyclovir to 
prevent certain viral infections. You will also receive a drug each day to be taken by mouth 
(orally) to guard against stomach ulcers, such as omeprazole. In addition, you will receive 
colace, or equivalent, by mouth twice daily to prevent constipation. If constipation becomes 
severe, you may also receive the laxative known as lactulose. 
The siplizumab-EPOCH-R therapy will be repeated every twenty-one (21) days, which is known 
as a “cycle” of therapy, for a total of 6 cycles. Following the fourth and sixth treatment cycles 
(approximately weeks 12 and 18) of siplizumab- EPOCH-R, your doctor will evaluate you with 
blood tests and CT/MRI scans.  
Study Chart 
Siplizumab-EPOCH-R Treatment Schema 
 
Day of Treatment 
 
0 
1 
2 
3 4 
5 
6 
7 
8 
9 
10 
11 12 
13 
… 
21* 
Siplizumab 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Rituximab 
 
 
 
 
 
X  
 
 
 
 
 
 
 
 
 
Etoposide 
 
X ⎯⎯⎯⎯⎯→ 
 
 
 
 
 
 
 
 
Prednisone 
X 
X 
X 
X X X  
 
 
 
 
 
 
 
 
 
Vincristine 
 
X ⎯⎯⎯⎯⎯→ 
 
 
 
 
 
 
 
 
Cyclophosphamide 
 
 
 
 
 
X  
 
 
 
 
 
 
 
 
 
Doxorubicin 
 
X ⎯⎯⎯⎯⎯→ 
 
 
 
 
 
 
 
 
Filgrastim 
 
 
 
 
 
 
X** ⎯⎯→ 
 
 
 
 
 
 
 
* This twenty-one day (21) period will be known as a “cycle” of therapy. Therapy will be repeated 
for a total of 6 cycles. During the course of treatment, you may also receive the following drugs: 


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PATIENT IDENTIFICATION 
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methotrexate, Bactrim, fluconazole, acyclovir, omeprazole, and colace. On the first cycle of therapy 
the start of EPOCH chemotherapy may be delayed until the following day if toxicity during the 
siplizumab infusion caused a prolonged infusion time. 
** Filgrastim will continue to be given to you until your blood counts have reached acceptable levels. 
Treatment of disease in the nervous system:   
Your lymphoma may spread to the central nervous system (CNS) which includes the brain and 
spinal cord.  It may be necessary to treat the CNS with chemotherapy which usually includes the 
instillation of chemotherapy drugs (methotrexate and/or cytarabine) directly into the fluid (the 
cerebrospinal fluid, or CSF) surrounding the brain.  This is usually done by first placing a small 
reservoir (called 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 respond to this therapy, it may be 
necessary to modify it and/or to also administer radiation to your brain and/or spinal cord.  Each 
of these therapies will be discussed with you if they are needed.  Patients who have lymphoma in 
their bone marrow or in multiple areas outside of their lymph nodes 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 day 1 of cycles 3-6 of their Siplizumab-EPOCH-R 
chemotherapy.  Your treating physicians will discuss this with you. 
Research tests:   
We would like to perform research studies on your blood and tumor tissue to look at different 
genes and proteins that may be involved in the development of your lymphoma or the reaction of 
the immune system.  We will not examine mutations of genes from your normal tissue without 
obtaining additional permission from you.  We plan to do a tissue biopsy before you start 
treatment.  Biopsies of tumor will be done with local or general anesthesia.  The tumor biopsies 
are being performed for two reasons; first to confirm your diagnosis and test for CD2 and second 
to perform research tests on the tumor.  These biopsies will give us important information about 
your tumor. Biopsies requiring major surgery (opening the chest or abdomen) will only be done 
if necessary for medical care and will not be done for experimental purposes.  It is important, 
however, for you to understand that in some cases, biopsies of tumor may be done primarily for 
experimental purposes.  These biopsies are optional for participation in the study but are 
important to help us learn how to better treat T cell lymphoma. 
Certain patients who have tumor cells in their blood stream may be asked to undergo a procedure 
called lymphapheresis or apheresis for research purposes. Lymphapheresis or apheresis is done 
by circulating your blood through the apheresis machine. To do this you must have two places 
where IV needles are placed. There are two ways to do this procedure. In the first method, a 
needle is placed into each of your arm veins. The second method uses a vascular access device. 
Both methods provide a route for your blood to be circulated through the apheresis machine. 
Your blood is removed from one IV site, and then flows through the tubing into the machine. 
The machine has a centrifuge that separates the part of the blood that is to be removed. Only a 


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small portion of your blood is circulated through the machine at any one time. The blood then 
returns to you through the other IV site. The procedure takes 2 - 4 hours to complete. Once the 
procedure is done, all of your blood is returned to you. You will be taken off the machine by the 
nurse. The needles are then removed and pressure is put over where the needles were to be sure 
that bleeding stops. After a period of rest, you will be told when to come in for your next 
procedure. The procedure may be done more than once. 
Blood samples will be collected to measure the level of the siplizumab in your blood. During the 
first cycle, you will have ten samples drawn over a 5 day period. During cycles 2-6, you will 
only have 3 blood samples drawn. Each one of these samples will be slightly more than a 
teaspoon of blood. 
You may have some discomfort when the nurse puts the needles into your veins. Keeping your 
arms in one position and staying still during a 2 - 4 hour procedure may also be a little 
uncomfortable. Some patients may feel dizzy, light-headed, nauseated, or cold during the 
procedure. Tell the staff right away if you feel any of these side effects. It is normal to feel tired 
for a short time after this procedure. 
What happens after treatment is completed:   
This depends on how you 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 does not disappear entirely or if it should recur after having disappeared 
for a period of time, then you may need further therapy.  At that time you will be given the 
opportunity of participating in additional research protocols that may be appropriate for you.  If 
no such protocols are available, you will be returned to the care of your local physician.  We will 
continue to contact you and/or your local physician to see how you are doing even after you have 
completed treatment on this protocol. It is important to stress that participation in this protocol 
does not constitute a promise of long-term medical care here at the Clinical Center.  It is 
conceivable that participation in this study may make you 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.  You may decide now not to receive treatment on this protocol, or you 
may choose at any point in time to stop the treatment and withdraw from the protocol; in either 
case you will be returned to the care of your referring physician.   
Risks or Discomforts of Participation 
In order to determine if you are eligible for this study, several tests need to be done.  This period 
of evaluation may take up to three weeks and may be done on an outpatient basis.  Evaluation 
may include some or all of the following tests: standard blood tests, 24 hour collections of urine, 
tests of lung and heart function, computerized tomography (CT) scans, nuclear medicine scans of 
the body (called a PET scan), bone marrow biopsies and biopsies of suspected areas of tumor.   
 


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The risks associated with bone marrow biopsies are pain, bleeding and local infection.  Risks of 
tissue biopsies include pain, bleeding, infection, and the risks to the particular area undergoing 
surgery.  A biopsy of tumor may require general anesthesia.  General anesthesia itself is 
generally very safe but has a very small risk of major complications such as heart attack or 
stroke.  The surgical and anesthetic risks will be explained to you in more detail at the time of 
surgery, if this is needed  
You 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.   
In order to receive this treatment, you will need to have a central venous catheter.  This is 
catheter is placed under the skin of the chest wall and enters a major vein in the chest.  There are 
several types of catheters including those which must be removed after each cycle of 
chemotherapy (temporary type) and those which may be kept for the duration of therapy 
(permanent type).  These options will be discussed with you.  The risks associated with placing 
some catheters include pain, bleeding, infection and collapsed lung.  The long term risks of the 
catheter include infection, and clotting of your veins.  If these occur, it may be necessary to 
remove the catheter.  These risks will be explained to you in more detail at the time of insertion.  
You may have side effects while on the study. Every one taking part in the study will be watched 
carefully for any side effects. However doctors don’t know all the side effects that may happen. 
Side effects may be mild or serious. Your health care team may give you medicines to help lessen 
side effects. In some cases, side effects can be serious or long-lasting or may never go away. There 
is also the risk of death from either the treatment or your disease. 
You should talk to your doctor about any side effects that you have while taking part in the study. 
Risks and side effects related to the treatment are identified below. 
Side Effects of Siplizumab: 
"Likely" side effects occur in greater than 50% of patients.  "Less likely" side effects occur in 
10-50% of patients.  "Occasional" side effects occur in <10% of patients.  "Unlikely" side effects 
occur in <1% of patients.  "Serious" side effects are severe, life threatening, or cause death.  
Most of the side effects are listed in this form, but they will vary from person to person.  There 
may be other side effects that we don't know about.   
Likely: 
• Mild flu-like symptoms such as chills, fever (usually occur only with the first dose and 
decreased or absent with each following dose).  Stopping or increasing the time it takes to 
give you siplizumab may make these side effects go away.   


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• Decreased white blood cells (including normal T-cells), which may increase the risk of 
infection (bacterial, viral, fungal, parasitic); you will be given medicines to prevent 
infections.   
Less likely--these usually occur only with the first dose and are decreased or absent with 
each following dose: 
• Dizziness 
• nausea 
• general sick feeling 
• muscle pain 
• headache  
Occasional: 
• Anemia (decreased red blood cells, which causes you to feel tired, lightheaded, and have 
a rapid heartbeat) 
• anorexia (lack of appetite) 
• diarrhea 
• cold sores (herpes simplex) 
• high or low blood pressure 
• paresthesia (abnormal touch sensation) 
• sore throat 
• itching 
• rapid or slow heart beat 
• sweating 
• abnormal taste  
• vasodilatation (increased blood flow) 
• weakness   
Unlikely: 
• Ecchymosis (small hemorrhagic spot in the skin) 
• hyperesthesia (increased pain sensitivity) 
• hypothermia (low body temperature) 
• difficulty sleeping 
• leg cramps 
• leukocytosis (temporary increase in white blood cells) 
• pain 


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• pleural (lining of the lung) disorder 
• decrease in platelets   
Unlikely, but serious: 
• Allergic reactions with any of the following symptoms: 
- 
Marked lowering of the blood pressure, throat tightness, shortness of breath, 
severe skin rash   
• Development of other cancers or recurrence of a past cancer.   
• Development of Epstein-Barr Virus associated disease that may be malignant (up to 
about 10% of patients treated with siplizumab. 
• Shock-like reaction, which may include heart, lung, and brain problems, caused by the 
killing of normal T-cells. 
• Heart rhythm, kidney, and lung problems caused by chemicals released into your blood 
from dead cancer cells; you will receive extra fluids before you start your treatment with 
siplizumab to flush any extra chemicals out of your body, and you will also be given 
medicine to help control the chemical balance of your blood.   
• Inflammation of the joints 
• Serious viral infection 
• Changes in liver enzymes 
 
Since siplizumab can cause a prolonged lowering of lymphocytes (white blood cells), you may 
develop an increased risk for serious infections, the development of other tumors, or the 
recurrence of a previous cancer.  Also, it is important to know that patients may develop other 
unexpected side effects and these could lead to serious organ damage or even death. 
Side Effects of EPOCH-R: 
Likely: 
• Lowered white blood cell count that may lead to infection 
• Lowered platelets which may lead to an increase in bruising or bleeding 
• Lowered red blood cells which may cause anemia, tiredness, or shortness of breath 
• Should low counts occur, they can be treated with blood products (transfusions), 
antibiotics, and there may be a reduction in the amount of drug given to you 
• Constipation 
• Fatigue or tiredness 
• Tingling of fingers and/or toes 
• Hair loss 


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• Fever and/or chills 
• Time away from work 
• Urine colored red for a day or two after the doxorubicin infusion 
• Fingernail and toenail changes 
• Tearing or dry eyes 
• Runny nose 
• Bony pain 
Less Likely: 
• Nausea and/or vomiting 
• Loss of appetite, change in taste and weight loss 
• Temporary shortness of breath or dizziness while receiving rituximab 
• Headaches 
• Muscle aches and muscle weakness 
• Hoarseness or pain in the jaw 
• Elevated blood sugar levels 
• Elevated or decreased blood pressure 
• Confusion 
• Mouth & throat sores. Temporary irritation to the mouth may lead to mouth ulcers (similar 
to canker sores). Medications to numb the mouth may ease the mouth discomfort. 
• Stomach ulcers 
• Skin rashes and/or dry skin 
• Loss of control of muscles or reflexes 
• Abnormalities in blood results such as elevated liver enzymes, low blood protein and low 
blood calcium 
• Mood changes such as agitation or depression 
• Trouble sleeping 
Rare, But Serious: 
• Severe constipation may result in abdominal pain and cramping 
• Bladder irritation with painful and bloody urine 
• Damage to the heart muscle 
• Skin rash that may be serious and life-threatening 
• Allergic reaction that may be severe or life-threatening. Symptoms may include difficulty 
breathing, low blood pressure, fast heart rate, and sweating. 


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• Severe hepatitis (liver infection) in those patients who are carriers of the hepatitis virus. 
Patients who may have had prior exposure to the hepatitis B and C virus may be at an 
increased risk of recurrence of the virus that may lead to severe liver damage that can be 
life-threatening. You doctor will screen you for the hepatitis virus before beginning 
treatment on this study. If you test positive for the virus, you will be closely monitored for 
signs of the infection, and you will be treated, if appropriate, by your doctor. 
Drugs used for the treatment of the nervous system:  
• 
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.  
• 
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 for low blood counts, and liver 
function abnormalities, which can occur with cytarabine when given by vein. 
Secondary Malignancy:  
A number of established chemotherapy agents have an inherent risk of causing another cancer 
(known as a “secondary malignancy”). Certain drugs in use today, not currently known to be 
associated with this risk may be shown at a later time to result in the development of these 
secondary malignancies.  Siplizumab, when used by itself, has rarely caused a secondary cancer 
related to the Epstein-Barr virus (EBV).  The rituximab is given in this regimen to help prevent 
this.  If you do develop an EBV related cancer, you will not receive any more siplizumab therapy.  
The treatment of EBV related cancer ranges from observation to treatment with rituximab alone 
or with chemotherapy. 
Reproductive Risks:  
Many of the drugs used in this treatment program are toxic to the cells in the ovary and testicle 
and may produce sterility.  Recovery of normal fertility is not well studied although we know that 
some patients treated with this combination have remained fertile after the therapy has been 
completed.  For this reason, men who are about to receive this treatment should, if they wish to 
have children in the future, consider sperm banking before start of the treatment.  These drugs, as 
well as the scans performed to assess your disease may also be very toxic to an unborn child or 
nursing baby.  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 


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of the pregnancy test will be made available to you prior to the initiation of the study. If you are a 
woman and become pregnant while on this study, treatment will be stopped. If you think that you 
may have become pregnant while you are on this study, please contact the Principal Investigator, 
Dr. Wyndham Wilson, Telephone: 240-760-6092, before taking any further study treatment or 
undergoing any imaging scans.  
Infection Risks:  
It is important to emphasize that when you have a decreased white blood cell count you are at risk 
of infection.  Such infections can be very serious and can even cause death if not quickly and 
properly treated.  If you have a temperature greater than 38.3o C (101o F), you must call your doctor 
immediately. If your temperature is higher than 38.0o C (100.4 o F) two times in a 24 hour period, 
you 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 at increased risk of 
serious bleeding.  It may be necessary to give you transfusions of platelets if your platelet counts 
reach very low levels.  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. 
Your physicians will watch you closely for side effects and will stop treatment if any side effects 
become a serious threat to your life or well-being. Your physicians will also stop the treatments if 
it becomes clear that the treatment is not successfully controlling your disease. For more 
information about risks and side effects, ask your study doctor. 
Risks of Treatment of the Central Nervous System:   
It may be necessary to treat the CNS with chemotherapy which usually includes the instillation 
of chemotherapy drugs (methotrexate and/or cytarabine) directly into the fluid (the cerebrospinal 
fluid, or CSF) surrounding the brain.  This is usually done by first placing a small reservoir 
(called 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. Complications of Ommaya insertion are 
uncommon when done by an experienced doctor 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, the complications of the lumbar puncture or Ommaya insertion and 
methotrexate instillation will be discussed in more detail.   


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Potential Benefits of Participation 
Are there benefits to taking part in this study? 
It is likely that most patients will have at least a temporary improvement from treatment with 
Siplizumab and EPOCH-R chemotherapy.  However, we cannot be certain if you will be cured 
of your lymphoma and it is possible that you may not respond to treatment. 
In addition, your participation in this protocol may contribute to advances in the understanding 
of and treatment for your disease.  
Alternative Approached or Treatments 
What other choices do I have if I do not take part in this study? 
It should be emphasized that we do not know at this point whether the combination of drugs we 
propose to give you is superior, inferior or equivalent to standard combination chemotherapy for 
your disease.  Alternative procedures that could be used to treat your disease include: 
• 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 condition. 
• Treatment with single drugs.  This is known to produce brief responses of a few months' 
duration in many patients but to have little beneficial effect in long-term control of the 
disease. 
• Radiation (X-ray) treatments.  This can stop tumor growth in particular locations, such as 
bone, abdomen, and other sites but is not successful in controlling the disease overall 
unless the disease is very localized at the start of therapy.  
• Surgery.   As with radiation, surgery can be successful in removing tumor from particular 
locations but cannot be used successfully to remove all lymphoma cells from the body, 
since the disease is almost always present in multiple locations.  Also, surgery cannot be 
used against tumor in some of the organs most commonly involved by lymphoma, such 
as the liver or the lungs. 
• Waiting, without active therapy.  Although a period of watchful waiting is appropriate 
treatment for some kinds of tumors, in lymphomas similar to yours, the disease will often 
grow and spread rapidly if no treatment is administered.  
• No treatment.  You can choose not to receive any therapy for your lymphoma.  In this 
case, your doctor can give you medications that will make you feel comfortable.   
Stopping Therapy 
Your doctor may decide to stop your therapy for the following reasons: 
• if he/she believes that it is in your best interest 
• if your disease comes back during treatment 


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• if you have side effects from the treatment that your doctor thinks are too severe 
• if new information shows that another treatment would be better for you 
In this case, you will be informed of the reason therapy is being stopped. 
You can stop taking part in the study at any time. However, if you decide to stop taking part in 
the study, we would like you to talk to the study doctor and your regular doctor first. 
If you decide at any time to withdraw your consent to participate in the trial, we will not collect 
any additional medical information about you. However, according to FDA guidelines, 
information collected on you up to that point may still be provided to MedImmune or designated 
representatives. If you withdraw your consent and leave the trial, any samples of yours that have 
been obtained for the study and stored at the NCI can be destroyed upon request. However, any 
samples and data generated from the samples that have already been distributed to other 
researchers or placed in the research databases cannot be recalled and destroyed. 
Research Subject’s Rights 
What are the costs of taking part in this study?  
If you choose to take part in the study, the following will apply, in keeping with the NIH policy: 
• You will receive study treatment at no charge to you. This may include surgery, 
medicines, laboratory testing, x-rays or scans done at the Clinical Center, National 
Institutes of Health (NIH), or arranged for you by the research team to be done outside 
the Clinical Center, NIH if the study related treatment is not available at the NIH.  
• There are limited funds available to cover the cost of some tests and procedures 
performed outside the Clinical Center, NIH.  You may have to pay for these costs if they 
are not covered by your insurance company. 
• Medicines that are not part of the study treatment will not be provided or paid for by the 
Clinical Center, NIH. 
• Once you have completed taking part in the study, medical care will no longer be 
provided by the Clinical Center, NIH. 
Will your medical information be kept private? 
We will do our best to make sure that the personal information in your medical record will be 
kept private.  However, we cannot guarantee total privacy.  Organizations that may look at 
and/or copy your medical records for research, quality assurance, and data analysis include: 
• The National Cancer Institute (NCI) and other government agencies, like the Food and 
Drug Administration (FDA), which are involved in keeping research safe for people. 
• National Institutes of Health Intramural Institutional Review Board 
• The study Sponsor (Medimmune) 
• Qualified representatives from Medimmune, the pharmaceutical company who produces 
siplizumab. 


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:  09-C-0065 
CONTINUATION: page 14 of 17 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 
. 
A description of this clinical trial will be available on http://www.Clinicaltrials.gov, as required 
by U.S. Law.  This Web site will not include information that can identify you.  At most the 
Web site will include a summary of the results.  You can search this Web site at any time.  
Certificate of Confidentiality  
To help us protect your privacy, we have obtained a Certificate of Confidentiality. The 
researchers can use this Certificate to legally refuse to disclose information that may identify you 
in any federal, state, or local civil, criminal, administrative, legislative, or other proceedings, for 
example, if there is a court subpoena. The researchers will use the Certificate to resist any 
demands for information that would identify you, except as explained below. 
You should also know that there are several circumstances in which the Certificate does not 
provide coverage. These include when information:  
• will be used for auditing or program evaluation internally by the NIH; or  
• must be disclosed to meet the legal requirements of the federal Food and Drug 
Administration (FDA).  
• is necessary for your medical treatment and you have consented to this disclosure;  
• is for other research.  
In addition, identifiable, sensitive information protected by this Certificate cannot be admissible 
as evidence or used for any purpose in any action, suit, or proceeding without your consent.  
You should understand that a Certificate of Confidentiality does not prevent you or a member of 
your family from voluntarily releasing information about yourself or your involvement in this 
research. If an insurer, employer, or other person obtains your written consent to receive research 
information, then the researchers will not use the Certificate to withhold that information. 
The Certificate of Confidentiality will not protect against the required reporting by hospital staff 
of information on suspected child abuse, reportable communicable diseases, and/or possible 
threat of harm to self or others. 
Conflict of Interest 
The National Institutes of Health (NIH) reviews NIH staff researchers at least yearly for conflicts 
of interest.  This process is detailed in a Protocol Review Guide.  You may ask your research 
team for a copy of the Protocol Review Guide or for more information.  Members of the research 
team who do not work for NIH are expected to follow these guidelines but they do not need to 
report their personal finances to the NIH. 
Members of the research team working on this study may have up to $15,000 of stock in the 
manufacturer of the product(s) used in this study. This is allowed under federal rules and is not a 
conflict of interest. 


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:  09-C-0065 
CONTINUATION: page 15 of 17 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 
. 
• The National Institutes of Health and the research team for this study are using siplizumab 
developed by MedImmune, Inc. through a joint study with your researchers and the 
company.   The company also provides financial support for this study.  
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:  09-C-0065 
CONTINUATION: page 16 of 17 pages 
-  
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH 
STUDY (Continuation Sheet) 
• Adult Patient or 
• Parent, for Minor Patient 
NIH-2514-1 (07-09) 
P.A.:  09-25-0099 
 
File in Section 4:  Protocol Consent 
 
. 
OTHER PERTINENT INFORMATION 
 
1. Confidentiality.  When results of an NIH research study are reported in medical journals or 
at scientific meetings, the people who take part are not named and identified.  In most cases, the 
NIH will not release any information about your research involvement without your written 
permission.  However, if you sign a release of information form, for example, for an insurance 
company, the NIH will give the insurance company information from your medical record.  This 
information might affect (either favorably or unfavorably) the willingness of the insurance 
company to sell you insurance. 
 
The Federal Privacy Act protects the confidentiality of your NIH medical records.  However, you 
should know that the Act allows release of some information from your medical record without 
your permission, for example, if it is required by the Food and Drug Administration (FDA), 
members of Congress, law enforcement officials, or authorized hospital accreditation 
organizations. 
 
2. Policy Regarding Research-Related Injuries.  The Clinical Center will provide short-term 
medical care for any injury resulting from your participation in research here.  In general, no 
long-term medical care or financial compensation for research-related injuries will be provided 
by the National Institutes of Health, the Clinical Center, or the Federal Government.  However, 
you have the right to pursue legal remedy if you believe that your injury justifies such action. 
 
3. Payments.  The amount of payment to research volunteers is guided by the National 
Institutes of Health policies.  In general, patients are not paid for taking part in research studies at 
the National Institutes of Health. Reimbursement of travel and subsistence will be offered 
consistent with NIH guidelines. 
 
4. Problems or Questions.  If you have any problems or questions about this study, or about 
your rights as a research participant, or about any research-related injury, contact the Principal 
Investigator, Wyndham Wilson, M.D., Ph.D.; Building 10, Room 4N115, Telephone:  240-760-
6092. You may also call the Clinical Center Patient Representative at (301) 496-2626. If you 
have any questions about the use of your specimens or data for future research studies, you may 
also contact the Office of the Clinical Director, Telephone: 240-760-6070. 
 
5. Consent Document.  Please keep a copy of this document in case you want to read it again. 
 
 


MEDICAL RECORD 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
STUDY NUMBER:  09-C-0065 
CONTINUATION: page 17 of 17 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 FEBRUARY 5, 2018 THROUGH FEBRUARY 4, 2019.  
 
 
 
 
 
 
 
 
Signature of Investigator 
Date 
Signature of Witness 
Date 
 
 
Print Name 
 
 
Print Name