Clinical trial NCT00001337
Conditions: Diffuse Large B-Cell Lymphoma (DLBCL) Primary Mediastinal Large B-cell Lymphoma Burkitt Lymphoma Anaplastic Large-Cell Lymphoma Gray Zone Lymphoma
Keywords: Primary Mediastinal B-Cell Lymphoma CD20 + Diffuse Large B-Cell Lymphoma Anaplastic Large Cell Lymphoma De Novo
Sponsor: National Cancer Institute (NCI)
Start date: 1993-05-08; Completion date: 2024-05-24
Enrollment: 348 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
5-Drug Combination Chemotherapy with Hematologic Toxicity Attenuation. Etoposide phosphate, prednisone, vincristine sulfate (Oncovin), cyclophosphamide, and doxorubicin hydrochloride (hydroxydaunorubicin)(EPOCH): Etoposide, VP-16, NSC-141540; Prednisone, PRED, NSC-10023; Vincristine, VCR, NSC-67574; Cyclophosphamide, CTX, NSC-26271; Doxorubicin, DOX, NSC-123127; with Granulocyte Colony-Stimulating Factor (Amgen), Granulocyte colony-stimulating factor (G-CSF), NSC-614629.

Detailed description:
Background:

The treatment of the intermediate and aggressive non-Hodgkin's lymphomas in adults and children commonly induces complete responses in a sizable fraction of the treated population, and about 2/3 of the complete responders appear to have prolonged disease-free survival.

The present study assesses the activity and tolerability in previously untreated patients of a regimen of etoposide phosphate, prednisone, vincristine sulfate (Oncovin), cyclophosphamide, and doxorubicin hydrochloride (hydroxydaunorubicin)(EPOCH) infusional chemotherapy given intensively with granulocyte colony-stimulating factor (G-CSF) support.

Objectives:

Primary:

Assess complete response (CR) and progression-free survival (PFS) of dose-adjusted EPOCH-Rituximab (DA-EPOCH-R) with G-CSF in aggressive B-cell lymphomas.

Eligibility:

Non-Hodgkin's lymphomas in the following categories: mediastinal gray zone lymphoma (MGZL) and primary mediastinal B cell lymphoma (PMBL).

Patients greater than or equal to 12 years old.

Any Stage for PMBL and MGZL.

No prior systemic chemotherapy.

Human immunodeficiency virus (HIV) negative.

Design:

This study will estimate the complete response rate of a group of previously untreated patients and the extent to which EPOCH infusional drug delivery accompanied by a hematopoietic growth factor can increase the dose intensity of treatment.

Patients receive prednisone orally for 5 days, a 96-hour infusion of vincristine, doxorubicin, and etoposide, and a bolus of cyclophosphamide on day 5.

Cycles are repeated every 21 days for a total of 6-8 cycles.

Patients with cluster of differentiation 20 (CD20) expressing tumors (i.e., mature B-cell lymphomas) will also receive rituximab, the humanized monoclonal antibody against the CD20 receptor on day 1 of each cycle.

A total of 348 patients will be enrolled on this protocol.

Arms: arm 1: Subgroup 1 (SG1) - All participants who received combination Rituximab (EPOCH-R). Rituximab 375 mg/m\^2 intravenous (IV) on day 1, every 21 days, prednisone 100mg by mouth (PO) twice a day (bid) on days 1 through 5 every 21 days, and cyclophosphamide 750mg/m\^2 on day 5 every 21 days. Doxorubicin 10mg/m\^2/day, vincristine 0.4mg/m\^2/day, and etoposide 50mg/m\^2/day were delivered as continuous intravenous (CIV) infusions over 96 hours starting on day 1 every 21 days. Dose levels were adjusted on doxorubicin, etoposide, and cyclophosphamide each cycle based on neutrophil nadir. arm 2: Subgroup 2 (SG2) - EPOCH alone: All participants who received Prednisone 100mg by mouth (PO) twice a day (bid) on days 1 through 5 every 21 days, and cyclophosphamide 750mg/m\^2 on day 5 every 21 days. Doxorubicin 10mg/m\^2/day, vincristine 0.4mg/m\^2/day, and etoposide 50mg/m\^2/day were delivered as continuous intravenous (CIV) infusions over 96 hours starting on day 1 every 21 days. Dose levels were adjusted on doxorubicin, etoposide, and cyclophosphamide each cycle based on neutrophil nadir.
Interventions: intervention 1: Etoposide intervention 2: Rituximab intervention 3: Prednisone intervention 4: Cyclophosphamide intervention 5: Vincristine intervention 6: Doxorubicin intervention 7: MRI intervention 8: CT intervention 9: Biopsy intervention 10: PET scan intervention 11: Laparotomy intervention 12: Ondansetron intervention 13: Prochlorperazine intervention 14: Omeprazole intervention 15: Docusate Sodium + Sennosides intervention 16: Lactulose
Intervention descriptions: intervention 1: Etoposide 50mg/m\^2/day were delivered as continuous intravenous (CIV) infusions over 96 hours starting on day 1 every 21 days.

Combination chemotherapy given with Rituximab, Etoposide, VP-16; Prednisone, Cyclophosphamide, Vincristine, and Doxorubicin (EPOCH-R) intravenous (IV) every 3 weeks for 6 cycles. intervention 2: Rituximab given on Day 1 of combination chemotherapy (EPOCH-R) every 3 weeks for 6 cycles.

Combination chemotherapy given with Rituximab, Etoposide, VP-16; Prednisone, Cyclophosphamide, Vincristine, and Doxorubicin (EPOCH-R) intravenous (IV) every 3 weeks for 6 cycles. intervention 3: Prednisone 100mg by mouth (PO) twice a day (bid) on days 1 through 5 every 21 days.

Combination chemotherapy given with Rituximab, Etoposide, VP-16; Prednisone, Cyclophosphamide, Vincristine, and Doxorubicin (EPOCH-R) intravenous (IV) every 3 weeks for 6 cycles. intervention 4: Cyclophosphamide 750mg/m\^2 on day 5 every 21 days.

Combination chemotherapy given with Rituximab, Etoposide, VP-16; Prednisone, Cyclophosphamide, Vincristine, and Doxorubicin (EPOCH-R) intravenous (IV) every 3 weeks for 6 cycles. intervention 5: Vincristine 0.4mg/m\^2/day.

Combination chemotherapy given with Rituximab, Etoposide, VP-16; Prednisone, Cyclophosphamide, Vincristine, and Doxorubicin (EPOCH-R) intravenous (IV) every 3 weeks for 6 cycles. intervention 6: Doxorubicin 10mg/m\^2/day.

Combination chemotherapy given with Rituximab, Etoposide, VP-16; Prednisone, Cyclophosphamide, Vincristine, and Doxorubicin (EPOCH-R) intravenous (IV) every 3 weeks for 6 cycles. intervention 7: Baseline and/or on completion of therapy. intervention 8: Baseline and/or on completion of therapy. intervention 9: Baseline and/or on completion of therapy. intervention 10: As clinically indicated. intervention 11: As clinically indicated. intervention 12: Nausea and/or vomiting. intervention 13: Nausea and/or vomiting. intervention 14: Gastroesophageal reflux disease (GERD). intervention 15: Constipation. intervention 16: Constipation

Protocol documents:
Prot_SAP_000.pdf: 
Abbreviated Title:  EPOCH/Rituximab NHL
Version Date:   04/20/2021
1
Abbreviated Title: EPOCH/Rituximab NHL
NIH Protocol #:  93-C-0133 
NCI Protocol #: T93-0023 (historical number)
Version Date: 04/20/2021
NCT Number:  NCT00001337
Dose-Adjusted EPOCH Chemotherapy and Rituximab (CD20+) in Adults and Children 
with Previously Untreated Aggressive Non-Hodgkin’s Lymphoma
NCI Principal Investigator: Mark Roschewski, M.D. 
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:  240-760-6183
Email:  mark.roschewski@nih.gov
Commercial Agents: 
EPOCH-R = etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, rituximab


Abbreviated Title:  EPOCH/Rituximab NHL
Version Date:   04/20/2021
2
PRÉCIS 
Background

The treatment of the intermediate and aggressive non-Hodgkin's lymphomas in adults and 
children commonly induces complete responses in a sizable fraction of the treated 
population, and about 2/3 of the complete responders appear to have prolonged disease-
free survival. 

The present study assesses the activity and tolerability in previously untreated patients of 
a regimen of EPOCH infusional chemotherapy given intensively with G-CSF support. 
Objective

Assess complete response (CR) and progression-free survival (PFS) of dose-adjusted 
EPOCH-Rituximab (DA-EPOCH-R) with G-CSF in aggressive B-cell lymphomas.
Eligibility

Non-Hodgkin's lymphomas in the following categories: mediastinal gray zone lymphoma 
(MGZL) and primary mediastinal B cell lymphoma (PMBL). 

Patients  12 years old.  

Any Stage for PMBL and MGZL.

No prior systemic chemotherapy. 

HIV negative. 
Design:

This study will estimate the complete response rate of a group of previously untreated 
patients and the extent to which EPOCH infusional drug delivery accompanied by a 
hematopoietic growth factor can increase the dose intensity of treatment.

Patients receive prednisone orally for 5 days, a 96 hour infusion of vincristine, 
doxorubicin, and etoposide, and a bolus of cyclophosphamide on day 5.

Cycles are repeated every 21 days for a total of 6-8 cycles.

Patients with CD20 expressing tumors (i.e. mature B-cell lymphomas) will also receive 
rituximab, the humanized monoclonal antibody against the CD20 receptor on day 1 of 
each cycle.

A total of 348 patients will be enrolled on this protocol.


Abbreviated Title:  EPOCH/Rituximab NHL
Version Date:   04/20/2021
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TABLE OF CONTENTS 
PRÉCIS............................................................................................................................................2
TABLE OF CONTENTS ................................................................................................................3
STATEMENT OF COMPLIANCE ................................................................................................6
1
INTRODUCTION....................................................................................................................6
1.1
Objectives..........................................................................................................................6
1.2
Background .......................................................................................................................6
2
ELIGIBILITY ASSESSMENT AND ENROLLMENT ........................................................12
2.1
Eligibility Criteria ...........................................................................................................12
2.2
RECRUITMENT STRATEGIES ...................................................................................12
2.3
Screening Evaluation ......................................................................................................13
2.4
Participant Registration and Status Update Procedures..................................................13
2.5
Baseline Evaluation.........................................................................................................14
3
STUDY DESIGN...................................................................................................................14
3.1
Study Drug Administration.............................................................................................15
3.2
Dose Modifications.........................................................................................................15
3.3
Studies During Therapy ..................................................................................................17
3.4
Duration Of Therapy.......................................................................................................18
3.5
Radiation Therapy Allowance ........................................................................................18
3.6
Studies On Completion of Therapy ................................................................................19
3.7
Follow-Up .......................................................................................................................19
3.8
Cost and Compensation ..................................................................................................19
3.9
Criteria for Removal from Protocol Therapy and Off Study Criteria.............................20
4
ANCILLARY THERAPY .....................................................................................................20
4.1
Prophylaxis for Pneumocystis Jiroveci (formerly pneumocystis carinii) .......................20
4.2
Recommendations for management of gastrointestinal issues in adults.........................21
4.3
Recommendations for management of gastrointestinal issues in Children ....................21
4.4
Prophylactic Central Nervous System Treatment...........................................................21
4.5
Treatment of Meningeal Lymphoma ..............................................................................22
4.6
Monitoring and Treatment to Prevent Hepatitis B Reactivation.....................................22
4.7
Prevention of Tumor Lysis Syndrome (Cycle 1 only)....................................................23
4.8
Treatment of Patients Who Fail to Achieve Complete Response...................................23
5
BIOSPECIMEN COLLECTION ...........................................................................................23


Abbreviated Title:  EPOCH/Rituximab NHL
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5.1
Correlative Studies for Research/Pharmacokinetic Studies............................................23
5.2
Sample Storage, Tracking and Disposition.....................................................................31
6
DATA COLLECTION AND EVALUATION ......................................................................34
6.1
Data Collection ...............................................................................................................34
6.2
Response Criteria ............................................................................................................35
7
NIH REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING PLAN .....36
7.1
Definitions.......................................................................................................................36
7.2
OHSRP Office Of Compliance And Training / IRB Reporting......................................36
7.3
NCI Clinical Director Reporting.....................................................................................36
7.4
NIH Required Data and Safety Monitoring Plan............................................................36
8
STATISTICAL CONSIDERATIONS...................................................................................36
9
HUMAN SUBJECTS PROTECTION...................................................................................39
9.1
Rationale For Subject Selection......................................................................................39
9.2
Participation of Children.................................................................................................40
9.3
Participation of Subjects Unable to Give Consent..........................................................40
9.4
Evaluation of Benefits and Risks/Discomforts ...............................................................40
9.5
Consent and Assent Process and Documentation ...........................................................42
10
REGULATORY AND OPERATIONAL CONSIDERATIONS...........................................45
10.1
Study Discontinuation and Closure.................................................................................45
10.2
Quality Assurance and Quality Control..........................................................................45
10.3
Conflict of Interest Policy...............................................................................................45
10.4
Confidentiality and Privacy ............................................................................................46
11
PHARMACEUTICAL INFORMATION ..............................................................................46
11.1
Cyclophosphamide..........................................................................................................47
11.2
Doxorubicin ....................................................................................................................47
11.3
Vincristine.......................................................................................................................48
11.4
Etoposide.........................................................................................................................48
11.5
Administration of vincristine/doxorubicin/etoposide. ....................................................48
11.6
Prednisone.......................................................................................................................48
11.7
Rituximab........................................................................................................................49
11.8
Filgrastim (NeupogenR) ..................................................................................................53
11.9
Methotrexate ...................................................................................................................53
11.10 Cytarabine .......................................................................................................................53


Abbreviated Title:  EPOCH/Rituximab NHL
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12
REFERENCES.......................................................................................................................55
13
APPENDIX 1:  EPOCH Admixtures: Preparation and Administration.................................56
14
APPENDIX 2: Letter to Female Patients and Questionnaire.................................................58
14.1
Letter to Patients .............................................................................................................58
14.2
Questionnaire ..................................................................................................................59


Abbreviated Title:  EPOCH/Rituximab NHL
Version Date:   04/20/2021
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STATEMENT OF COMPLIANCE
The trial will be carried out in accordance with International Conference on Harmonisation Good 
Clinical Practice (ICH GCP) and the following: 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 
CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812) 
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are 
responsible for the conduct, management, or oversight of NIH-funded clinical trials have 
completed Human Subjects Protection and ICH GCP Training.
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the Institutional Review Board (IRB) for review and approval.  Approval of both 
the protocol and the consent form must be obtained before any participant is enrolled.  Any 
amendment to the protocol will require review and approval by the IRB before the changes are 
implemented to the study.  In addition, all changes to the consent form will be IRB-approved; an 
IRB determination will be made regarding whether a new consent needs to be obtained from 
participants who provided consent, using a previously approved consent form.
1
INTRODUCTION
1.1
OBJECTIVES 
1.1.1
Primary Objective

Assess complete response (CR) and progression-free survival (PFS) at five (5) years of 
follow-up of dose-adjusted EPOCH-Rituximab (DA-EPOCH-R) with G-CSF in 
aggressive B-cell lymphomas
1.1.2
Secondary Objectives

Assess PFS in bcl-2 + lymphomas treated with dose-adjusted EPOCH-R, and determine 
if it is significantly better than dose-adjusted EPOCH alone at five (5) years of follow-up

Obtain pilot information on the CR and PFS of dose-adjusted EPOCH with G-CSF in 
CD20 negative B cell lymphomas, anaplastic large cell lymphomas (ALCL) and 
peripheral T-cell lymphomas (PTCL)

Assess toxicity of dose-adjusted EPOCH-Rituximab with G-CSF in aggressive 
lymphomas

Characterize the patterns of mdr-1, bcl-2, MIB-1 and mutant p53 expression in previously 
untreated lymphoma patients

Assess the effect of EPOCH-R on ovarian function and reserve in female patients with 
PMBL

Determine if molecular monitoring of the peripheral blood before, during or after therapy 
is predictive of long-term progression-free survival
1.2
BACKGROUND
Over the past 15 years the treatment of the intermediate and aggressive non-Hodgkin's 
lymphomas has undergone considerable evolution. The initial demonstration that these diseases 


Abbreviated Title:  EPOCH/Rituximab NHL
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were curable with combination chemotherapy (1) was followed by many attempts to improve the 
efficacy of treatment. After the general acceptance of CHOP (2) as an unofficial national 
standard, the development of newer regimens focused on the incorporation of additional active 
agents into combination regimens and a general increase in the dose intensity of therapy.  Data 
from single institution studies strongly suggest that CR rates have risen from the 40-60% range 
historically reported with CHOP to about 80-85% (3,4,5), this despite the now widespread use of 
much more sensitive imaging modalities that should make CR more difficult to diagnose. Not 
surprisingly, in parallel with the rise in CR rates, these same studies suggest an apparent 
doubling (from about 30% to about 60%) in long-term survival over this period. 
Over the past few years intramural studies in the diffuse aggressive NHL subtypes have focused 
on the evaluation of ProMACE-CytaBOM(PC)(5). The original version of this regimen, which 
featured treatment for two weeks out of every three with alternating myelosuppressive and non-
myelosuppressive components, produced CR in about 85% of patients and apparently long-term 
disease-free survival in about 2/3 of the treated population; in addition, PC proved superior to 
ProMACE-MOPP (PM) in a randomized comparative trial (5). Although the basis for this 
superiority is not entirely clear, it seems most likely that the significantly increased dose 
intensity of PC compared to PM plays a role. To explore the effects of further increases in 
delivered DI, the PC regimen was subsequently altered by shortening the treatment cycle from 3 
weeks to 2 and by administering the regimen for a planned total of 8 cycles, thus permitting 
comparable total doses of drug. This altered regimen ("short-course" PC), which also permits 
within-patient escalation to tolerance, appears highly active. At the time of last analysis, with 53 
patients on study and 46 having completed therapy, 91% of patients have achieved CR and only 
17% have relapsed. In terms of prognostic factors the patients on short-course PC were generally 
comparable to those on the previous PC trial. Analysis of DI for each constituent agent shows 
that 27-65% more drug can be given on the short-course schedule than on the original PC 
schedule. To the extent permitted by interim analyses, therefore, the results to date are consistent 
with the notion that further increases in delivered DI may convey further therapeutic benefit.
Formally, however, whether the alleged superiority of the newer regimens compared to CHOP is 
real or not can only be answered rigorously by studies such as the recently completed Intergroup 
trial, which compares the newer regimens (ProMACE-CytaBOM, m-BACOD, MACOP-B) with 
CHOP in a prospective randomized fashion. Interim results (median follow-up 31 months) of this 
study (6) reported at the 1992 ASCO meeting show no significant differences in overall response, 
complete response, disease-free survival, or overall survival between the various treatment arms 
and the CHOP control. Although numerically there is actually a 9 percentage-point difference in 
the estimated four-year DFS rate between ProMACE-CytaBOM (45.1%) and the CHOP control 
(36.4%), the difference is not statistically significant, and the curves appear nearly 
indistinguishable over their entire time-course. The apparent equivalence of the four regimens 
was seen in stages III and IV analyzed separately, as well as across the five prognostic groups 
recently defined in the Shipp-Harrington meta-analysis of trials results from many centers 
worldwide. The lack of superiority of ProMACE-CytaBOM to CHOP cannot be explained by 
failure of the study participants to give ProMACE-CytaBOM as written; as shown by Fisher 
during the presentation, the received dose intensity of ProMACE-CytaBOM in this trial is 
equivalent to that reported by the NCI in Reference 5, using, according to Fisher, identical 
techniques for the calculation (personal communication). 
At present, therefore, these results are consistent with the essential therapeutic equivalence of 


Abbreviated Title:  EPOCH/Rituximab NHL
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CHOP and ProMACE-CytaBOM, at least as both regimens are currently administered in a well-
disciplined cooperative group. It is somewhat disturbing to note, however, that ProMACE-
CytaBOM appears to do less well in the Intergroup trial than in the NCI experience (% alive 
without disease: NCI 62% at 5 yrs. versus Intergroup 45% at 4 yrs.).  Comparison of the 
ProMACE-CytaBOM patient populations in the two studies reveals the following:
Intergroup
NCI
Median Age
57
47
Age Range
19-79
18-80
Age > 64 years
24%
15% (>65)
Positive BM
27%
26%
Bulky disease
40%
22%
LDH >250
42%
56%
Working Formulation D or E
14%
6%
Working Formulation F, G, H
82%
89%
Working Formulation J
4%
5%
Unassessable
21%
5%
Median F/U
31 mo.
60 mo.
Thus, the NCI cohort is younger, has fewer patients with bulk disease, but has a somewhat 
higher incidence of significant LDH elevation; distribution of histologies and prevalence of 
bone-marrow involvement appear quite comparable. Comparison of non-randomized groups in 
this way is hazardous at best, but it seems at least possible that differences in the patient 
population might well explain some of the apparent difference in therapeutic results between the 
NCI cohort and the Intergroup one.  Although there may be subtle differences in how the 
regimens are administered between the cooperative group and the NCI, the dose-intensity 
comparisons would appear to rule out major differences in this parameter as an explanation of 
the differences in results. It seems likely that, if this issue is resolvable at all, it will only be by 
attempts to fit the ProMACE-CytaBOM raw data from each study into a multivariate model. 
Finally, although the Intergroup results will probably be stable with further follow-up, it remains 
possible that significant differences may emerge with the passage of time. 
 In summary, given these uncertainties, it seems reasonable to hypothesize that the essential 
equivalence seen in the Intergroup study results from a combination of two factors: (a) better 
results with CHOP than cooperative groups were able to achieve in the past, perhaps because 
oncologists are much more conscious now of the importance of dose intensity and delivering 
therapy on time than they were in the 1970's; and (b) results with ProMACE-CytaBOM that are 
numerically inferior to the NCI results, not because the regimen is being delivered incorrectly 
but because of probable differences in the patient population. Whether this latter point is correct 
or not will perhaps emerge from further analysis. It should also be noted that none of the 
intramural experience at NCI is directly relevant to the question of the relative merits of CHOP 


Abbreviated Title:  EPOCH/Rituximab NHL
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and ProMACE-CytaBOM, since CHOP itself has never been tested systematically here, either 
alone or in comparison to either ProMACE-CytaBOM or ProMACE-MOPP.
Despite the interim Intergroup results, we also think it highly like that much, if not all, of the 
improvement in results within the intramural NCI's patient population over the past 15 years 
represents a real improvement in treatment rather than an altered pattern of case selection. As 
previously noted, we cannot say whether any improvement in results is due to the incorporation 
of additional active agents or to a general increase in the dose intensity of therapy, since both 
have occurred as new regimens have evolved here. Nevertheless, the case for the importance of 
treatment intensity in the diffuse aggressive lymphomas (7) seems sufficiently persuasive to lead 
us to hypothesize that further increases in treatment intensity will translate into additional benefit 
to the patient.
In considering the most promising avenues for future exploration, we are most interested in 
exploiting the opportunities presented by two separate sets of observations:
a) Intramural studies of infusional chemotherapy (EPOCH) in previously treated patients 
with lymphoma have yielded very promising results. This trial was motivated by two sets 
of considerations: (I) the laboratory observation that cell lines expressing P-glycoprotein 
are much more sensitive to cytotoxic natural products given for prolonged periods at very 
low concentrations than to the same drugs given for brief periods at much higher 
concentrations (9); (ii) the finding that lymphoma cells can express PgP (10), though they 
frequently do so at quite low levels. Accordingly, a regimen (EPOCH) was devised to 
administer three natural products (vincristine, doxorubicin, and etoposide) by continuous 
infusion for several days, in combination with oral prednisone and a bolus of 
cyclophosphamide at the end of the infusion. Patients were to be treated with cycles of 
EPOCH until their tumor burden reached a plateau, at which time treatment with EPOCH 
would continue with the addition of the PgP antagonist r-verapamil. At a recent analysis, 
of 33 patients with intermediate or aggressive NHL at presentation, 14 (42%) 
experienced CR after EPOCH therapy, and 12 (36%) had PR. An additional 20 patients 
with histological conversion from an originally indolent lymphoma to a more aggressive 
subtype were also treated with EPOCH; of these, 4 had CR and 14 PR. We were very 
encouraged by these results, particularly since these patients were a very heavily 
pretreated group, having received a median of 8 (range 3-15) drugs and 2 (range 1-8) 
regimens prior to entry on study. Treatment was in general well tolerated; 51% of 345 
cycles were complicated by neutropenia (ANC<500) but only 17% of total cycles (33% 
of those cycles for which ANC<500), involving 42% of the patients on study, were 
attended by hospitalization for fever in the presence of neutropenia. In comparison with 
ProMACE-CytaBOM, the delivered DI of the three natural products was significantly 
higher with EPOCH; that of cyclophosphamide was the same. We think, therefore, that 
the promising nature of these results justifies incorporation of infusional delivery of 
natural products into a regimen for previously untreated patients. 
b) The isolation, cloning, characterization, production, and imminent availability for clinical 
use of a large number of hematopoietic growth factors (G-CSF, GM-CSF. M-CSF, EPO, 
IL1, 3, 4, 6, 11, and the stem-cell factor) have brought much closer the possibility of 
eliminating the bone marrow as a limitation on the dose intensity of cytotoxic treatment. 
Physiological studies have shown that myeloid growth factors appear to act in concert in 
the bone marrow micro-environment to stimulate the growth and differentiation of 


Abbreviated Title:  EPOCH/Rituximab NHL
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hematopoietic stem cells and lineage-restricted progenitors. Although the clinical use of 
growth factors to ameliorate the myelosuppression of cancer treatment is still in its 
infancy, human trials have already established that the use of G-CSF or GM-CSF in 
combination with either conventional or transplant doses of chemotherapy can shorten 
significantly the duration of drug-induced granulocytopenia. Studies in cell culture 
systems and in animal models have given plausibility to the notion that combinations of 
growth factors will likely be able to shorten the duration of platelet nadirs in a clinically 
meaningful manner, though this has yet to be demonstrated in the clinical setting.  
Although the optimal sequencing of growth factors and cytotoxic chemotherapy has not 
been worked out in detail either in animal models or in the clinic, available data suggest 
that it is probably safer to separate temporally the administration of cytotoxic drugs from 
that of growth factors that cause progenitors to enter the cell cycle.
In vitro, rituximab has been shown to sensitize drug-resistant lymphoma cell lines to 
chemotherapy (11).  Additionally, preliminary results of CHOP and rituximab in untreated 
patients with aggressive lymphomas suggest that the combination is more active than CHOP 
alone (12). In this trial of CHOP and rituximab, the response rate was 96% with 63% CR in 30 
evaluable patients.  Toxicities were those expected with CHOP or rituximab.  Thus, there is 
significant evidence to suggest that rituximab may sensitize cells to the effects of chemotherapy 
and this may lead to an increase in cure rate. Based on these results and the lack of significant 
toxicity associated with combining rituximab with chemotherapy, we believe it important to 
rapidly gain experience in a pilot study with the combination of rituximab and EPOCH in 
patients with untreated aggressive lymphomas.  The results of this pilot experience in 15 to 20 
patients may be used by the cooperative groups to develop a protocol of rituximab and EPOCH.  
Rituximab has been well tolerated as a single agent. Of 315 patients treated in studies in which 
rituximab was administered as a single agent, 87% developed an adverse event.  Common 
toxicities included fever (49%), chills (32%), nausea (18%), asthenia (16%), headache (14%), 
angioedema (13%), pruritus (10%), and rash (10%).  Leukopenia occurred in 10.5%, but only six 
cases (1.9%) of grade 3 or 4 neutropenia were reported.  Hypotension occurred in 10% of 
patients during rituximab infusion.  This included a total of four grade 3 events and all recovered 
with saline administration and did not require vasopressors. Bronchospasm and urticaria 
associated with rituximab infusion each occurred in fewer than 10% of patients with grade 3 
events occurring in only 1% of patients. Other toxicities occurring in fewer than 10% of 
individuals treated with rituximab included abdominal pain, vomiting, thrombocytopenia, 
anemia, myalgia, arthralgia, dizziness, and rhinitis. There have been eight reports of severe 
infusion-related adverse events associated with the use of rituximab, which have resulted in fatal 
outcomes.  In 7 of the 8 cases, severe symptoms occurred during the first rituximab infusion. 
These symptoms included severe bronchospasm, dyspnea, hypotension, angioedema, hypoxia, 
pulmonary infiltrate and adult respiratory distress syndrome. Infections occurring during the 
treatment period and subsequently during follow-up were generally mild grade 1 or 2 adverse 
experiences.  Infections that the investigator indicated were possibly or probably related to study 
treatment included pneumonia and herpes virus infection. Despite B-cell depletion, mean IgG, 
IgA, and IgM serum levels remained within the normal range throughout the study treatment 
period and during follow-up.
Hepatitis B virus (HBV) reactivation with fulminant hepatitis, hepatic failure, and death has been 
reported in some patients with hematologic malignancies treated with rituximab.  The majority of 


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patients received rituximab in combination with chemotherapy.  The median time to diagnosis of 
hepatitis was approximately 4 months after the initiation of rituximab and approximately one 
month after the last dose.
A recent analysis of 50 patients with large B-cell lymphomas treated with dose-adjusted EPOCH 
showed an overall complete remission rate of 92%.  Furthermore, progression-free (PFS) and 
overall survival (OS) were 70% and 74%, respectively, at a median follow-up of 52 months.  Of 
potential importance, there was no relationship between any outcome measure and the risk 
factors identified in the International Prognostic Index (IPI) or the index itself, suggesting that 
dose-adjusted EPOCH has a different profile of cell kill compared with CHOP-based regimens.  
These results suggest that dose-adjusted EPOCH may produce superior outcomes to CHOP-
based regimens, even when adjusted for IPI.  We were interested to assessing the relationship of 
markers of treatment failure, bcl-2, p53 and tumor proliferation rate (MIB-1), and outcome.  This 
analysis showed that bcl-2 was the only factor associated with the outcome measure of PFS, with 
50% and 82% PFS at 52 months, in the bcl-2 positive and negative cases, respectively (13).  These 
results suggest that bcl-2 expression may identify a subgroup of patients who will do poorly with 
dose-adjusted EPOCH and are consistent with the recent observations showing bcl-2 is increased 
in patients with activated B-cell genotypes.   Based on these observations, we hypothesized that 
rituximab, potentially through its ability to modulate apoptosis, may increase the PFS and OS of 
patients with large B-cell lymphoma expressing bcl-2.  Furthermore, we are interested in 
assessing the effects of dose-adjusted EPOCH-R in blc-2 negative cases, although to show a 
difference in outcome from dose-adjusted EPOCH alone will require a large number of patients 
and would not be the intent of this study.   
Protocol update: One subset of patients with Primary Mediastinal B-cell Lymphoma was 
reviewed.  The intent was to improve the rate of cure and eliminate the need for mediastinal 
radiation.  There were 51 patients with untreated PMBL who were treated with DA-EPOCH-R.  
During a median of 5 years of follow-up, the event free survival rate was 93% and the overall 
survival rate was 97%.  Therapy with DA-EPOCH-R obviated the need for mediastinal radiation.  
These results were published in the New England Journal of Medicine this year.
Another subset of patients with Burkitt Lymphoma was reviewed. They were followed for a 
median of 86 months.  Rate of Progression Free Survival was 95% and Overall Survival was 
100%.  This was a comparator arm and these data were published in the New England Journal of 
Medicine this year.  
Overall Survival
Progression -Free Survival
0
1
2
3
4
5
6
7
8
20
100
80
60
40
Years on Study
Survival (%)
bcl-2 -
bcl-2 +
0
1
2
3
4
5
6
7
8
20
100
80
60
40
Years on Study
Progression-Free (%)


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2
ELIGIBILITY ASSESSMENT AND ENROLLMENT
2.1
ELIGIBILITY CRITERIA
2.1.1
Non-Hodgkin's lymphomas in the following categories: mediastinal gray zone lymphoma 
and primary mediastinal B cell lymphoma.  
2.1.2
Diagnosis confirmed by staff of the Hematopathology Section, Laboratory of Pathology, 
NCI.  
2.1.3
Patients  12 years old.
2.1.4
Stage of Patients: Any stage for MGZL and PMBL.
2.1.5
No prior systemic chemotherapy. Patients may be entered if they have had prior limited-
field radiotherapy, a short course of glucocorticoids and/or cyclophosphamide for an 
urgent problem at diagnosis (e.g. epidural cord compression, superior vena cava 
syndrome).
2.1.6
HIV negative. 
2.1.7
Not pregnant or nursing.
2.1.8
Adequate major organ function [in adults: serum creatinine ≤ 1.5 mg/dl or creatinine 
clearance > 60 ml/min; and in children serum Cr ≤ age-adjusted normal (See Table 
Below)]; bilirubin < 1.5 mg/dl; ANC > 1000 and platelets > 100,000) unless impairment 
is due to lymphoma or immune-mediated mechanism caused by lymphoma. 
Age(Years)
Maximum Serum Creatinine (mg/dl)
12 - 15
1.2
> 15
1.5
2.1.9
No active symptomatic ischemic heart disease, myocardial infarction or congestive heart 
failure within the past year. If MUGA is obtained, the LVEF should exceed 40%.
2.1.10 No other serious concomitant medical illnesses or uncontrolled active infection that 
would jeopardize the patient's ability to receive the regimen with reasonable safety.
2.1.11 No history of unrelated (non-lymphomatous) neoplasms within past 5 years other than 
non-melanoma skin cancer or in-situ cancer. 
2.1.12 Ability to give informed consent. 
2.2
RECRUITMENT STRATEGIES
This protocol may be abstracted into a plain language announcement posted on NIH websites on 
NIH websites and NIH Social Media platforms.  
Study participants will be recruited from the population of patients screened in the lymphoid 
malignancy clinics of the National Institutes of Health. These will include both referrals from 
outside physicians as well as patient self-referrals. In addition, we participate in a locoregional 
consortium of eight academic institutions within the mid-Atlantic region that shares information 


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regarding active clinical protocols and aims to enhance patient recruitment across the region.
2.3
SCREENING EVALUATION
Note:  Screening evaluation testing/procedures are conducted under the separate screening 
protocol, 01-C-0129 (Eligibility Screening and Tissue Procurement for the NIH Intramural 
Research Program Clinical Protocols).
Note:  Staging studies should be completed within 4 weeks and laboratory studies completed 
within 1 week to confirm study eligibility prior to the patient receiving any study intervention on 
the protocol.
2.3.1
Complete history and physical examination including formal documentation of 
measurable lesions.
2.3.2
Hgb, WBC, differential, platelets, prothrombin time, partial thromboplastin time.
2.3.3
SGOT, SGPT, LDH, alkaline phosphatase, bilirubin, albumin, calcium, phosphate, uric 
acid, BUN, creatinine, and electrolytes.
2.3.4
Creatinine clearance if serum creatinine > 1.5 mg/dl.
2.3.5
Computed tomography of chest, abdomen, and pelvis; and neck if indicated. 
2.3.6
Bone marrow aspiration and biopsy.
2.3.7
Electrocardiogram.
2.3.8
Pregnancy test in women of childbearing potential. 
2.3.9
HIV serology, hepatitis B IgG, core and surface antigen and anti-HCV Antibody.
2.3.10 MUGA or ECHO to assess cardiac ejection fractions as clinically indicated. 
2.3.11 PET scan if clinically indicated or required for staging purposes. 
2.4
PARTICIPANT REGISTRATION AND STATUS UPDATE PROCEDURES
Registration and status updates (e.g., when a participant is taken off protocol therapy and when a 
participant is taken off-study) will take place per CCR SOP ADCR-2, CCR Participant 
Registration & Status Updates found here.
2.4.1
Treatment Assignment Procedures
2.4.1.1
Cohorts
Number
Name
Description
1
Cohort 1
Patients with previously untreated aggressive non-Hodgkin’s lymphoma 
(NHL)
2.4.1.2
Arms
Number
Name
Description
1
Arm 1
EPOCH-R every 3 weeks for 6 cycles
2.4.1.3
Arm Assignment
Subjects in Cohort 1 directly assigned to Arm 1.


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2.5
BASELINE EVALUATION
2.5.1
Two 10 mL red top tubes for storage of serum in registered patients (NCI only). Samples 
will be sent to the Clinical Support Laboratory (CSL), Leidos Biomedical Research, Inc. 
in Frederick MD and stored as described in Section 5.2.1 Procedures for stored serum 
specimens.
2.5.2
One 10 mL cell-free DNA Tube (e.g. Streck collection tubes). Samples will be sent to 
CSL, Leidos Biomedical Research, Inc. in Frederick MD and stored as described in 
Section 5.2.1 Procedures for stored serum specimens.
2.5.3
Urinalysis
2.5.4
Lumbar puncture for CSF cytology and flow cytometry if bone marrow contains 
malignant cells or if there are neurological signs or symptoms.
2.5.5
Computed tomography of head if neurological signs or symptoms or if CSF cytology is 
positive. Use MRI with and without gadolinium if history of allergy to contrast.
2.5.6
Biopsy of accessible lymph node, where possible, for confirmation of histological 
diagnosis.  Biopsies may be obtained for cytogenetics, immunophenotype, molecular 
analyses, and mdr-1, p53, MIB-1 expression. At the NCI, biopsy of easily accessible 
lymph nodes should be performed for research purposes even if the diagnosis is clearly 
established from submitted material. 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.
3
STUDY DESIGN
Update: As of January 3, 2017, the administrative hold has been removed for this protocol. 
Patient enrollment may begin after IRB Approval of Amendment CCC.
Please note that as of October 17, 2016 this protocol is on Administrative Hold. Amendment 
BBB (version date: 10/26/2016) serves as the formal notification to the IRB of the 
Administrative Hold. No new patients will be enrolled; however, patients currently on-study will 
continue to be followed per protocol.
3.1
STUDY DRUG ADMINISTRATION
All patients initiate therapy at Dose Level 1 of DA-EPOCH-R shown below.  Doses are based on 
actual body weight for all patients. Future dose adjustments based on hematological toxicity as 
shown below.   
Drugs
Dosages & Administration/Schedule
Prednisone
60 mg/m2 PO BID days 1-5 (first dose should be given 60 minutes before 
starting rituximab)
Rituximab
375 mg/m2 day 1 (before etoposide+doxorubicin+vincristine infusion 
begins; see Section 11.7 for administration instructions)
Rituximab will only be given to patients whose tumor is CD20 +.  
Etoposide1
50 mg/m2/day CIV days 1- 4 (96 hour infusion)
Doxorubicin1
10 mg/m2/day CIV days 1-4 (96 hour infusion)


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Drugs
Dosages & Administration/Schedule
Vincristine1
0.4 mg/m2/day CIV days 1-4 (96 hour infusion)
Cyclophosphamide2
750 mg/m2 IV day 5 over 30-60 mins
Filgrastim
Body weight <75 kg: 300 mcg/dose
Body weight ≥75 kg: 480 mcg/dose
Starting on Day 6, doses are given once daily by subcutaneous injection 
until ANC > 5000/mcL after the neutrophil nadir.  
Cycle Length3
Repeat cycle every 21 days
1Begin the infusional agents immediately after rituximab is completed.
1Infusional agents should be administered through a central venous access device. 
2Administer cyclophosphamide immediately after infusions are completed. 
3Repeat cycles every 3 weeks (21 days). Delay cycle until ANC ≥ 1000/mcL and platelets ≥ 
75,000/mcL.  Use filgrastim to increase ANC and begin next cycle as soon as ANC recovers.  
3.2
DOSE MODIFICATIONS
3.2.1
Goals and General Strategy
The aim of this protocol is to use neutrophil nadir as a means to normalize drug doses. Since we 
expect neutropenia to be the major manifestation of toxicity, we shall aim to adjust doses to 
achieve an acceptable level of neutropenia. If the patient has extensive bone marrow involvement 
at the start of therapy, the responsible physician has the option not to attenuate drug doses for 
unacceptable durations of neutropenia.  If a patient has severe life-threatening complications, 
such as infection requiring intubation or pressor support, the responsible physician has the option 
not to escalate or to reduce doses.  However, in the absence of severe complications, the dose-
adjusted paradigm should be followed. 
Special Note: If a patient is unable to complete all 6 cycles of EPOCH chemotherapy and 
the PI determines that it is in the patient’s best interest; the patient may receive all 
remaining doses of rituximab.
3.2.2
Dose-Adjustment Paradigm for Hematologic Toxicities

Dose adjustments above starting dose level (level 1) apply to etoposide, doxorubicin and 
cyclophosphamide

Dose adjustments below starting dose level (level 1) apply to cyclophosphamide only.  

Drug Doses based on previous cycle ANC nadir:

If Nadir ANC  500/l on all measurements:           1 dose level above last cycle 

If Nadir ANC  500/l on 1 or 2 measurements:        Same dose level as last cycle  

If Nadir ANC  500/l  3 measurements:               1 dose level below last cycle
Or

If nadir platelet  25,000/l** on 1 measurement:    1 dose level below last cycle. 

If ANC  1000/l and platelets  75,000/l on day 21, begin treatment.

If ANC < 1000/l or platelets < 75,000/l** on day 21, delay up to 1 week.  G-CSF may 
be started for ANC < 1000/l and stopped 24 hours before treatment.  If counts still low 


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after 1 week delay,  1 dose level below last cycle. 
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. 
**Please Note: This does not apply to patients who have low platelets at baseline due to 
lymphoma or immune-mediated mechanism caused by lymphoma. In those cases, no 
delay or dose reduction is required. The dose adjustments for these patients will be 
based solely on the ANC nadir and the PI or designee’s clinical judgment.
Table of doses per level for adjusted agents:  
Drug Doses per Dose Levels
Drugs
-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
3.2.3
Ileus 
Constipation commonly occurs in patients receiving vincristine so patients should receive 
stool softeners as indicated.  Occasionally, symptomatic ileus may occur and this should 
be treated with a vincristine dose reduction.  Because the severity of ileus is dose related, 
it is usually unnecessary to stop the vincristine altogether.  Furthermore, because the 
therapy administered in this study is potentially curative, every effort should be made to 
not unnecessarily reduce vincristine doses.  The following guidelines for symptomatic 
ileus on a previous cycle should be followed.      
1.
Clinical ileus < 8 days with abdominal pain requiring narcotics and/or persistent 
nausea/vomiting >2 days: Reduce vincristine dose 25%.
2.
Clinical ileus 8-12 days with abdominal pain requiring narcotics and/or persistent 
nausea/vomiting > 2 days: Reduce vincristine dose 50%.        
3.
Clinical ileus > 12 days with abdominal pain requiring narcotics and/or persistent 
nausea/vomiting > 2 days: Hold vincristine on next cycle.  May restart at 50% 
reduction on subsequent cycle.
3.2.4
Neurological Toxicity 

Sensory neuropathy 
Grade
% Dose of Vincristine
2
100
3
50

Motor neuropathy
Grade
% Dose of Vincristine


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1
100
2
75
3
25
4
0
3.2.5
Hepatic and Renal Dysfunction 
No dose modifications are required for hepatic dysfunction. Specifically, our results have shown 
no clinically significant changes in doxorubicin or vincristine drug clearance. 
Etoposide should be reduced 25% on cycle one for creatinine clearance < 50 cc/min. If the 
creatinine clearance remains low on subsequent cycles, etoposide should remain at the reduced 
level as in the previous cycle.   Etoposide should be returned to full dose (or escalated if 
indicated) once creatinine clearance > 50 cc/min. No other dose modifications for abnormal renal 
indices will be made for enrolled patients. 
3.2.6
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. 
3.2.7
Rituximab Infusion related Adverse Events
Side effects of rituximab may be infusion rate related and may be reduced by slower 
administration or premedication. Thus, dose reductions of rituximab will not be made. Rituximab 
will be discontinued for the duration of the cycles in patients with grade 4 allergic reactions.  At 
the discretion of the local PI, rituximab may be administered on the following cycles using 
slower infusion rates.
3.3
STUDIES DURING THERAPY
3.3.1
On day 1 (or Day-1) of each cycle: Physical exam, Hgb, WBC, diff, platelets, BUN, 
creatinine, alk P'tase, SGOT, SGPT, LDH, and one plain 10 mL red top tube for storage. 
Red top tubes will be sent to the Clinical Support Laboratory (CSL), Leidos Biomedical 
Research, Inc. in Frederick MD and stored as described in Section 5.2.1 Procedures for 
stored serum specimens.
3.3.2
Twice weekly [3 days apart (+/- 1 day)]: CBC/diff.
3.3.3
Twenty-four (24) hours after the start of chemotherapy in patients who start Cycle 1 
Monday – Thursday: One 10 mL cell-free DNA Tube (e.g. Streck collection tubes). 
Samples will be sent to CSL, Leidos Biomedical Research, Inc. in Frederick MD and 
stored as described in Section 5.2.1 Procedures for stored serum specimens.
3.3.4
At the end of Cycle 6: One 10 mL cell-free DNA Tube (e.g. Streck collection tubes). 
Samples will be sent to CSL, Leidos Biomedical Research, Inc. in Frederick MD and 
stored as described in Section 5.2.1 Procedures for stored serum specimens.
3.3.5
At end of cycle 4 and cycle 6:  Restage with physical examination, repeat of all initially 
positive imaging studies, repeat BM asp and biopsy if initially positive. PET scan should 
be performed in patients who have a residual mass after cycle 4 and 6 as clinically 


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indicated. If therapy is to stop at the end of cycle 6, See Section 4.8 for what to do with 
patients having residual masses. 
3.3.6
In selected patients, restaging may be done after cycle 2 to obtain additional information 
on rapidity of response. 
3.4
DURATION OF THERAPY
3.4.1
Patients in clinical CR
Patients in clinical CR: at the end of cycle 4 receive 2 more cycles for a total of 6 cycles.
3.4.2
Patients in PR
Patients in PR with an estimated >80% reduction in initial tumor bulk whose measurable disease 
does not change between cycles 4 and 6, and have negative imaging after cycles 4 or 6 will be 
considered to be in clinical CR and receive no further treatment after cycle 6. See Section 3.6 for 
guidance on biopsy of residual masses.
3.4.3
Responding patients 
Responding patients whose disease continues to regress between cycles 4 and 6 may (at the 
discretion of the PI) receive 2 more cycles following cycle 6 with a restaging of residual disease 
sites following cycle 8. 
3.5
RADIATION THERAPY ALLOWANCE
In the following specific situations, patients may receive Radiation Therapy. These patients will 
remain enrolled on this study as the vehicle for the radiation treatment so that we can obtain pilot 
information on these treatment approaches. 

Patients with mediastinal B cell lymphomas (PMBL and Gray Zone) who have evidence 
of disease progression and/or residual disease after completing DA-EPOCH-R may 
receive radiation therapy if it is determined by PI to be the best course for a curative 
treatment. 

As noted in Section 4.5, Patients who fail to clear or relapse in the CSF will be 
considered for other intraventricular therapy and/or radiation.
3.6
STUDIES ON COMPLETION OF THERAPY
On completion of therapy, all initially positive or abnormal blood tests, radiologic imaging 
studies (i.e., CT and/or MRI) , and positive biopsies (bone marrow) will be repeated. Any 
persistent masses will ordinarily be carefully observed and a PET scan should be performed.  
Because PET scans are not performed routinely during initial staging, only positive results at the 
termination of therapy will be interpretable. For cases in which the investigators strongly suspect 
residual disease (e.g. abdominal masses is PET avid), imaging-guided needle biopsy may be 
performed. If this is negative or unsuccessful, laparotomy may also be considered. In view of the 
generally negative results with invasive restaging procedures in the past, observation alone will 
also be acceptable.  Accessible residual nodes or accessible residual masses in extranodal sites 
should be biopsied to confirm disease-free status.  It should be noted that the decision to perform 
PET scans or any additional work-up would be as clinically indicated.
End of treatment visit will occur approximately 30 days after the last dose of study drug. If the 
patient cannot return to the Clinical Center for this visit, a request will be made to collect 


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required clinical labs (specify as needed) from a local physician or laboratory.  If this is not 
possible, patients may be assessed by telephone for symptoms.  
3.7
FOLLOW-UP 
3.7.1
Patients who achieve remission should be seen every 3 months (+/- 4 weeks) during the 
first follow-up year, every 4 months (+/- 4 weeks) during the second year, every 6 
months (+/- 4 weeks) during the third year, and annually for years four and five  (+/- 4 
weeks).  
3.7.2
At each planned follow-up visit: Hgb, HCT, WBC, differential, platelets, electrolytes, 
BUN, creatinine, SGOT, SGPT, alkaline phosphatase, LDH one 10 mL plain red top tube 
for storage. Red top tubes will be sent to the Clinical Support Laboratory (CSL), Leidos 
Biomedical Research, Inc. in Frederick MD and stored as described in Section 5.2.1 
Procedures for stored serum specimens.
3.7.3
At each planned follow-up visit for three years for selected patients: one 10 mL cell-free 
DNA Tube (e.g. Streck collection tubes). Samples will be sent to CSL, Leidos 
Biomedical Research, Inc. in Frederick MD and stored as described in Section 5.2.1 
Procedures for stored serum specimens.
3.7.4
CT of chest, abdomen, and pelvis: every 3 months (+/- 4 weeks) during the first follow-
up year, every 4 months (+/- 4 weeks) during the second follow-up year, every 6 months 
(+/- 4 weeks) during the third follow-up year and yearly (+/- 4 weeks) thereafter for 2 
years. 
3.8
COST AND COMPENSATION 
3.8.1
Costs
NIH does not bill health insurance companies or participants for any research or related clinical 
care that participants receive at the NIH Clinical Center.  If some tests and procedures performed 
outside the NIH Clinical Center, participants may have to pay for these costs if they are not 
covered by insurance company.  Medicines that are not part of the study treatment will not be 
provided or paid for by the NIH Clinical Center.  
3.8.2
Compensation
Participants will not be compensated on this study.
3.8.3
Reimbursement 
The NCI will cover the costs of some expenses associated with protocol participation.  Some of 
these costs may be paid directly by the NIH and some may be reimbursed to the 
participant/guardian as appropriate.  The amount and form of these payments are determined by 
the NCI Travel and Lodging Reimbursement Policy.  
3.9
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.  
3.9.1
Criteria for Removal from Protocol Therapy
3.9.1.1
Completion of protocol treatment


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3.9.1.2
Inability to tolerate therapy as outlined in the protocol
3.9.1.3
Disease progression requiring new treatment
3.9.1.4
Extraordinary medical circumstances: if at any time the constraints of the protocol are 
judged to be detrimental to the patient's health, remove the patient from study and 
document the reason(s) for withdrawal. 
3.9.1.5
Patient's refusal to continue treatment. In this event, document the reason(s) for 
stopping treatment
3.9.1.6
Positive pregnancy test
3.9.2
Off Study Criteria
3.9.2.1
Patient voluntarily withdraws from study
3.9.2.2
Physician’s determination that withdrawal is in the patient’s best interest
3.9.2.3
Death
3.9.2.4
Completed study follow-up period
4
ANCILLARY THERAPY
4.1
PROPHYLAXIS FOR PNEUMOCYSTIS JIROVECI (FORMERLY PNEUMOCYSTIS CARINII) 

Adult patients will receive prophylaxis for Pneumocystis Jiroveci during EPOCH 
chemotherapy. Trimethoprim/sulfamethoxazole 1 DS P.O. QD for three days each 
week. Monday, Wednesday, Friday is the preferred schedule. Children ages 12-17 
receive the same Trimethoprim/sulfamethoxazole dose as adults.

Patients allergic to either component may receive inhaled pentamidine 300 mg once a 
month or other standard treatments.
4.2
RECOMMENDATIONS FOR MANAGEMENT OF GASTROINTESTINAL ISSUES IN ADULTS
4.2.1
Prevention and/or treatment of nausea and vomiting prior to and during chemotherapy:

Ondansetron 24 mg PO x1 dose 30–60 min prior to Cyclophosphamide, followed by 
Ondansetron 8 mg every 12 hours for 3 more days (5 or 6 doses)

Prochlorperazine 10 mg PO every 6 hours PRN for nausea or vomiting
4.2.2
Prevention of symptoms of gastroesophageal reflux disease (GERD) and other conditions 
caused by excess stomach acid:

Omeprazole 20 mg PO once daily
4.2.3
Prevention and/or treatment of constipation:

Docusate Sodium 50 mg + Sennosides 8.6 mg 1 tablet PO twice daily.

Lactulose 10-20 grams (15–30 mL) PO every 6 hours PRN for constipation
4.3
RECOMMENDATIONS FOR MANAGEMENT OF GASTROINTESTINAL ISSUES IN CHILDREN
4.3.1
Prevention and/or treatment of nausea and vomiting prior to and during chemotherapy:


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
Ondansetron 24 mg PO x1 dose 30–60 min prior to Cyclophosphamide, followed by 
Ondansetron 8 mg every 12 hours for 3 more days PRN (5 or 6 doses)

Prochlorperazine (oral or IV): 
o
For children < 45 kg: 2.5-5 mg Q6-8H prn for nausea or vomiting (maximum 15 
mg per day) 
o
For adolescents >45 kg: 10 mg PO every 6 hours PRN for nausea or vomiting
4.3.2
Prevention of symptoms of gastroesophageal reflux disease (GERD) and other conditions 
caused by excess stomach acid:

Omeprazole 20 mg PO once daily (except if <20 kg – use 10 mg once daily); this is 
especially important during the days of prednisone (Days 1-5 of every Cycle).
4.3.3
Prevention and/or treatment of constipation:

Docusate Sodium 50 mg + Sennosides 8.6 mg 1 tablet PO twice daily.

Lactulose 10-20 grams (15–30 mL) PO every 6 hours PRN for constipation (except if 
<20 kg – use 1-1.5 mL/kg BID prn) 
4.4
PROPHYLACTIC CENTRAL NERVOUS SYSTEM TREATMENT  

Up to 30% of patients with bone marrow involvement with large cell lymphoma, 
Burkitt’s histology or DLBCL with c MYC-rearrangement may recur in the CNS.  Thus, 
all patients with Burkitt’s lymphoma, DLBCL with c MYC-rearrangement and all 
patients with other histologies who have bone marrow or disseminated bone involvement, 
or > 1 extranodal site and an elevated LDH will receive prophylactic CNS treatment with 
intrathecal methotrexate on the following schedule: methotrexate 12 mg IT on day 1 and 
5 of cycles 3, 4, 5 and 6 (total of 8 treatments).  Every effort should be made to 
administer IT therapy on Days 1 and 5. However, if scheduling or clinical constraints 
prohibit adhering to this schedule, it will not be considered a protocol deviation. 

Children ages 12-17 receive the same prophylactic CNS treatment as adults.
4.5
  TREATMENT OF MENINGEAL LYMPHOMA

If the CSF is cytologically positive for malignant cells at the start of therapy, the CSF 
should be treated with methotrexate and/or cytarabine as soon as possible. Suggested 
treatment as follows: 
o
Induction- intrathecal methotrexate (6 mg by Ommaya or 12 mg by lumbar route) 
or cytarabine (70 mg by Ommaya or lumbar route).  Alternatively, if combined 
with methotrexate, administer cytarabine 30 mg (by Ommaya or lumbar route) and 
hydrocortisone (15 mg by Ommaya or lumbar route).  Administer induction 
treatment twice a week for 2 weeks past negative cytology with a minimum of 4 
weeks treatment. 
o
Consolidation-Following induction, change therapy frequency to weekly x 6.  
o
Maintenance- Following consolidation, change therapy frequency to monthly x 4. 
Due to unforeseeable events, the above therapy may be modified as clinically 
indicated.  In some cases, it may be necessary to administer radiation to the head 


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and/or spine or to administer intrathecal therapy using methotrexate 12 mg 
intrathecal (I.T.) two times a week. for 4 treatments beyond clearing, then once 
every other week for 4 treatments, and then once monthly for 6 treatments. Patients 
who fail to clear or relapse in the CSF will be considered for other intraventricular 
therapy and/or radiation.

Children ages 12-17 receive the same CNS Induction, Consolidation and Maintenance 
treatment as adults.
4.6
MONITORING AND TREATMENT TO PREVENT HEPATITIS B REACTIVATION
Patients who are positive for either Hepatitis B core antibody (anti-HBc) or Hepatitis B surface 
antigen (HBsAg) and not acutely infected are at varying risk for reactivation of Hepatitis B, 
when treated with combination therapy and rituximab.  These patients will have quantitative 
PCR testing performed for Hepatitis B virus. 
Where indicated, patients will be treated with entecavir (or equivalent) to prevent hepatitis B 
reactivation and should have HBV DNA levels obtained monthly for at least 12 months after the 
last cycle of therapy by means of real-time PCR with the use of an assay that has a sensitivity of 
at least 10 IU/mL.
If the HBV DNA assay becomes positive during combination therapy, study treatment should be 
held, and the patient should be immediately referred to a gastroenterologist or hepatologist for 
management recommendations.
If a patient’s HBV DNA level exceeds 100 IU/mL while the patient is receiving antiviral 
medication, study treatment must be permanently discontinued.
4.7
PREVENTION OF TUMOR LYSIS SYNDROME (CYCLE 1 ONLY) 

At the discretion of the PI, patients at risk of tumor lysis will receive allopurinol 600 
mg 24 hours prior to the initiation of therapy followed by 300 mg daily for up to 7 days 
following administration of the first cycle of therapy. Additional measures such as 
hospitalization with aggressive IV hydration and urinary alkalization will be used at the 
discretion of the investigator. 

Children ages 12-17 receive the same dose of allopurinol as adults.

Risk factors for tumor lysis include but are not limited to a diagnosis of Burkitt’s 
lymphoma or large B-cell lymphoma with elevated LDH and uric acid.  
4.8
TREATMENT OF PATIENTS WHO FAIL TO ACHIEVE COMPLETE RESPONSE

Patients in PR, but with biopsy-proven residual disease should be considered for entry 
onto salvage therapy with high-dose chemotherapy.  

These patients will stay on this study and be followed for survival.
5
BIOSPECIMEN COLLECTION
5.1
CORRELATIVE STUDIES FOR RESEARCH/PHARMACOKINETIC STUDIES
5.1.1
Assessment of Ovarian Function and Reserve


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5.1.1.1
The following hormone levels will be measured, using stored serum samples, to assess 
the effect of EPOCH-R on ovarian function and reserve in female patients with PMBL:

Luteinizing hormone (LH)

follicle-stimulating hormone (FSH)

inhibin B

anti-Muellerian hormone (AMH)

testosterone and 25-hydroxy-vitamin D
5.1.1.2
All hormone measurements will be performed by the Clinical Center Department of 
Laboratory Medicine, except inhibin B and AMH, which will be sent by the laboratory 
staff to American Esoteric Laboratories.
5.1.1.3
Stored samples from the following time points will be used:

before treatment 

after the last cycle of DA-EPOCH-R (after cycle 6 or 8)

12 months after completion of chemotherapy
5.1.1.4
Female patients with PMBL may be contacted by telephone, by mail or in-person and 
asked to participate in an interview, using the questionnaire in APPENDIX 2, to assess 
the effect of EPOCH-R on fertility and psychosocial/emotional well-being in female 
patients with PMBL. Their consent to participate in this sub-study will be documented 
in the medical record.
5.1.2
Blood for serum storage
Blood will be drawn at the time points identified in Sections 2.4 Baseline Evaluation, 3.3 Studies 
During Therapy and 3.7 Follow-up and stored in the conditions described below.
5.1.3
Tissue biopsy 
Tumor biopsies may be obtained for cytogenetics, immunophenotype, molecular analyses, and 
mdr-1, p53, MIB-1 expression. For storage of tissue specimens see below.
5.1.4
Lymphomagenesis in HIV positive vs HIV negative individuals 
[Beginning with Amend VV (version date: 04/14/2014)] In select patients, per PI discretion.
5.1.4.1
Rationale for lymphomagenesis correlative studies 
The incidence of certain types of lymphomas in HIV positive patients is significantly 
higher than in HIV negative individuals. Unlike other HIV-associated malignancies such 
as Kaposi’s Sarcoma, the establishment of ART has not improved these statistics. The 
mechanism for lymphomagenesis in HIV positive vs HIV negative individuals and 
whether there is a difference in tumor response of T cells derived from these populations 
is largely unknown. 
Cytotoxic T cells (CTL) play a major role in fighting viral infections, including HIV and 
EBV. They also play a role in anti-tumor immunity. The infusion of CD8, single-epitope 
specific T cells have been shown to be safe in HIV patients but currently has not shown 


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long-term efficacy. In the cancer setting, the infusion of EBV-specific CTLs has been 
largely safe and successful. Over 90% of HIV-associated Hodgkin’s Lymphoma is EBV+ 
and 30-40% of HIV-associated Burkitt Lymphoma is EBV+. 
Therefore, we hypothesize that we can generate polyclonal CTL products that are specific 
for both HIV (gag, pol, and nef) and EBV latency antigens expressed in HL (LMP1, 
LMP2, and EBNA1). We hypothesize that these CTLs can effectively target both HIV 
infection as well as tumor cells which will (1) allow for immune reconstitution following 
HIV clearance and (2) provide direct anti-tumor activity.
5.1.4.2
Methods
We plan to ex vivo expand T cell lines targeting both HIV and EBV antigens from HIV 
positive and HIV negative patients with any type of lymphoma (either currently receiving 
treatment or completed treatment). We can achieve this by isolating T cells from 50-
100mL of whole blood and stimulating them with antigen presenting cells pulsed with 
peptides from HIV gag, pol, nef and EBV LMP1, LMP2, and EBNA1. We will then use a 
variety of immunoassays to determine these T cells’ specificity and function. Our goal is 
to determine whether there are differences in the anti-lymphoma response between HIV 
positive and HIV negative patients and ultimately, to determine whether these T cells 
could have clinical efficacy in the setting of adoptive T cell therapy.
5.1.4.3
Sample collection time points

After completion of chemotherapy

One to 4 episodes in a 24 month period 

Minimum of 3 months between blood draws 
5.1.4.4
Samples to be collected

100 mL of blood per collection. If other research blood is being collected and the 
amount approaches the research blood limit, the amount of blood collected for 
CNMC may be adjusted. The CNMC collaborators need at least 40 mL of blood per 
collection. 

Blood should be collected in sodium heparin green top tubes and kept at room 
temperature

Blood will be used as whole blood or processed to obtain plasma/serum, peripheral 
blood mononuclear cells, or lymphocyte subsets
5.1.4.5
Sample processing

Samples collected from select patients will be coded and sent under an MTA to:
Children’s National Medical Center 
111 Michigan Ave NW
Washington DC 20010

For sample pick up, contact Marcus Dean. If not available, contact one of the other 
individuals as provided below.  


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Catherine Bollard
Phone #: 202-476-4776
Email: CBollard@childrensnational.org 
Russell Cruz
Phone #: 202-476-2046
Email: ccruz@cnmc.org     
Marcus Dean
Phone #: 202-476-4776
Email:  MTDEAN@childrensnational.org 
Lauren McLaughlin
Phone #:  202-476-3201
Email:  LMcLaugh@childrensnational.org  
5.1.4.6
Clinical information to be provided with samples

Samples and data will be coded

The following patient details will be sent with the samples: 
o
Age and sex
o
Lymphoma diagnosis and Stage at diagnosis
o
EBV positivity of the tumor
o
Lymphoma treatment received
o
Date lymphoma treatment completed
o
HIV serostatus 
o
HLA-type, if available
o
CD4 Nadir before chemotherapy    
o
Peak HIV Viral Load, if available 
o
HIV viral load at or near time of sample collection, if available
5.1.5
Detecting Minimal Residual Disease (MRD)
5.1.5.1
Rationale for MRD assessment
Detecting Minimal Residual Disease (MRD) can be a powerful tool to monitor patients’ 
response to treatment and early detection of relapse.
Coded, frozen or formalin fixed and paraffin embedded (FFPE) human tissue, blood 
samples (serum, plasma and/or buffy coat) and data from select patients will be sent to 
Adaptive Biotechnologies Corp. It is of research interest to determine if circulating tumor 
DNA before, during or after therapy is predictive of long-term disease-free survival. 
Adaptive Biotechnologies Corp will assess whether immune repertoire data (B-cell 
immunoglobulin receptor sequences or T-cell receptor sequences) from the Human 
Material can be used as biomarkers that correlate with disease-free survival. Adaptive 
Biotechnologies Corp will use a proprietary method, Immune Cell Receptor Sequencing 
(ICRS) platform, for amplifying and analyzing immune cell receptor sequences, allowing 
unprecedented sensitivity and specificity.  Data from experiments conducted by Adaptive 
Biotechnologies Corp using the Human Material will be provided to NCI and such data 
provided by Adaptive Biotechnologies Corp to NCI may be used by NCI for any purpose.
5.1.5.2
Stored serum samples to be sent to Adaptive Biotechnologies Corp 


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Serum samples that were collected from select patients at the following collection time 
points:

Baseline (pre-treatment) 

After each cycle of therapy 

At each planned follow-up clinic visit until disease progression
The samples and data will be retrieved from the Clinical Support Laboratory, Leidos 
Biomedical Research, Inc., batched and sent to Adaptive Biotechnologies Corp at the 
address listed below.
Adaptive Biotechnologies Corp.
1551 Eastlake Ave E
Suite 200
Seattle WA 98102
5.1.5.3
Blood samples will be collected prospectively after approval of Amendment AAA 
(version date 8/11/2016) at the following time points:

Baseline (pre-treatment) 

24 hours after the start of chemotherapy (when feasible)

After Cycle 6 

Each planned follow-up clinic visit for 3 years
The samples (plasma and/or buffy coat) and data collected prospectively will be stored in 
the Clinical Support Laboratory, Leidos Biomedical Research, Inc. and later sent in 
batches to Adaptive Biotechnologies Corp at the address listed below.
Adaptive Biotechnologies Corp.
1551 Eastlake Ave E
Suite 200 
Seattle WA 98102
5.1.6
Systemic ALK-positive anaplastic large-cell lymphoma (ALCL) of adults: Meta-analysis 
of prognostic factors
5.1.6.1
Rationale for contributing data to this international study 
Anaplastic large cell lymphoma (ALCL) is a rare T-cell lymphoma and in an effort to 
gain better understanding into the outcome and prognosis of this disease with standard 
approaches, we were invited to participate in an international study/meta-analysis led by 
David Sibon, MD, PhD and Kerry Savage, MD. They will use the data as above in a 
meta-analysis from various international centers and groups. This is a rare disease and 
few sites will be able to contribute. We have already published data on our patients and it 
will strengthen the results of meta-analysis if the samples size is large. Contributing our 
data to the study will increase the sample size.
The following coded data from adult patients with ALK+ ALCL will be sent:
Patient and disease characteristics at diagnosis:

Age at diagnosis


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
Sex

Date of pathologic diagnosis or study entry

B symptoms (yes or no)

Performance status (0 to 4)

Ann Arbor stage (I to IV)

Extranodal sites more than 1

Bulky disease ≥ 10 cm

Site of involvement:
o
Mediastinum
o
Bone marrow
o
Bone
o
Liver
o
Spleen
o
Skin
o
Lung
o
Central nervous system
o
Soft tissue
o
Kidney
o
Adrenal
o
Gastrointestinal
o
Epidural
Labs at diagnosis

Lactate dehydrogenase (LDH): normal vs elevated

Beta2-microglobulin (< vs ≥ 3 mg/L)

Hemoglobin (g/dL)

Platelets (G/L)
Pathology (by definition all cases are CD30+ and ALK+):

Morphologic variant (presence vs absence of a small cell/lymphohistiocytic 
component)

CD2

CD3

CD4

CD5

CD8

EMA

TIA1 / granzyme B / perforin
First-line treatment (chemotherapy with or without radiotherapy):

Anthracycline included in first-line chemotherapy regimen (yes or no).

Etoposide included in first-line chemotherapy regimen (yes or no).

Radiotherapy included in first-line treatment (yes or no).

Chemotherapy regimen:
o
CHOP-14
o
CHOP-21
o
CHOEP-14
o
CHOEP-21


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o
HiCHOEP-14
o
HiCHOEP-21
o
MegaCHOEP
o
ACVBP
o
DA-EPOCH
o
Other regimen (state regimen)

Number of cycles of chemotherapy regimen

Upfront autologous stem-cell transplantation (yes or no)
Outcomes after first-line treatment:

Relapse/progression (yes or no)
o
If yes: date of relapse/progression

Date of last follow-up

Status at last follow-up (alive or dead)
o
If dead: cause of death:

ALCL

Other (state cause)
5.1.7
Comparison of methods of monitoring circulating tumor DNA
5.1.7.1
Rationale for comparing ctDNA methods 
The detection of Minimal Residual Disease (MRD) in aggressive lymphomas can be a 
powerful tool to monitor patients’ response to treatment and early detection of relapse.  
The field of molecular monitoring of circulating tumor DNA (ctDNA) is an emerging 
field, however, and the most effective technique is unknown.  Multiple methods that 
interrogate the peripheral blood for tumor-specific molecules are under development.  
Some technologies that assay for the VDJ region of the immunoglobulin receptor (i.e. 
Adaptive Biotechnologies) have been clinically validated, but newer technologies are 
capable of detecting multiple somatic mutations in the ctDNA in addition to detecting the 
VDJ gene sequence.  The ctDNA genotyping method may provide additional information 
that captures a broader range of patients and may identify novel patterns of clonal 
evolution.  One such technology is the Cancer Personalized Profiling by Deep 
Sequencing (CAPP-Seq) method developed by the Alizadeh lab at Stanford University.  
The CAPP-Seq method is an ultrasensitive capture-based targeted sequencing method 
that can be used on lymphoid tissue and cell-free DNA in order to define key biological 
features from the tumor.
Coded,  frozen or formalin fixed and paraffin embedded (FFPE) human tissue, blood 
samples (serum, plasma and/or buffy coat) and data from select patients will be sent to 
Alizadeh lab. It is of research interest to determine how the CAPP-Seq method compares 
with the Adaptive Biotechnologies method (i.e. clonoSEQ) for monitoring ctDNA before, 
during or after therapy. 
The CAPP-Seq sequencing panel (i.e. ‘selector’) was designed to maximize the number 
of patients (and mutations per patient) detected, while simultaneously minimizing the 
panel size and sequencing cost. Genomic regions with recurrent somatic alterations in 
DLBCL were therefore prioritized for selector design. As an initial step, single nucleotide 
variants (SNVs) and indels were collected from multiple whole exome and whole 
genome sequencing studies, spanning a total of 102 DLBCL tumors. A bioinformatics 


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approach was then applied to identify recurrently mutated regions of the genome 
harboring single nucleotide variants (SNVs) and/or indels that maximally cover both 
patients and mutations per patient. As a second step, the CAPP-Seq includes reported 
translocation breakpoints involving IGH, BCL2, BCL6 or MYC in order to identify 
hyper-localized and recurrent breakpoint regions. In order to capture MYC translocations, 
CAPP-Seq incorporates two IGH regions covering ~50% of MYC/IGH translocations 
and a single MYC hotspot encompassing 15% of MYC/non-IGH translocations as well as 
2 more MYC breakpoint hotspots spanning ~5kb, yielding a final predicted coverage of 
90% of all MYC translocations. As a third step, CAPP-Seq includes genomic regions 
encompassing Ig VDJ recombination sites and mutations arising from activation-induced 
cytidine deaminase activity (AID/AICDA). Specifically, it includes the 10 most 
commonly used IgVH regions in DLBCL along with the heavy joining cluster consisting 
of 6 IgJH regions. CAPP-Seq also incorporates several aberrant non-Ig AID target genes, 
including the region spanning the transcription start site and first exon of BCL6 as well as 
the transcription start sites of BCL2, MYC, PIM1 and CD83. The final selector design 
covers 1,053 genomic regions from 268 genes, totaling 242 kb (247 kb when including 
additional MYC regions. 
The Alizadeh lab will use the CAPP-Seq method to determine whether the tumor-specific 
genetic aberrations from the Human Material can be used as biomarkers that correlate 
with disease-free survival. Alizadeh lab will use a proprietary method, CAPP-Seq, for 
analyzing tumor genomic DNA. Data from experiments conducted by the Alizadeh lab 
using the Human Material will be provided to NCI and such data provided by Alizadeh 
lab to NCI may be used by NCI for any purpose.
5.1.7.2
Stored serum samples to be sent to Alizadeh lab 
Serum samples that were collected from select patients at the following collection time 
points:
Baseline (pre-treatment) 
After each cycle of therapy 
At each planned follow-up clinic visit until disease progression
The samples and data will be retrieved from the Clinical Support Laboratory, Leidos 
Biomedical Research, Inc., coded batched and sent to the Alizadeh lab at the following 
address.
Alizadeh Lab
1291 Welch Road
Lorry Lokey Building, SIM1 Rm. G2115
Stanford, CA 94305-5458
5.1.8
Determining clinical significance of post-therapy positron emission tomography (PET) 
scans 
5.1.8.1
Rationale for post-therapy PET imaging
The aggressive lymphomas included in this protocol are treated with curative intent.  Dose-
adjusted EPOCH-R has demonstrated the ability to cure a high proportion of patients with 
DLBCL subtypes, especially primary mediastinal B-cell lymphoma (PMBL).  In the 
original series from this protocol, 51 patients were treated with DA-EPOCH-R and the 5-


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year event-free survival was 93%.  Importantly, this study demonstrated that many patients 
who were free of disease at the end-of-therapy had persistent areas of focal uptake on PET 
scans.  Thus, the positive predictive value of end-of-therapy PET scans was limited.  After 
more years of follow-up, it is critically important to update the series, demonstrate lack of 
late relapses, and validate these findings in a cohort of patients treated at an outside 
institution, Stanford University.
5.1.8.2
Clinical information to be sent to Stanford University
Coded clinical information including baseline demographics, clinical outcomes, and 
results of imaging scans (CT scans and PET scans, if done) will be sent to Ranjana 
Advani at Stanford University. She will collate the clinical information to determine if 
post-therapy PET scans are predictive of disease-free survival in PMBL and mediastinal 
gray zone lymphomas (MGZL).

Age at diagnosis

Sex

Date of pathologic diagnosis or study entry

B symptoms (yes or no)

Performance status (0 to 4)

Ann Arbor stage (I to IV)

Extranodal sites more than 1

Bulky disease ≥ 10 cm

Site of involvement:
o
Mediastinum
o
Bone marrow
o
Bone
o
Liver
o
Spleen
o
Skin
o
Lung
o
Central nervous system
o
Soft tissue
o
Kidney
o
Adrenal
o
Gastrointestinal
o
Epidural

Labs at diagnosis
o
Lactate dehydrogenase (LDH): normal vs elevated
o
Beta2-microglobulin (< vs ≥ 3 mg/L)
o
Hemoglobin (g/dL)
o
Platelets 
5.2
SAMPLE STORAGE, TRACKING AND DISPOSITION
All specimens obtained in the protocol are used as defined in the protocol.  Samples will be 
ordered in CRIS and tracked through a Clinical Trial Data Management system.  Should a CRIS 
screen not be available, the CRIS downtime procedures will be followed.  Samples will not be 
sent outside NIH without appropriate approvals and/or agreements, if required.  


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All specimens obtained in the protocol are used as defined in the protocol.  Any specimens that 
are remaining at the completion of the protocol will be stored in the conditions described below 
for an indefinite amount of time. The PI will report any loss or any unanticipated destruction of 
samples as a deviation.  Reporting will be per the requirement in section 7.2.  
5.2.1
Procedures for stored serum specimens
The Clinical Support Laboratory, Leidos Biomedical Research, Inc., processes and cryopreserves 
samples in support of IRB-approved, NCI clinical trials.  All laboratory personnel with access to 
patient information annually complete the NIH online course in Protection of Human 
Subjects.  The laboratory is CLIA certified for CD4 immunophenotyping and all laboratory areas 
operate under a Quality Assurance Plan with documented Standard Operating Procedures that are 
reviewed annually.  Laboratory personnel are assessed for competency prior to being permitted 
to work with patient samples.  Efforts to ensure protection of patient information include:

The laboratory is located in a controlled access building and laboratory doors are kept 
locked at all times. Visitors to the laboratory are required to be accompanied by 
laboratory staff at all times.  

Hard copy records or electronic copies of documents containing patient information are 
kept in the locked laboratory or other controlled access locations.   

An electronic database is used to store information related to patient samples processed 
by the laboratory.  

The database resides on a dedicated program server that is kept in a central, locked 
computer facility.  

The facility is supported by two IT specialists who maintain up to date security features 
including virus and firewall protection.  

Program access is limited to specified computers as designated by the laboratory 
director.  Each of these computers has a password restricted login screen.  

The database sample entry program itself is accessed through a password protected entry 
screen.  

The database program has different levels of access approval to limit unauthorized 
changes to specimen records and the program maintains a sample history.  

Upon specimen receipt each sample is assigned a unique, sequential laboratory accession 
ID number.  All products generated by the laboratory that will be stored either in the 
laboratory freezers or at a central repository facility are identified by this accession ID.

Inventory information will be stored at the vial level and each vial will be labeled with 
both a sample ID and a vial sequence number.  

Vial labels do not contain any personal identifier information.   

Samples are stored inventoried in locked laboratory freezers and are routinely transferred 
to the NCI-Frederick repository facilities for long term storage.    

Access to stored clinical samples is restricted.  Investigators establish sample collections 
under “Source Codes” and the investigator responsible for the collections, typically the 


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protocol Principal Investigator, specifies who has access to the collection. Specific 
permissions will be required to view, input or withdraw samples from a collection. 

Sample withdrawal requests submitted to approved laboratory staff by anyone other than 
the repository source code owner are submitted to the source code owner for approval.  
The repository facility will also notify the Source Code holder of any submitted requests 
for sample withdrawal.  

It is the responsibility of the Source Code holder (generally the NCI Principal 
Investigator) to ensure that samples requested and approved for withdrawal are being 
used in a manner consistent with IRB approval.  

The Clinical Support Laboratory does perform testing services that may be requested by 
clinical investigators including, but not limited to, immunophenotyping by flow 
cytometry and cytokine testing using ELISA or multiplex platforms.  

When requests are submitted by the NCI investigator for shipment of samples outside of 
the NIH it is the policy of the laboratory to request documentation that a Material 
Transfer Agreement is in place that covers the specimen transfer.  The laboratory does 
not provide patient identifier information as part of the transfer process but may, at the 
discretion of the NCI investigator, group samples from individual patients when that is 
critical to the testing process.   

The NCI investigator responsible for the sample collection is responsible for ensuring 
appropriate IRB approvals are in place and that a Material Transfer Agreement has been 
executed prior to requesting the laboratory to ship samples outside of the NIH.  
5.2.2
Procedures for storage of tissue specimens
Tumor biopsies will be submitted in native condition to the Department of Pathology, NCI, NIH 
and handled according to routine procedures.  Initial processing of samples for research will 
depend on the size of the tumor biopsy.  For core biopsies the research sample will typically 
consist of 2 cores in a microcentrifuge vial snap frozen on dry ice. Surgical lymph node biopsies 
may in addition be processed for single cell suspension, additional vials of snap frozen tissue and 
OCT embedded tissue.
Tumor samples may be viably frozen, typically at concentrations of 20-100x106/mL in FCS with 
10% DMSO using a temperature controlled freezing process to optimize sample viability.  
Samples will be transferred to Nitrogen tanks for long term storage. 
Tumor samples may 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 or similar kit) 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.
5.2.3
Blood for Pharmacokinetic analysis
The blood that was collected for PK analysis is currently stored as plasma in screw-capped 
polypropylene vials in a -70 C degree freezer which is located in a common freezer room in the 
1W lab area of the Pediatric Oncology Branch.  The freezer temperature is continuously 


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monitored for +/- temperature differences of 10 degrees C.  Samples are stored by patient initials 
as well as date and time of sample in individual boxes within this freezer.  Records of samples 
stored are catalogued in a Filemaker database which is maintained by Pharmacology and 
Experimental Therapeutics research nurses and is password protected so that only members of 
the section have access to patient sample information.  Results from the analyses of drug levels 
from these samples are maintained in an Excel database maintained on a password-protected 
computer in the laboratory of Dr. Brigitte Widemann.  Both computers containing patient sample 
information are backed on a regular (at least one time per week) basis. 
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 
with the data management efforts. 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. 
Document AEs from the first study intervention, Study Day 1, through 30 days after the last 
study intervention was administered.  Beyond 30 days after the last intervention, only adverse 
events which are serious and related to the study intervention need to be recorded.
An abnormal laboratory value will be recorded in the database as an AE only if the laboratory 
abnormality is characterized by any of the following:

Results in discontinuation from the study

Is associated with clinical signs or symptoms 

Requires treatment or any other therapeutic intervention

Is associated with death or another serious adverse event, including hospitalization. 

Is judged by the Investigator to be of significant clinical impact

If any abnormal laboratory result is considered clinically significant, the investigator will 
provide details about the action taken with respect to the test drug and about the patient’s 
outcome.
6.1.1
Special Considerations for Data Collection/Recording

As the toxicity profile of EPOCH-R is well defined and published, grade 1 clinical 
adverse events will not be recorded in the database.  Only the highest grade of each event 
during a cycle of treatment will be recorded in the database.

No Concomitant therapy except intrathecal therapy and blood product transfusions will 
be recorded in the database.
6.1.2
Other Information


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End of study procedures: Data will be stored according to HHS, FDA and NIH Intramural 
Records Retention Schedule regulations 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, this will be reported expeditiously per 
requirements in section 7.2.1.
6.2
RESPONSE CRITERIA
6.2.1
Complete response (CR)
Disappearance of all signs and symptoms of lymphoma for a period of at least one month. All 
lymph nodes and nodal masses must have regressed to normal size ( 1.5 cm in their greatest 
transverse diameter for nodes > 1.5 cm before therapy).  Previously involved nodes that were 1.1 
to 1.5 cm in their greatest transverse diameter before treatment must have decreased to  1 cm in 
their greatest transverse after treatment or by more than 75% in the sum of the products of the 
greatest diameters.  The spleen, if consider to be enlarged before therapy on the basis of a CT 
scan must have regressed in size and must not be palpable on physical examination. Any 
macroscopic nodules in any organs detectable on imaging techniques should no longer be 
present. 
6.2.2
Complete response unconfirmed (CRu)
A residual lymph node mass > 1.5 cm in greatest transverse diameter that has regressed by > 
75% in sum of the products of the greatest diameters, does not change over the last two 
treatments, has a negative PET scan, and any biopsies obtained are negative will be considered to 
be in CR.  In organs involved by disease, any residual lesions that have decreased by > 75% in 
sum of the products of the greatest diameters or are < 1 cm, are consistent with scar, and stable 
over the last two treatments will be considered to fulfill criteria for CR.  
6.2.3
Partial response (PR)
50% or greater decrease in the sum of the products of the longest perpendicular diameters of all 
measured lesions lasting for a period of at least one month. No individual lesions may increase in 
size and no new lesions may appear.

Patients in PR with an estimated >80% reduction in initial tumor bulk whose measurable 
disease does not change between cycles 4 and 6, and have a negative PET scan after 
cycles 4 or 6 will be considered to be in clinical CR.
6.2.4
Stable disease (SD)
Tumor measurements not meeting the criteria of CR, PR, or PD.
6.2.5
Progression (PD)
Increase of 25% or more in the sum of the products of the longest perpendicular diameters of all 
measured lesions compared to the smallest previous measurements, or the appearance of any new 
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7
NIH REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING PLAN
7.1
DEFINITIONS
Please refer to definitions provided in Policy 801: Reporting Research Events found here.
7.2
OHSRP OFFICE OF COMPLIANCE AND TRAINING / IRB REPORTING
7.2.1
Expedited Reporting
Please refer to the reporting requirements in Policy 801: Reporting Research Events and Policy 
802 Non-Compliance Human Subjects Research found here.
7.2.2
IRB Requirements for PI Reporting at Continuing Review
Please refer to the reporting requirements in Policy 801: Reporting Research Events found here.
7.3
NCI CLINICAL DIRECTOR REPORTING
Problems expeditiously reported to the OHSRP/IRB in iRIS will also be reported to the NCI 
Clinical Director.  A separate submission is not necessary as reports in iRIS will be available to 
the Clinical Director.
In addition to those reports, all deaths that occur within 30 days after receiving a research 
intervention should be reported via email to the Clinical Director unless they are due to 
progressive disease.  
To report these deaths, please send an email describing the circumstances of the death to Dr. 
Dahut at NCICCRQA@mail.nih.gov within one business day of learning of the death.
7.4
NIH REQUIRED DATA AND SAFETY MONITORING PLAN
The clinical research team will meet 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 PI and/or lead associate 
investigator for toxicity.  Events meeting requirements for expedited reporting as described in 
section 7.2.1 will be submitted within the appropriate timelines.  
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. 
This study was monitored by the Clinical Data Update System (CDUS) version 1.1 through 
amendment dated 3-8-10.  Cumulative CDUS data was submitted quarterly to CTEP by 
electronic means.  Reports were due January 31, April 30, July 31 and October 31.  The final 
report to CTEP via CDUS was submitted 3-31-2010.
8
STATISTICAL CONSIDERATIONS
The objectives of this amendment are to determine whether large B-cell lymphomas expressing 
BCL-2 (+) patients may experience an improved progression free survival with EPOCH-R 
compared to EPOCH alone, and to obtain a concurrent, precisely determined measure of 


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progression free survival in patients who are BCL-2(-) in order to provide a reliable target for the 
BCL-2 (+) patients to try to achieve. The sample size for this amendment will be guided by the 
number of BCL-2 (+) patients. In order to rapidly address this issue, patients entered with large 
B-cell lymphomas expressing CD20+ will all be assigned to receive EPOCH-R, and the 
determination of BCL-2 level will be made subsequent to commencement of treatment. It should 
also be noted that at this time 25 patients with CD20+ large B-cell lymphomas have been 
entered, and of 20 evaluable patients for response, 17 have achieved complete remission and 
none have relapsed (100% DFS), with a median follow-up of 12 months (14). Of these, at least 8 
are known to be bcl-2. 
The Dixon-Simon method will be used to determine the number of BCL-2 (+) patients to enroll 
onto the trial, using the 8 patients enrolled on the prior EPOCH alone arm who are BCL-2 (+) as 
controls.  For these calculations, it is assumed that the 5 of 12 patients who have not yet 
progressed on the EPOCH trial are still allowed to be followed, that we would have only 12 
patients in this historical group, and that the median PFS for this group was reached by 2 years. 
We will assume 3 years of accrual of new patients, 4 years of follow-up, 0.05 one-sided 
significance, and 80% power.
Use of this method determined that a total of 33 new BCL-2 (+) patients would be required in 
order to detect a difference of 75% PFS at 2 years (EPOCH-R) vs. 50% at 2 years (EPOCH), 
while only 20 such patients would be needed to detect a difference of 80% PFS vs. 50% PFS at 2 
years. We intend to accrue 20 newly identified, additional BCL-2 (+) patients, but to also use the 
(8) prior BCL-2 (+) patients, with the analyses being done in two ways. First, the most rigorous 
analysis with 21 future BCL-2 (+) patients on EPOCH-R will be done comparing their PFS, 
using Kaplan-Meier curves and a log-rank test, to the 12 EPOCH alone BCL-2 (+) patients.  
Then, an analysis using the (8) already accrued BCL-2 (+) patients plus the 20 newly accrued 
BCL-2 (+) patients will be done compared to the 12 with EPOCH alone; because it could be 
argued that this analysis includes patients who were already identified as doing well prior to the 
start of this amendment, this analysis will be considered secondary to the one with 20 
prospectively enrolled patients.
Accrual of CD20 large B-cell patients to the dose-adjusted EPOCH-R arm will be halted after 20 
prospectively enrolled (20+(8) = 28 total) evaluable BCL-2 (+) patients have been accrued.  
Since it is expected that slightly more than half of all patients will be BCL-2 (-), this is expected 
to require up to 50 newly accrued patients. The prior EPOCH alone arm demonstrated that the 
BCL-2 (-) patients had a significantly longer PFS than the (+) patients.  As such, the large B-cell 
lymphomas do not necessarily comprise a completely homogeneous group prognostically, and 
the outcome for the BCL-2 (-) patients would constitute a valid target for the (+) patients.   Since 
BCL-2 status cannot be determined until several weeks after enrollment, and delay of therapy 
would negatively impact outcome and recruitment, the BCL-2 (-) patients will enrolled and 
analyzed, both  to provide a more precise estimate of the overall PFS experience in these patients 
than would be realized by the limited number of such patients enrolled already, and will also  be 
used in a formal comparison with the BCL-2 (+) patients in order to determine whether the two 
groups now have similar prognosis, which would signify improvement for the (+) group.  While 
the sample size will not be set precisely for the BCL-2 (-) patients, a group of approximately 30 
or more BCL-2 (-) patients would be useful for a statistically useful comparison with the BCL-2 
(+) patients.  Since the evaluation of the BCL-2 (+) patients between EPOCH and EPOCH-R is 
based on a historical comparison, some caution must be exercised in the interpretation of the 


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comparison. In its favor, however, is that the historical group is recently accrued from the same 
institution, using the same eligibility criteria, and is treated by the same principal investigator. 
We have met the original accrual goal and have treated 33 patients with BCL-2(+) DLBCL.  The 
overage in number of accrued BCL-2+ cases is due to the delay in obtaining tissue blocks for 
analysis. Our results have been extremely favorable, with 94% CR and 82% PFS.  As a result of 
this study, a phase 3 study of CHOP-R vs. EPOCH-R will be opened, and we will be a 
participating site. In order not to disturb our critically important accrual stream, we wish to 
increase the accrual of DLBCL patients by 15 to bridge the time gap until the phase 3 study 
opens. These additional patients will be included in the overall analysis and will contribute to the 
overall confidence of the data when published.  
This trial also aims to establish the CR rate and toxicities of dose-adjusted EPOCH in other 
subsets of aggressive T-cell lymphomas which have been historically combined with large B-cell 
lymphomas.  Hence, the present trial has already enrolled 13 patients with ALCL and 11 patients 
with peripheral/aggressive T-cell lymphomas.  At this time, the PFS of ALCL is 80% with dose-
adjusted EPOCH.  Thus, to adequately establish the CR rate and survival outcomes of dose-
adjusted EPOCH in these groups, we wish to treat up to 30 patients each with ALCL and 
peripheral/aggressive T-cell lymphomas. We will also occasionally encounter a CD20 negative 
B-cell lymphoma or gray zone lymphoma which may be treated on this study at the National 
Cancer Institute.  Such patients would be enrolled because it would not be in their best medical 
interest to deny treatment and non-protocol therapy is not allowed.  Although they would not 
contribute to the primary research endpoints, they would provide pilot information.  
As of March 2010, this study has accrued 266 patients, of which 21 have ALCL and 18 have 
PTCL. Furthermore, patients with mediastinal PBML and GZL are currently being enrolled onto 
the trial and are useful to increase the precision of the ongoing molecular, laboratory, and clinical 
evaluations of these latter groups. It is desirable to have this study remain open for 
approximately one more year in order to enroll further patients with GZL and PMBL. Since 
approximately 10-15 such patients will be enrolled in a year, and the intended ceiling for ALCL 
and PTCL is 30 patients apiece, the accrual ceiling will be increased from 277 to 298. This will 
permit the trial to enroll, approximately, 11 additional patients with GZL and PMBL, 9 
additional patients with ALCL and 12 additional patients with PTCL.  This will allow accrual of 
sufficient additional patients with GZL and PMBL to increase the precision of the estimates of 
values obtained on these patients, and will permit accrual to 30 in each of the other two 
categories.
As of June 2012, the study has accrued 290 patients. The trial continues to recruit and enroll 
patients with different aggressive lymphomas; and patients are typically having excellent clinical 
results. To allow the trial to remain open in order to increase the precision of the estimates of 
PFS in subsets of patients based on disease type, the accrual ceiling will be increased by 20 
patients to a total of 318—28 more than are presently enrolled. This will allow patients to 
continue to enroll for approximately 2 more years and to permit better estimates of outcomes in 
patients with rare forms of NHL. Our plan is to replace this study with new trials that are 
dedicated to specific histologies (PMBL, Grey Zone Lymphoma, etc.). In the meantime, as we 
create these new disease-specific studies, we would like to continue to provide highly curative 
treatment on a clinical trial for these complex patients.
As of December 2014, the study has accrued 314 patients. The trial continues to recruit and 


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enroll patients with different aggressive lymphomas and patients are typically having excellent 
clinical results. To allow the trial to remain open in order to increase the precision of the 
estimates of PFS in subsets of patients based on disease type while awaiting new protocols 
dedicated to specific histologies (PMBL, Grey Zone Lymphoma, etc.), the accrual ceiling will be 
increased by 20 patients to a total of 338, which is 24 more than are presently enrolled.   This 
will allow patients to continue to enroll for approximately 2 more years and to permit better 
estimates of outcomes in patients with rare forms of NHL. In the meantime, as we create new 
disease-specific studies, we would like to continue to provide highly curative treatment on a 
clinical trial for these complex patients.
As of April 2016, the study has accrued 335 patients. The trial continues to recruit and enroll 
patients with different aggressive lymphomas and patients are typically having excellent clinical 
results. To allow the trial to remain open in order to increase the precision of the estimates of 
PFS subsets of patients based on disease type while awaiting new protocols dedicated to specific 
histologies (PMBL, Grey Zone Lymphoma, etc.), the accrual ceiling will be increased by 10 
patients to a total of 348, which is 13 more than are presently enrolled.   This will allow patients 
to continue to enroll for approximately one more year and to permit better estimates of outcomes 
in patients with rare forms of NHL. In the meantime, as we create new disease-specific studies, 
we would like to continue to provide highly curative treatment on a clinical trial for these 
complex patients. 
Effective with Amendment ZZ (version date 04-06-2016), the accrual ceiling will be set at 348.
Effective with Amendment FFF, all patients on trial will be followed for PFS for up to 5 years 
from the date they sign the consent form. Any future analysis will focus on evaluations taking 
place no more than 5 years after study entry. This will apply both to previously enrolled patients 
as well as to any patients who enroll after this amendment is in effect. 
9
HUMAN SUBJECTS PROTECTION
9.1
RATIONALE FOR SUBJECT SELECTION 
Non-Hodgkin’s lymphomas affect all races and genders.  However, males are more likely than 
females to be affected and this will be reflected in the gender distribution of our cases.  Non-
Hodgkin’s lymphomas are the 9th leading cause of cancer death for men and the 6th leading cause 
of cancer death in women, and thus represent a significant public health risk.  Although 
potentially curable, close to 50% of patients achieve a durable complete remission with standard 
R-CHOP chemotherapy, and most of the remaining patients die of their disease. Patients with 
HIV infection will be excluded as AIDS-related lymphoma is a distinct biological entity which is 
not being studied in this protocol, and pregnant or nursing mothers are excluded because of the 
potential teratogenic effects of therapy. 
9.2
PARTICIPATION OF CHILDREN
The age range of pediatric patients eligible for this trial is 12 years and older. Physicians, nurses, 
and multidisciplinary support teams of the Pediatric Oncology Branch (POB), Lymphoid 
Malignancies Branch, and Clinical Center (CC) will provide patient care. The staff of the POB 
has expertise in the management of children with complex oncologic disorders and 
complications of therapy. Full pediatric support and subspecialty services are available at the 
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While participating in this protocol, children and their families can stay at the Children's Inn, 
located close to the Clinical Center on the NIH campus, which is a private, non-profit residence 
with the purpose of keeping children together with their families while they are in Bethesda to 
participate in research studies. 
Minors who reach the age of consent while still on-study will be asked to sign the informed 
consent document to indicate that they agree to continue participating in the study. 
9.3
PARTICIPATION OF SUBJECTS UNABLE TO GIVE CONSENT
Adults unable to give consent are excluded from enrolling in the protocol.  However re-consent 
may be necessary and there is a possibility, though unlikely, that subjects could become 
decisionally impaired. For this reason and because there is a prospect of direct benefit (Section 
9.4), all subjects ≥ age 18 will be offered the opportunity to fill in their wishes for research and 
care, and assign a substitute decision maker on the “NIH Advance Directive for Health Care and 
Medical Research Participation” form so that another person can make decisions about their 
medical care in the event that they become incapacitated or cognitively impaired during the 
course of the study. Note: The PI or AI will contact the NIH Ability to Consent Assessment 
Team (ACAT) for evaluation to assess ongoing capacity of the subjects and to identify an LAR, 
as needed. Please see section 9.5 for consent procedure.
9.4
EVALUATION OF BENEFITS AND RISKS/DISCOMFORTS 
 
9.4.1
Risks
9.4.1.1
Biopsy collection
The risks associated with biopsies are pain and bleeding at the biopsy site. In order to minimize 
pain, local anesthesia will be used. Rarely, there is a risk of infection at the sampling site.
9.4.1.2
Bone marrow aspirate and/or biopsy 
Bone marrow biopsy is minimally invasive and is typically a very safe procedure. Usually 
hipbone is numbed with anesthesia. Using a needle, the solid and liquid portion of bone marrow 
is taken out. This procedure causes some pain. Very rarely, infection or bleeding may occur at 
the needle site.
9.4.1.3
CT scans
In addition to the radiation risks discussed below, scans may include the risks of an allergic 
reaction to the contrast. Participants might experience hives, itching, headache, difficulty 
breathing, increased heartrate and swelling. 
9.4.1.4
MRI  
People are at risk for injury from the MRI magnet if they have some kinds of metal in their body. 
People with fear of confined spaces may become anxious during an MRI. Those with back 
problems may have back pain or discomfort from lying in the scanner.  The noise from the 
scanner is loud enough to damage hearing, especially in people who already have hearing loss. 
There are no known long-term risks of MRI scans.
During part of the MRI patient will receive gadolinium, a contrast agent, through an intravenous 
(IV) catheter (small tube). It will be done for research purposes. 


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The risks of an IV catheter include bleeding, infection, or inflammation of the skin and vein with 
pain and swelling.  Participants undergoing gadolinium enhanced MRIs may also be at risk for 
kidney damage.
9.4.1.5
Radiation
The study will involve radiation from the following sources in an annual maximum:

Up to 1 CT (Head) scans 

Up to 4 CT (Chest, Abdomen, Pelvis, Neck) scans 
Subjects in this study may be exposed to approximately 5.3 rem. This amount is more than 
would be expected from everyday background radiation. Being exposed to excess radiation can 
increase the risk of cancer. The risk of getting cancer from the radiation exposure in this study is 
0.5 out of 100 (0.5%) and of getting a fatal cancer is 0.3 out of 100 (0.3%). The procedures for 
performing the CT will follow clinical policies, no special procedures will apply to these 
assessments for research purposes.
9.4.1.6
Risks related to blood sampling
Side effects of blood draws include pain and bruising, lightheadedness, and rarely, fainting.
9.4.1.7
Urine collection
There is no physical risk involved with urine collection.
9.4.1.8
Lumbar puncture
Risks of lumbar puncture include headache, dizziness, infection, back discomfort, minor 
radicular numbness and brainstem herniation.
9.5
CONSENT AND ASSENT PROCESS AND DOCUMENTATION
The informed consent document will be provided to the participant or consent designee(s) as 
applicable for review prior to consenting.  A designated study investigator will carefully explain 
the procedures and tests involved in this study, and the associated risks, discomforts and benefits. 
In order to minimize potential coercion, as much time as is needed to review the document will 
be given, including an opportunity to discuss it with friends, family members and/or other 
advisors, and to ask questions of any designated study investigator. A signed informed consent 
document will be obtained prior to entry onto the study.
The initial consent process as well as re-consent, when required, may take place in person or 
remotely (e.g., via telephone or other NIH approved remote platforms) per discretion of the 
designated study investigator and with the agreement of the participant/consent designee(s).  
Whether in person or remote, the privacy of the subject will be maintained. Consenting 
investigators (and participant/consent designee, when in person) will be located in a private area 
(e.g., clinic consult room). When consent is conducted remotely, the participant/consent designee 
will be informed of the private nature of the discussion and will be encouraged to relocate to a 
more private setting if needed.
9.5.1
Consent Process for Minors
Consent will be obtained from parent(s)/guardians of minor children as described in Section 9.5.
Where deemed appropriate by the clinician and the child’s parents or guardian, the child will also 


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be included in all discussions about the trial and age-appropriate language will be used to 
describe the procedures and tests involved in this study, along with the risks, discomforts and 
benefits of participation. The assent process will take place in conjunction with consent; 
therefore, in person and remote assent are permitted under the same circumstances as in person 
and remote consent.  Written assent will not be obtained from children as the study holds out the 
prospect of direct benefit that is important to the health and well-being of the child and is 
available only in the context of the research. Verbal assent will be obtained as appropriate for 
children ages 12-17. The consent/assent process will be documented in the child’s medical 
record, including the assessment of the child’s ability to provide assent.
All children will be contacted after they have reached the age of 18 to determine whether they 
wish to continue on the trial and informed consent will be obtained from them at that time. 
9.5.2
Consent for minors when they reach the age of majority
When a pediatric subject reaches age 18, continued participation (including ongoing interactions 
with the subject or continued analysis of identifiable data) will require that consent be obtained 
from of the now adult with the standard protocol consent document to ensure legally effective 
informed consent has been obtained. We request waiver of informed consent for those 
individuals who become lost to follow up or who have been take off study prior to reaching the 
age of majority.
Requirements for Waiver of Consent consistent with 45 CFR 46.116 (d):
(1) The research involves no more than minimal risk to the subjects.
a.
Analysis of samples and data from this study involves no additional risks to 
subjects.
(2) The waiver or alteration will not adversely affect the rights and welfare of the 
subjects.
a.
Retention of these samples or data does not affect the welfare of subjects. 
(3) The research could not practicably be carried out without the waiver or alteration.
a.
Considering the length of time between the minor’s last contact with the 
research team and their age of majority, it will likely be very difficult to locate 
them again.  A significant reduction in the number of samples analyzed is 
likely to impact the quality of the research. 
(4) Whenever appropriate, the subjects will be provided with additional pertinent 
information after participation.
a.
We only request a waiver of consent for those subjects who have been lost to 
follow-up or who have been taken off study prior to reaching the age of 
majority.
9.5.3
Consent Process for Adults Who Lack Capacity to Consent to Research Participation
For participants addressed in section 9.3, an LAR will be identified consistent with Policy 403 
and informed consent obtained from the LAR, as described in Section 9.5. 


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10 REGULATORY AND OPERATIONAL CONSIDERATIONS 
10.1 STUDY DISCONTINUATION AND CLOSURE
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause.  Written notification, documenting the reason for study suspension or 
termination, will be provided by the suspending or terminating party to study participants, 
investigator, funding agency, the Investigational New Drug (IND) or Investigational Device 
Exemption (IDE) sponsor and regulatory authorities.  If the study is prematurely terminated or 
suspended, the Principal Investigator (PI) will promptly inform study participants, the 
Institutional Review Board (IRB), and sponsor and will provide the reason(s) for the termination 
or suspension.  Study participants will be contacted, as applicable, and be informed of changes to 
study visit schedule.
Circumstances that may warrant termination or suspension include, but are not limited to:

Determination of unexpected, significant, or unacceptable risk to participants

Demonstration of efficacy that would warrant stopping   

Insufficient compliance to protocol requirements

Data that are not sufficiently complete and/or evaluable

Determination that the primary endpoint has been met

Determination of futility
Study may resume once concerns about safety, protocol compliance, and data quality are 
addressed, and satisfy the sponsor, and IRB.
10.2 QUALITY ASSURANCE AND QUALITY CONTROL
Each clinical site will perform internal quality management of study conduct, data and biological 
specimen collection, documentation and completion.  An individualized quality management 
plan will be developed to describe a site’s quality management.
Quality control (QC) procedures will be implemented beginning with the data entry system and 
data QC checks that will be run on the database will be generated. Any missing data or data 
anomalies will be communicated to the site(s) for clarification/resolution.
Following written Standard Operating Procedures (SOPs), the monitors will verify that the 
clinical trial is conducted and data are generated and biological specimens are collected, 
documented (recorded), and reported in compliance with the protocol, International Conference 
on Harmonisation Good Clinical Practice (ICH GCP), and applicable regulatory requirements 
(e.g., Good Laboratory Practices (GLP), Good Manufacturing Practices (GMP)). 
The investigational site will provide direct access to all trial related sites, source data/documents, 
and reports for the purpose of monitoring and auditing by the sponsor, and inspection by local 
and regulatory authorities.
10.3 CONFLICT OF INTEREST POLICY
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical.  Therefore, any actual conflict of interest of persons who 
have a role in the design, conduct, analysis, publication, or any aspect of this trial will be 
disclosed and managed. Furthermore, persons who have a perceived conflict of interest will be 


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required to have such conflicts managed in a way that is appropriate to their participation in the 
design and conduct of this trial.  The study leadership in conjunction with the National Cancer 
Institute has established policies and procedures for all study group members to disclose all 
conflicts of interest and will establish a mechanism for the management of all reported dualities 
of interest.
10.4 CONFIDENTIALITY AND PRIVACY
Participant confidentiality and privacy is strictly held in trust by the participating investigators, 
their staff, and the sponsor(s). This confidentiality is extended to cover testing of biological 
samples and genetic tests in addition to the clinical information relating to participants. 
Therefore, the study protocol, documentation, data, and all other information generated will be 
held in strict confidence. No information concerning the study or the data will be released to any 
unauthorized third party without prior written approval of the sponsor. 
All research activities will be conducted in as private a setting as possible.
The study monitor, other authorized representatives of the sponsor, representatives of the 
Institutional Review Board (IRB), and/or regulatory agencies may inspect all documents and 
records required to be maintained by the investigator, including but not limited to, medical 
records (office, clinic, or hospital) and pharmacy records for the participants in this study. The 
clinical study site will permit access to such records.
The study participant’s contact information will be securely stored at each clinical site for 
internal use during the study. At the end of the study, all records will continue to be kept in a 
secure location for as long a period as dictated by the reviewing IRB, Institutional policies, or 
sponsor requirements.
Study participant research data, which is for purposes of statistical analysis and scientific 
reporting, will be stored at the NCI CCR. This will not include the participant’s contact or 
identifying information. Rather, individual participants and their research data will be identified 
by a unique study identification number. The study data entry and study management systems 
used by the clinical site(s) and by NCI CCR research staff will be secured and password 
protected. At the end of the study, all study databases will be archived at the NIH.
To further protect the privacy of study participants, a Certificate of Confidentiality has been 
issued by the National Institutes of Health (NIH).  This certificate protects identifiable research 
information from forced disclosure. It allows the investigator and others who have access to 
research records to refuse to disclose identifying information on research participation in any 
civil, criminal, administrative, legislative, or other proceeding, whether at the federal, state, or 
local level. By protecting researchers and institutions from being compelled to disclose 
information that would identify research participants, Certificates of Confidentiality help achieve 
the research objectives and promote participation in studies by helping assure confidentiality and 
privacy to participants.
11 PHARMACEUTICAL INFORMATION
There will be no IND obtained for the use of any of the commercial agents used in this study. 
This study meets the criteria for exemption for an IND as this investigation is not intended to 
support a new indication for use or any other significant change to the labeling; the drugs are 
already approved and marketed and the investigation is not intended to support a significant 


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change in advertising; and the investigation does not involve a route of administration or dosage 
level in use in a patient population or other factor that significantly increases the risks (or 
decreases the acceptability of the risks) associated with the use of the drug product.
11.1 CYCLOPHOSPHAMIDE
Commercially available in white crystalline formulation for intravenous injection, in vials 
containing 100 mg, 200 mg, 500 mg, 1 gm, or 2 gm. Intact vials are stable at room temperature 
storage (not to exceed 30oC). Reconstitute with appropriate amounts of Sodium Chloride 
Injection (0.9% NS) to produce a solution with final concentration of 20 mg/ml.  Discard 
solution after storage for 24 hours at room temperature. After reconstitution, cyclophosphamide 
is stable for up to 6 days if refrigerated (2º-8oC). Cyclophosphamide will be diluted in 100 mL of 
5% Dextrose Injection or 0.9%NS and infused over 30-60 minutes.  Patients will be instructed to 
drink an adequate amount of fluids and empty their bladders frequently during 
cyclophosphamide administration.

Toxicities: myelosuppression, nausea and vomiting, hemorrhagic cystitis, alopecia. 
Cystitis can be largely prevented by maintaining a good state of hydration and good urine 
flow during and after drug administration using the following guidelines. Please refer to 
the package insert for a complete listing of all toxicities.  

Hydration Guidelines:  All patients should receive 0.9% NS at the following volumes 
(based on cyclophosphamide dose levels) and rates with half the specified volume given 
before starting cyclophosphamide administration and half the volume given after 
completion of the cyclophosphamide administration.  
Cyclophosphamide
Dosage Levels
Fluid Volume and Administration Rate
1 & 2
1000 mL 0.9%NS @ 300 – 500 mL/h
Levels 3, 4, & 5
2000 mL 0.9%NS @ 300 – 500 mL/h
Levels 6
2500 mL 0.9%NS @ 300 – 500 mL/h
11.2 DOXORUBICIN
Commercially available as a lyophilized powder in 10, 20, and 50 mg vials with 50 mg, 100 mg, 
and 250 mg of lactose, respectively. Store unreconstituted, lyophilized product at controlled 
room temperature and protect from light. Once reconstituted, solution is stable for 7 days at room 
temperature under normal room light and 15 days under refrigeration (2º- 8oC).
Also available as a 2 mg/mL solution for injection in 10, 20, 50, and 200 mg vials. Store 
2mg/mL solution in the refrigerator at 2º- 8oC and protect from light.

Toxicities: Myelosuppression, stomatitis, alopecia, nausea and vomiting, and acute and 
chronic cardiac toxicity, manifested as arrhythmias or a congestive cardiomyopathy, the 
latter uncommon at total cumulative doses less than 500 mg/m2. The drug causes local 
necrosis if infiltrated into subcutaneous tissue. Please refer to the package insert for a 
complete listing of all toxicities.  


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11.3 VINCRISTINE
Commercially available in 1 mg and 2 mg vial sizes. Each ml contains 1 mg of vincristine and 
100 mg mannitol. Sulfuric acid or sodium hydroxide are added for pH control (pH ranges from 4 
– 5). Drug should be stored at 2-8oC and should be protected from light. 

Toxicities: peripheral neuropathy, autonomic neuropathy, alopecia. Local necrosis if 
injected subcutaneously. Please refer to the package insert for a complete listing of all 
toxicities.  
11.4 ETOPOSIDE
Commercially available as a concentrate for parenteral use in 100 mg, 500 mg, and 1 gram 
sterile, multidose vials. The pH of the clear yellow solution is 3 to 4; each ml contains 20 mg 
etoposide, 2 mg citric acid, 30 mg benzyl alcohol, 80 mg polysorbate 80, 650 mg of polyethylene 
glycol 300, and 30.5% alcohol. Drug should be stored at controlled room temperature.

Toxicities: myelosuppression, nausea, vomiting, anaphylactoid reactions, alopecia, and 
hypotension if infusion is too rapid. Please refer to the package insert for a complete 
listing of all toxicities.  
11.5 ADMINISTRATION OF VINCRISTINE/DOXORUBICIN/ETOPOSIDE. 
Stability studies conducted by the Pharmaceutical Development Section, Pharmacy Department, 
NIH Clinical Center, have demonstrated that admixtures of vincristine, doxorubicin, and 
etoposide in 0.9% Sodium Chloride Injection, USP (0.9% NS) at concentrations, respectively, of 
1, 25, and 125 mcg/mL; 1.4, 35, and 175 mcg/mL; 2, 50, and 250 mcg/mL; and 2.8, 70, 350 
mcg/mL are stable for at least 36 hours at room temperature when protected from light. Also, 
admixtures containing vincristine, doxorubicin, and etoposide concentrations of 1.6, 40, and 200 
mcg/mL are stable for at least 30 hours at 32°C.
For this study, etoposide, doxorubicin, and vincristine comprising a daily dose (a 24-hour 
supply) will be diluted in 0.9% NS. Product containers will be replaced every 24 hours to 
complete the planned duration of infusional treatment. Product volumes will be determined by 
the amount of etoposide present in a 24-hour supply of medication. For daily etoposide doses 
≤130 mg, admixtures will be diluted in approximately 500 mL 0.9% NS.  For daily etoposide 
doses >130 mg, admixtures will be diluted in approximately 1000 mL 0.9% NS.
For more detailed description, see APPENDIX 1.
Etoposide + doxorubicin + vincristine admixtures will be administered by continuous IV 
infusion over 96 hours with a suitable rate controller pump via a central venous access device.
11.6 PREDNISONE
Commercially available in a large number of oral dosage strengths including pills and liquid 
formulations. Tablets should be stored in well-closed containers at temperatures between 15-
30oC. 

Doses:  Prednisone utilization may be simplified by using only 20- and 50-mg tablets to 
produce individual doses and by stratifying prednisone doses by a patient’s body surface 
area (BSA) according to the chart below. These are recommendations and not 
requirements.


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BSA (m2)
Each Dose
1.25 – 1.49
80 mg
1.5 – 1.83
100 mg
1.84 – 2.16
120 mg
2.17 – 2.41
140 mg
2.42 – 2.6
150 mg
2.61 – 2.69
160 mg
2.7 – 3
170 mg

Toxicities: proximal muscle weakness, glucose intolerance, thinning of skin, 
redistribution of body fat, Cushingoid facies, immunosuppression, propensity to 
gastrointestinal ulceration. Please refer to the package insert for a complete listing of all 
toxicities.  
11.7 RITUXIMAB  
The NIH Clinical Center Pharmacy Dept. will purchase rituximab from commercial sources. 
Rituximab is provided in pharmaceutical grade glass vials containing 10 mL (100 mg) or 50 mL 
(500 mg) at a concentration of 10 mg of protein per milliliter. Please refer to the FDA-approved 
package insert for rituximab for product information, extensive preparation instructions, and a 
comprehensive list of adverse events.
IDEC rituximab (IND # 7028) was being supplied by Genentech Inc. through the 
Division of Cancer Treatment, Diagnosis, and Centers, NCI, for this protocol through 
amendment dated 3-8-10. After that date, Rituximab will be supplied by the Clinical 
Center Pharmacy. Rituximab is a mouse/human antibody. The antibody is produced by a 
Chinese hamster ovary transfectoma.  

Storage: Rituximab for clinical use should be stored in a secure refrigerator at 2 to 8 
degrees C. 

Preparation: Rituximab will be diluted with 0.9% Sodium Chloride or 5% Dextrose 
Injection to prepare a standard product with concentration of 2 mg/ml.  Caution should be 
taken during the preparation of the drug, as shaking can cause aggregation and 
precipitation of the antibody.

Stability: After dilution, rituximab is stable at 2-8 degrees C (36-46 degrees F) for 24 
hours and at room temperature for an additional 12 hours. 

Administration: A peripheral or central intravenous line will be established. During 
rituximab infusion, a patient's vital signs (blood pressure, pulse, respiration, temperature) 
should be monitored according to the standard of care. Medications readily available for 
the emergency management of anaphylactoid reactions should include: epinephrine 
(1:1000, 1 mg/mL) for subcutaneous injection, diphenhydramine hydrochloride for 
intravenous injection, and resuscitation equipment.


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Prophylaxis against hypersensitivity and infusion-related reactions associated with rituximab 
will include acetaminophen 650 mg and diphenhydramine hydrochloride 50-100 mg 
administered 30 to 60 minutes prior to starting rituximab. Patients will also receive their first 
dose of prednisone 60 mg/m2 (or a glucocorticoid equivalent dose of an alternative steroid) at 
least 60 minutes before rituximab treatment commences.
Rituximab will be administered as an intravenous infusion at 375 mg/m2 on day 1 of each 
cycle of EPOCH, immediately prior to starting etoposide + doxorubicin + vincristine 
administration. Rituximab infusions will be administered to patients primarily in an 
outpatient clinic setting.  
First dose:
The initial dose rate at the time of the first rituximab infusion should be 50mg/hour (25 
mL/hr) for the first 30 minutes. If no toxicity is seen, the dose rate may be escalated 
gradually in 50 mg/hour (25 mL/h) increments at 30 minute intervals) to a maximum of 400 
mg/hour (maximum rate = 200 mL/h). 
Second and Subsequent Doses (select the appropriate administration timing):
90-minute Administration
If the first dose of rituximab was well tolerated, subsequent doses may be administered 
over 90 minutes with 20% of the total dose given in the first 30 minutes, and remaining 
80% of the total dose administered over the subsequent 60 minutes; e.g.:
Two-Step Rate Escalation
Volume to administer (X mL)
1st portion (0 – 30 minutes)
Total Dose (mg)
2
0.2 X mL (over 30 min)
2nd portion (30 – 90 minutes)
Total Dose (mg)
2
0.8 X mL (over 60 min)
Special Note: The 90-minute infusion scheme is not recommended for patients with 
clinically significant cardiovascular disease or high circulating lymphocyte counts 
(≥5000/mcL).
Standard Administration for Second & Subsequent Infusions
Patients who tolerate initial treatment without experiencing infusion-related adverse 
effects but for whom the 90-minute infusion scheme during subsequent treatments is 
considered inappropriate, may receive subsequent rituximab doses at the Standard Rate 
for Subsequent Infusions, which is as follows:
Begin at an initial rate of 100 mg/hour (50 mL/h) for 30 minutes. If administration is well 
tolerated, the administration rate may be escalated gradually in 100-mg/hour (50-mL/h) at 
30-minute intervals to a maximum rate of 400 mg/hour (maximum rate = 200 mL/h).
CAUTION:  DO NOT ADMINISTER AS AN INTRAVENOUS PUSH OR BOLUS.  


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
Toxicities: 
No dose-limiting effects were observed in the Phase I/II studies.  Reported adverse events 
including fever, chills, headache, nausea, vomiting, rhinitis, asthenia, and hypotension, 
occurred primarily during rituximab infusions and typically responded to an interruption 
of the infusion and resumption at a slower rate.  
Fatal Infusion Reactions:  Severe and fatal cardiopulmonary events, including 
angioedema, hypoxia, pulmonary infiltrates, acute respiratory distress syndrome, 
myocardial infarction, and cardiogenic shock, have been reported.  These severe reactions 
typically occurred during the first infusion with time to onset of 30-120 minutes.
Cardiac Events:  Patients with preexisting cardiac conditions, including arrhythmia and 
angina, have had recurrences of these cardiac events during rituximab infusions.
Tumor Lysis Syndrome:  Tumor lysis syndrome, some with fatal outcome, has been 
reported and is characterized in patients with a high number of circulating malignant cells 
(≥25,000/µL) by rapid reduction in tumor volume, renal insufficiency, hyperkalemia, 
hypocalcemia, hyperuricemia, and hyperphosphatemia.
Renal Events:  Rituximab has been associated with severe renal toxicity including acute 
renal failure requiring dialysis, and in some cases has led to death.  Renal toxicity has 
occurred in patients with high numbers of circulating malignant cells (≥25,000/mm2) or 
high tumor burden who experience tumor lysis syndrome and in patients administered 
concomitant cisplatin.
Mucocutaneous Reactions:  Severe bullous skin reactions, including fatal cases of toxic 
epidermal necrolysis and paraneoplastic pemphigus, have been reported in patients 
treated with rituximab.  The onset of reaction has varied from 1 to 13 weeks following 
rituximab exposure.
Hematologic Events:  In clinical trials, Grade 3 and 4 cytopenias were reported in 48% of 
patients treated with rituximab; these include: lymphopenia (40%), neutropenia (6%), 
leukopenia (4%), anemia (3%), and thrombocytopenia (2%).  The median duration of 
lymphopenia was 14 days (range, 1 to 588 days) and of neutropenia was 13 days (range, 
2 to 116 days).  A single occurrence of transient aplastic anemia (pure red cell aplasia) 
and two occurrences of hemolytic anemia following Rituximab therapy were reported. 
In addition, there have been a limited number of post marketing reports of prolonged 
pancytopenia, marrow hypoplasia, and late onset neutropenia. 
Infectious Events:  Rituxan induced B-cell depletion in 70% to 80% of patients with NHL 
and was associated with decreased serum immunoglobulins in a minority of patients; the 
lymphopenia lasted a median of 14 days (range, 1-588 days).  Infectious events occurred 
in 31% of patients: 19% of patients had bacterial infections, 10% had viral infections, 1% 
had fungal infections, and 6% were unknown infections.  Serious infectious events 
(Grade 3 or 4), including sepsis, occurred in 2% of patients.
Hepatitis B Reactivation:  Hepatitis B virus (HBV) reactivation with fulminant hepatitis, 
hepatic failure, and death has been reported in some patients with hematologic 
malignancies treated with rituximab.  The majority of patients received rituximab in 
combination with chemotherapy.  The median time to the diagnosis of hepatitis was 


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approximately four months after the initiation of rituximab and approximately one month 
after the last dose.
Other Serious Viral Infections:  The following additional serious viral infections, either 
new, reactivated or exacerbated, have been identified in clinical studies or post-marketing 
reports. The majority of patients received Rituxan in combination with chemotherapy or 
as part of a hematopoietic stem cell transplant. These viral infections included JC virus 
(progressive multifocal leukoencephalopathy [PML]), cytomegalovirus, herpes simplex 
virus, parvovirus B19, varicella zoster virus, West Nile virus, and hepatitis C. In some 
cases, the viral infections occurred up to one year following discontinuation of Rituxan 
and have resulted in death.
Progressive multifocal leukoencephalopathy (PML)
PML is a rare disease caused by the reactivation of latent JC virus in the 
brain.  Immunosuppression allows reactivation of the JC virus which causes 
demyelination and destruction of oligodendrocytes resulting in death or severe 
disability.  Rare cases of PML, some resulting in death, have been reported in patients 
with hematologic malignancies who have received rituximab.  The majority of these 
patients had received rituximab in combination with chemotherapy or as part of a 
hematopoietic stem cell transplant.  Cases of PML resulting in death have also been 
reported following the use of rituximab for the treatment of autoimmune diseases. The 
reported cases had multiple risk factors for PML, including the underlying disease and 
long-term immunosuppressive therapy or chemotherapy.  Most cases of PML were 
diagnosed within 12 months of their last infusion of rituximab. 
Physicians should consider PML in any patient presenting with new onset neurologic 
manifestations. Consultation with a neurologist, brain MRI, and lumbar puncture should 
be considered as clinically indicated.  In patients who develop PML, rituximab should be 
discontinued and reductions or discontinuation of any concomitant chemotherapy or 
immunosuppressive therapy should be considered.
Bowel Obstruction and Perforation:  Abdominal pain, bowel obstruction and perforation, 
in some cases leading to death, were observed in patients receiving Rituxan in 
combination with chemotherapy for DLBCL. In post-marketing reports, which include 
both patients with low-grade or follicular NHL and DLBCL, the mean time to onset of 
symptoms was 6 days (range 1−77) in patients with documented gastro-intestinal 
perforation. Complaints of abdominal pain, especially early in the course of treatment, 
should prompt a thorough diagnostic evaluation and appropriate treatment.
Immunogenicity:  Patients may develop a human anti-chimeric antibody (HACA) 
response with rituximab treatment.  The clinical significance of this is unclear.
Pregnancy:  B-cell lymphocytopenia generally lasting less than 6 months can occur in 
infants exposed to rituximab in utero.
Immunization:  Response rates may be reduced with non live vaccines.
Additional Safety Signals:  The following serious adverse events have been reported to 
occur in patients following completion of rituximab infusions: arthritis, disorders of 
blood vessels (vasculitis, serum sickness and lupus-like syndrome), eye disorders (uveitis 
and optic neuritis), lung disorders including pleuritis and scarring of the lung 


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(bronchiolitis obliterans), that may result in fatal outcomes, and fatal cardiac failure.
See the rituximab Investigator Brochure for additional details regarding safety experience 
with rituximab.
11.8 FILGRASTIM (NEUPOGENR)
CTEP supplied commercial over labeled vials of filgrastim until the supply was depleted 
(approximately 2-01-02), after which filgrastim will be obtained from commercial sources. 
The filgrastim injection will be supplied in single use vials containing 300 mcg (1 ml/vial) and 
480 mcg (1.6 mL/vial). Filgrastim will be stored at 2º- 8o C.  DO NOT FREEZE and DO NOT 
SHAKE the drug product.  Filgrastim will be given by subcutaneous injection; patient or other 
caregiver will be instructed on proper injection technique.    

Toxicities: Rare anaphylactic reactions with the first dose; bone pain at sites of active 
marrow with continued administration. Local reactions at injection sites. Constitutional 
symptoms, increased alkaline phosphatase, LDH, uric acid; worsening of pre-existing 
inflammatory conditions. Please refer to the package insert for a complete listing of all 
toxicities.  
11.9 METHOTREXATE
Only the preservative-free preparation should be used for intrathecal or intraventricular injection. 
Preservative-free methotrexate is commercially available as either a lyophilized powder or 
solution in 50, 100, 200, 250, and 1000 mg vial sizes. Sodium hydroxide and/or hydrochloric 
acid are also added to adjust the pH to 8.5 to 8.7. When reconstituted, each ml contains 25 mg of 
methotrexate; the commercially available preservative-free solution also contains 25 mg of 
methotrexate per 1 mL. Methotrexate should be stored at 15 – 30o C and protected from light. 
Prior to intrathecal or intraventricular injection, the prescribed dose of methotrexate should be 
further diluted with preservative-free 0.9% sodium chloride to a total volume of 3 to 5 mL. 
Prepared doses of methotrexate should be utilized within 4 hours of preparation.

Toxicities: myelosuppression, headache, nausea, drowsiness, and blurred vision. A 
transient acute neurologic syndrome manifested by confusion, hemiparesis, seizures, and 
coma may also occur. Please refer to the package insert for a complete listing of all 
toxicities.  
11.10 CYTARABINE
Only the preservative-free preparation should be used for intrathecal or intraventricular injection. 
Preservative-free cytarabine is commercially available as either a lyophilized powder or solution 
in 100, 500, 1000, and 2000 mg vial sizes. Sodium hydroxide and/or hydrochloric acid are also 
added to adjust the pH to 7.7. When prepared for intrathecal injection, each mL contains 100 mg 
of cytarabine. Intact vials of lyophilized powder should be stored at 20 – 25o C and intact vials of 
solution should be stored at 15 – 30o C. Prior to intrathecal or intraventricular injection, the 
prescribed dose of cytarabine should be reconstituted and diluted with preservative-free 0.9% 
sodium chloride to a total volume of 3 to 5 mL. Prepared doses of cytarabine should be utilized 
within 4 hours of preparation.

Toxicities: myelosuppression, fever, nausea, dizziness, somnolence, and arachnoiditis. 
Please refer to the package insert for a complete listing of all toxicities. 


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12 REFERENCES
1. DeVita VT Jr et al. Lancet 1:248, 1975.
2. McKelvey EM et al. Cancer 38: 1484, 1976.
3. Coltman CA et al. In Skarin AT (ed): Advances in Cancer Chemotherapy 1986; 71-78.
4. Klimo P, Connors JM. Ann Int Med 102: 596, 1985.
5. Longo DL et al. J Clin Oncol 9:25, 1991.
6. Fisher RI, Gaynor E, Dahlberg S, et al. PASCO 11: 315 (#1067), 1992.
7. DeVita VT Jr et al. Cancer Res 47:5810, 1987.
8. Goldie JH, Coldman AJ. Cancer Treat Rep 63:1727, 1979.
9. Lai GM et al (Fojo). Int J Cancer 49:696, 1991.
10. Goldstein L et al. JNCI 81:116, 1989.
11. Demidem A, Lam T, alas S, et al: Cancer Biother Radiopharm 12:177, 1997. 
12. Link BK, Grossbard ML, Fisher RI, et al: Proc ASCO 17:7, 1998. 
13. Wilson WH, et al: BLOOD 99 2685-93, 2002.
14. Wilson WH et al:  Semin Oncol 29:41-47, 2002.
15. Wilson WH, et al:  J Clin Oncol 26:2717-2724, 2008. 
16. Dixon DO and Simon RM:  J Clin Epidemiol 41: 1209-1213, 1988.
17. Dunleavy K, et al:  Dose-Adjusted-EPOCH-R Therapy in Primary Mediastinal B-cell 
Lymphoma. NEJM. April 11, 2013. 
18. Dunleavy K, et al: Low Intensity Therapy in Adults with Burkitt’s Lymphoma. NEJM. 
November 14, 2013.


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13 APPENDIX 1:  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


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 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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14 APPENDIX 2: LETTER TO FEMALE PATIENTS AND QUESTIONNAIRE
14.1 LETTER TO PATIENTS
Dear 
Thank you for your participation in our study using EPOCH-R chemotherapy to treat primary 
mediastinal B-cell lymphoma. We are very happy that the treatment has been helpful to you.
As we continue to follow individuals on this study, we would like to learn if the 
chemotherapy had any effect on the hormone levels and/or fertility of female patients. To 
gather this information, we are asking our female patients to take part in a telephone 
interview during which we will ask for information about gynecologic and obstetric history, 
as well as symptoms and emotions that may have been experienced during the time of 
diagnosis with lymphoma and then during the treatment and follow-up phases. We will use 
the list of questions which is enclosed with this letter. 
We would appreciate, if you would consider taking part in this very important portion of our 
study. 
If you agree to take part, please contact your research nurse to set up a time that is convenient 
for you to undergo a 30-minute phone interview. You will then be contacted at the appointed 
time and interviewed, using the enclosed questionnaire for guidance.
We hope you will be willing to assist us with this important project and we look forward to 
hearing from you.
Sincerely, 
Lymphoid Malignancies Branch
Center for Cancer Research
National Institutes of Health
Building 10 Room 4N115


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14.2 QUESTIONNAIRE
1. What was your menstrual history before chemotherapy? 
[ ] Regular (21-35 days) 
[ ] Irregular
2. Do you have a history of thyroid disorder?
         
               
[ ] Yes - What type of disorder? When were you diagnosed with it?  
[ ] No
3. Do you have a positive family history of infertility?
               
[ ] Yes - Who is/was affected? 
[ ] No 
4. Did you ever attempt to become pregnant before your diagnosis of lymphoma?
[ ] Yes - successful
[ ] Yes - unsuccessful
[ ] No
5. Did you become pregnant naturally?
             
[ ] Yes 
[ ] No
6. Did you deliver at term?
           
             
[ ] Yes
[ ] No
 
7. Did you ever have a miscarriage? 
             
[ ] Yes - How many times? During which trimester of pregnancy?
[ ] No
8. Did your menstrual periods stop while undergoing chemotherapy?   
[ ] Yes
[ ] No
9. Did your menstrual periods recur after completion of chemotherapy? 
[ ] Yes - How many weeks/months after completion of chemotherapy?  
[ ] No
If yes, were they:  [ ] Regular (21-35 days)  or  [ ] Irregular
10. If your menstrual periods did not recur after completion of chemotherapy, did you/are you 
experiencing symptoms such as hot flashes, sleep disturbances, vaginal dryness and 
discomfort or pain with intercourse?
[ ] Yes - What type of symptoms do you have?             
 [ ] No 
11. Have you attempted to become pregnant after chemotherapy was completed?     
 
[ ] Yes - successful
[ ] Yes - unsuccessful
[ ] No
12. Were you worried about the risk of infertility or early menopause due to chemotherapy? 
[ ] Yes 
[ ] No  
13. Did you at any point in time consider pursuing fertility preservation before starting 
chemotherapy? 
              
[ ] Yes - What were the barriers to following through? 
[ ] No  

ICF_001.pdf: 
PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 04/20/2021
Page 1 of 19
CC pre rCR ICF template v. 12.01.20
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
PRINCIPAL INVESTIGATOR: Mark Roschewski, M.D.
STUDY TITLE:
Dose-Adjusted EPOCH Chemotherapy and Rituximab 
(CD20+) in Adults and Children with Previously Untreated 
Aggressive Non-Hodgkin's Lymphoma
STUDY SITE:
NIH Clinical Center
Cohort: 
Standard
Consent Version:   
04/20/2021
WHO DO YOU CONTACT ABOUT THIS STUDY? 
Principal Investigator: Mark Roschewski, M.D. 
Phone:  240-760-6183
Email:  mark.roschewski@nih.gov
This consent form describes a research study and is designed to help you decide if you would like 
to be a part of the research study.  
The remaining document will now describe the research study in more detail.  This information 
should be considered before you make your choice. Members of the study team will talk with you 
about the information in this document. Some people have personal, religious, or ethical beliefs 
that may limit the kinds of medical or research interventions in which they would want to 
participate. Take the time you need to ask any questions and discuss this study with NIH staff, and 
with your family, friends, and personal health care providers. 
If the individual being enrolled is a minor then the term “you” refers to “you and/or your child” 
throughout the remainder of this document.
If the individual being asked to participate in this research study is not able to give consent to be 
in this study, you are being asked to give permission for this person as their decision-maker. The 
term “you” refers to you as the decision-maker and/or the individual being asked to participate in 
this research, throughout the remainder of this document.
IT IS YOUR CHOICE TO TAKE PART IN THE STUDY
You may choose not to take part in this study for any reason. If you join this study, you may change 
your mind and stop participating in the study at any time and for any reason. In either case, you 
will not lose any benefits to which you are otherwise entitled. However, to be seen at the NIH, you 
must be taking part in a study or are being considered for a study. If you do choose to leave the 
study, please inform your study team to ensure a safe withdrawal from the research.  
WHY IS THIS STUDY BEING DONE?
You have a disease called non-Hodgkin's lymphoma which your doctor’s think would be better 
treated with chemotherapy than surgery or radiation.  For your particular kind of non-Hodgkin's 
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lymphoma, previous studies have shown that combinations of drugs are much more likely to make 
the disease go away for appreciable periods of time than single drugs, which have only very limited 
effectiveness against this group of lymphomas.  Studies have also shown that more intensive (i.e. 
higher dose) treatments have a greater chance of success than more gentle approaches.  Studies 
conducted at the National Cancer Institute suggest that certain chemotherapy drugs may be more 
effective if given by continuous infusion into the vein rather than by the standard method of rapid 
intravenous injection.  One such combination, which we call EPOCH (each letter stands for one 
of the drugs used in the combination), seems to have a high degree of effectiveness in patients 
whose tumors have stopped responding to standard regimens.  We therefore plan to test this 
combination in patients who have never received chemotherapy previously.  Research indicates 
that the effects of chemotherapy with EPOCH may be improved by the use of a drug called 
Rituximab.  Rituximab is a special kind of drug called an antibody which binds to a specific 
molecule (called CD20) present on some types of lymphomas called B-cell lymphomas.  If 
you/your child have/has one of the lymphoma types which have the CD20 molecule present, then 
you will also receive rituximab along with the EPOCH chemotherapy.
How many people will take part in this study? 
Approximately 348 patients will take part in 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.  In this study five chemotherapy drugs are given together in an intensive 
combination called EPOCH.  Each series of treatments is called a cycle; a cycle is repeated every 
three weeks and drugs are administered during the first five days of every cycle.  EPOCH consists 
of prednisone by mouth on days 1-5, and etoposide, doxorubicin, and vincristine as a continuous 
infusion on days 1 through 5 (total of 96 hours).  In addition, cyclophosphamide is given by 
intravenous injection over about 30-60 minutes on day 5.  If your tumor has the CD20 molecule, 
you will also receive a dose of rituximab on day 1, immediately before the chemotherapy begins.  
Each cycle lasts 3 weeks: 5 days of chemotherapy followed by 16 days of no chemotherapy.  You 
will receive repeated cycles of EPOCH until remission (disappearance of tumor) is achieved or 
until the tumor shows no further evidence of shrinkage.  Between cycles of treatment we give 
another drug, G-CSF, whose purpose is to help your normal bone marrow cells recover from the 
chemotherapy and produce normal white cells.  The use of G-CSF in this way may help us increase 
the total amount of chemotherapy you can receive.
We will test whether giving the drugs by continuous infusion with G-CSF will allow us to give 
more intensive and more effective therapy than was possible previously.  If you are individually 
capable of tolerating more drug than the initial amount you receive, the treatment plan allows us 
to increase your doses of some of the drugs in later treatment cycles, so that we can be sure of 
giving you as much drug as you can tolerate without unacceptable side effects.  However, the doses 
of rituximab, vincristine and prednisone will not be increased.  In summary, then, the specific 
objective of this study is to assess whether EPOCH (and possibly rituximab) has excellent clinical 
response in patients like you and to see whether the use of continuous infusion of some of the 
drugs, coupled with the use of the bone marrow stimulator G-CSF, will permit us to give 
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significantly higher quantities of drug than is possible when the treatment is given in standard 
fashion.
A laboratory objective of this protocol is to study why some patient’s tumors are not cured by 
therapy.  To help determine this, we will do some experimental tests on your tumor biopsies, blood 
and other fluids from you to look at different genes and proteins.  However, we will not examine 
mutations of normal genes from your tissue without obtaining additional permission from you.  It 
may be important to obtain repeat biopsies of tumor tissue, even if you have already had such a 
biopsy before coming here.  We do this sometimes to confirm the diagnosis or to obtain fresh 
tumor tissue for research purposes. Biopsies requiring major surgery (e.g. in the chest or the 
abdomen) will not be performed for research purposes alone but only if absolutely necessary for 
your medical care.  You may decide not to have a biopsy for research purposes and this will not 
affect your eligibility for this study. We may request biopsies after you sign the consent form, at 
Cycle 4 and at Cycle 6.
If you agree to have the optional biopsy, you will be asked to sign a separate procedure consent 
before you have the procedure.
WHAT WILL HAPPEN IF YOU TAKE PART IN THIS RESEARCH STUDY?  
Treatment consists of the following drugs:
1. Doxorubicin, etoposide, and vincristine - These three drugs are given by continuous IV 
infusion over four days, beginning on day 1 and ending on day 5 of each cycle.  We deliver 
these drugs with the aid of one lightweight, portable infusion pump, each about the size of a 
portable tape recorder; this permits treatment on an outpatient basis.  The pumps deliver the 
therapy through an intravenous catheter which is placed in your vein beforehand.  You will be 
taught about the use and care of the pump and what to do if it stops working. 
2. Cyclophosphamide - This is given over about 30-60 minutes on day 5 of each treatment cycle.
3. Prednisone - These are pills given by mouth twice a day for the first 5 days of every cycle.
4. Rituximab – Administered only in patients with CD20+ B-cell lymphomas.  This drug is given 
by vein over several hours on the first day of each cycle, immediately before the chemotherapy 
infusion begins.
5. G-CSF - This is given by injection under the skin once daily beginning on day 6 of each cycle 
and continuing until recovery of the white blood cell count.  If your white blood cell count is 
still very low on the day treatment is due to begin again, the chemotherapy may be deferred 
and the G-CSF restarted until fuller recovery of the white count.  You will be taught how to 
administer the G-CSF to yourself during the first treatment cycle.
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EPOCH-R Treatment Schema
Day of Treatment
1
2
3
4
5
6
7
8
9
10
11
12
13
…
21*
Rituximab
X
Etoposide
X 
Prednisone
X
X
X
X
X
Vincristine
X 
Cyclophosphamide
X
Doxorubicin
X 
G-CSF
X** 
* This twenty-one day (21) period will be known as a “cycle” of therapy. Therapy will be repeated 
for a total of 6-8 cycles. 
** G-CSF will continue to be given to you until your blood counts have reached acceptable levels.
We expect that treatment will be given for approximately 6 to 8 cycles (about 18 to 24 weeks).  In 
general, you will receive two cycles past the point of maximum response. In very rare situations, 
your study doctors may recommend radiation treatment to a specific area of your body after you 
complete the chemotherapy. If this occurs, your study doctors will explain the radiation therapy, 
other treatment options and side effects to expect.
Since several of these drugs can lower your resistance to infection, we also require that you take a 
combination antibiotic, trimethoprim/sulfamethoxazole (SeptraR or BactrimR) for three days each 
week while you are receiving EPOCH chemotherapy (Monday, Wednesday and Friday is the 
preferred schedule).  If allergic to these preparations, you will receive another drug, pentamidine, 
by inhalation once monthly or other standard treatment.
Hepatitis B testing and prophylaxis:
As part of our study, we will test you for infection with Hepatitis B. We will tell you what the 
results mean and if you will require more frequent testing for Hepatitis B and need to take 
medicine to prevent Hepatitis B reactivation while on the study.
If you need to take medicine, you will take one, such as entecavir, by mouth every day until 12 
months after your last chemotherapy.
Treatment of disease in the nervous system  
It occasionally happens that lymphomas spread to the coverings of the brain (the meninges) at 
some point during the illness.  If this should happen, the treatment usually includes the instillation 
of one of two chemotherapy drugs (methotrexate and cytarabine) directly into the fluid (the 
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cerebrospinal fluid, or CSF) surrounding the brain.  This is usually done by first placing a small 
reservoir (an Ommaya reservoir) under the skin of the scalp; this reservoir is connected to a 
catheter that is placed through the brain itself into the fluid.  This procedure is performed by a 
neurosurgeon under general anesthesia.  These drugs may also be administered through a spinal 
tap (also called a lumbar puncture).  Depending on how you respond to this therapy, it may be 
necessary to modify it and to also administer radiation to your brain and spinal cord.  Each of these 
therapies will be discussed with you if they are needed.  Patients who have lymphoma in their bone 
marrow or who have certain sub-types of lymphoma are at higher risk of developing lymphoma in 
the brain areas.  To reduce this risk, patients at higher risk will receive methotrexate by a spinal 
tap on days 1 and 5 of cycles 3-6 of their EPOCH chemotherapy.  This will be discussed with you 
by your treating physicians.
When you are finished taking the treatment
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.  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
What side effects or risks can I expect from being in this study?
In order to determine whether this study is suitable for you, a number of tests will have to be done.  
This period of evaluation may take up to two weeks and is usually done on an outpatient basis.  
Depending on the tests you have already had before coming here, these may include blood and 
urine tests, studies of lung function, CAT or MRI scans, radioisotope scans, and biopsies of tumor 
tissue, bone marrow, liver, or other sites.  Biopsies will, when possible, be done under local 
anesthesia.  The risks associated with blood draws include pain, blood clots, bruises, infection and 
nerve damage.  The risks associated with bone marrow biopsies include pain, bleeding, and 
infection.  Risks of biopsies include pain, bleeding, infection, and the risks to the particular area 
undergoing surgery.  General anesthesia itself is generally very safe but has a very small risk of 
major complications such as heart attack or stroke.  The surgical and anesthetic risks will be 
explained to you in more detail at the time of surgery, if this is needed. 
In order to receive this therapy, you will need to have an intravenous catheter placed.  This catheter 
is usually placed in the arm, chest or neck area into a major vein inside your chest.  We usually 
remove the catheter after each cycle but on occasion it can be left in for several cycles.  The catheter 
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is necessary for infusion of chemotherapy and for the drawing of blood.  It is usually inserted under 
local anesthesia.  The risks associated with the procedure include pain, bleeding, infection, and 
puncture of the underlying lung. Lung puncture can result in lung collapse, which might require 
that a chest tube be placed into the chest cavity (usually for a day or two) to help the lung reinflate.  
The long-term risks of the catheter include infection and clotting of the vein in which the catheter 
sits.  If these occur, it may be necessary to remove the catheter.  These risks will be explained to 
you in more detail at the time of the insertion. 
You may have side effects while on the study. Everyone 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 symptoms that you experience while taking part in the 
study.
Risks and side effects related to the treatment are identified below:
Side Effects from Treatment
Side Effects of EPOCH
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.

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.
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
Loss of appetite, change in taste and weight loss.

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.

Hand and foot syndrome, a condition that causes the skin on your hands and feet to become 
reddened, peel and be painful.
Side Effects of Rituximab
Likely:

Lowered lymphocyte (a specific white blood cell) count

Tiredness

Fever and chills while receiving rituximab

Nausea
Less Likely:

Temporary shortness of breath or dizziness while receiving rituximab.

Flushing, rash, itching and/or hives while receiving rituximab

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.

Lowered white blood cell count that may lead to infection.

Runny nose and sneezing
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
Cough, wheezing, and/or infiltrates in your lungs

Abnormal heart rhythms including a heart attack

Allergic reaction that may be severe or life-threatening. Symptoms may include difficulty 
breathing, low blood pressure, fast heart rate, and sweating.

Serum sickness or acute infusion reaction (both similar to allergic reactions)

Elevated or decreased blood pressure

Muscle or joint aches

Pain at the site of your tumor

Headache

Abdominal pain, diarrhea, and/or vomiting

Bowel perforation

Infections with other viruses, such as JC virus, varicella zoster, herpes simplex, and West 
Nile virus could occur during or after treatment with rituximab.  You will be closely 
monitored and appropriately treated for any infections.

Abnormalities in blood results such as low calcium, high glucose, potassium, and uric acid

Seizure

Mood changes such as anxiety
Rare, But Serious:

Skin rash that may be serious and life-threatening.

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.

Tumor lysis syndrome, which causes abnormal levels of chemicals in your blood and 
kidney failure. This is the results of rituximab killing a very large number of tumor cells in 
the blood and decreased oxygen in the blood.

Lung problems such as adult respiratory distress syndrome (ARDS)
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.  Therefore, if you have a temperature greater than 38.3° C (101° F), you must 
call your doctor immediately.  
Hepatitis B Reactivation
Hepatitis B reactivation has occurred in patients treated with combination chemotherapy and 
rituximab. Signs of hepatitis B reactivation may include: fever, fatigue, loss of appetite, nausea, 
vomiting, abdominal pain, dark urine, clay colored bowl movement, joint pain and yellowing of 
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the skin and/or eyes (jaundice).  It may lead to long-term health problems, including liver damage, 
liver failure, liver cancer, and even death.  
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.
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.  
Birth Control
If you are a woman who is breast feeding or pregnant, you may not take part in the study because 
we don’t know how this medicine would affect your baby or your unborn child. If you are a woman 
who can become pregnant, or are the partner of a woman who can become pregnant, you will need 
to practice an effective form of birth control before starting study treatment, during study 
treatment, and for 12 months after you finish study treatment.  If you think that you or your partner 
is pregnant, you should tell your study doctor or nurse at once.  
Effective forms of birth control include: 
•
abstinence 

intrauterine device (IUD)

hormonal [birth control pills, injections, or implants]

tubal ligation

vasectomy
Complications of Treatment of the Central Nervous System
Complications of Ommaya insertion are uncommon when done by an experienced physician 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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Risks from Other Study Procedures 
Blood sampling
The blood samples collected as part of this study are not expected to produce any important 
decrease in the total amount of blood in your body. Side effects may include pain and discomfort, 
bruising, and rarely inflammation of the vein, bleeding or infection. Additionally, some patients 
can experience light-headedness or fainting. The most amount of blood to be drawn during any 
study visit/cycle is expected to be about 3 tablespoons. This includes testing for standard of care 
tests (i.e., complete blood counts) as well as blood for research.
Biopsy
Once treatment is complete as part of follow-up assessments, you may agree to the biopsy now 
and change your mind later. If at any time you do not want to have a biopsy done, please tell us, it 
will not affect your care. If you agree to have the biopsy, you will be asked to sign a separate 
procedure consent before you have the procedure(s). The likely side effects include discomfort or 
pain, redness, swelling, and/or bruising at the site of the needle insertion.  Bleeding from the site 
of the needle insertion is a less likely risk.  Rarely, significant infection or bleeding from this 
procedure, allergic reaction to the anesthetic, or formation of a scar at the site of needle entry 
occurs.  If you will have sedation with the procedure, these risks will be discussed with you prior 
to the procedure.  You will be asked to sign a separate consent form prior to any biopsy procedure.
Bone Marrow Aspiration
These procedures usually cause only brief discomfort at the site from which the biopsy is taken.  
Rarely, infection or bleeding may occur at the needle site.  A numbing agent that can cause a 
stinging or burning sensation may be injected at the site of your bone marrow biopsy.  The biopsy 
needle will go through the skin into the bone and may produce a brief, sharp pain.  As the bone 
marrow liquid is taken from the bone, there may be a brief, sharp pain.  Since the inside of the 
bone cannot be numbed, this procedure may cause some discomfort, however not all patients 
experience discomfort.  The possible side effects associated with a bone marrow biopsy include 
pain, bleeding, bruising, and infection, as well as a reaction to the numbing agent.  
Imaging – CT scans and MRI
Risks from CT scans:  
CT scans are used to monitor your disease while you are in this study.  CT scans expose you to 
radiation; the amount depends on the number of body areas scanned.  In addition, scans involve 
use of contrast (oral and/or IV) that the cancer may be seen better on the images.  You will have 
scans done (based on your disease at the discretion of your doctor) prior to treatment (if these need 
to be repeated from screening), after you sign the consent, at Cycle 4, and at Cycle 6.
The below describes more information about the risks of the contrast and imaging:
o
Contrast Agents:  There is a chance of developing an allergic reaction from the 
contrast material, which may cause symptoms ranging from mild itching or a rash 
to severe difficulty breathing, shock or rarely, death.  The contrast material may 
also cause kidney problems.  The study doctors will do a blood test prior to the test 
to confirm that it is safe you to receive the contrast.
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For IV contrast: You may feel discomfort when the contrast material is injected. 
You may feel warm, flushed, get a metallic taste in your mouth or, rarely, may 
make you vomit or feel sick to your stomach.  
For oral contrast:  You may experience vomiting, nausea, cramping, bloating, 
constipation or diarrhea after drinking the contrast.
o
CT Scans:  The CT scanner is a doughnut-shaped machine that uses x-rays to create 
computer pictures showing the inside of your body.  During the procedure, you will 
need to lie still on a table inside the CT machine.  The table will move you in and 
out of the machine during the scan and you will be instructed to hold your breath.  
The scan itself will only take a few minutes to complete, the entire visit will take 
about 30 minutes.  For the risks, see “Radiation” below & “Contrast Agent” above.
Radiation Risks:  
During your participation in this research study, you may be exposed to radiation from up to a 
maximum of 5 CT Scans in a single year.  The amount of radiation exposure from these procedures 
is equal to approximately 5.3 rem. A rem is a unit of absorbed radiation. 
Every day, people are exposed to low levels of radiation that come from the sun and the 
environment around them.  The average person in the United States receives a radiation exposure 
of 0.3 rem per year from these sources.  This type of radiation is called “background radiation.”  
This study will expose you to more radiation than you get from everyday background radiation. 
No one knows for sure whether exposure to these low amounts of radiation is harmful to your 
body. 
The CT Scans that you get in this study will expose you to roughly the same amount of radiation 
as 17.7 years’ worth of background radiation. Being exposed to too much radiation can cause 
harmful side effects such as an increase in the risk of cancer.  The risk depends on how much 
radiation you are exposed to. Please be aware that about 40 out of 100 people (40%) will get cancer 
during their lifetime, and 20 out of 100 (20%) will die from cancer. The risk of getting cancer from 
the radiation exposure in this study is 0.5 out of 100 (0.5%) and of getting a fatal cancer is 0.3 out 
of 100 (0.3%).
Risks related to MRI:
People are at risk for injury from the MRI magnet if they have some kinds of metal in their body. 
It may be unsafe for you to have an MRI scan if you have pacemakers or other implanted electrical 
devices, brain stimulators, some types of dental implants, aneurysm clips (metal clips on the wall 
of a large artery), metal prostheses (including metal pins and rods, heart valves, and cochlear 
implants), permanent eyeliner, tattoos, an implanted delivery pump, or shrapnel fragments. 
Welders and metal workers may have small metal fragments in the eye. You will be screened for 
these conditions before having any MRI scan. If you have a question about metal in your body, 
you should inform the staff. You will be asked to complete an MRI screening form before each 
MRI scan you have.
People with fear of confined spaces may become anxious during an MRI. Those with back 
problems may have back pain or discomfort from lying in the scanner. The noise from the scanner 
is loud enough to damage hearing, especially in people who already have hearing loss. Everyone 
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having a research MRI scan will be fitted with hearing protection. If the hearing protection comes 
loose during the scan, you should let us know right away. 
There are no known long-term risks of MRI scans.
Risks related to Gadolinium enhanced MRI:
During part of the MRI you will receive gadolinium, a contrast agent, through an intravenous (IV) 
catheter (small tube). It will be done for research purposes. It is not known if MRI with contrast is 
completely safe for a developing fetus.  Therefore, all women of childbearing potential will have 
a pregnancy test performed no more than 24 hours before each MRI scan with contrast. The scan 
will not be done if the pregnancy test is positive.
Risks: The risks of an IV catheter include bleeding, infection, or inflammation of the skin and vein 
with pain and swelling.
Mild symptoms from gadolinium infusion occur in fewer than 1% of those who receive it and 
usually go away quickly.  Mild symptoms may include coldness in the arm during the injection, a 
metallic taste, headache, and nausea.  In an extremely small number, fewer than one in 300,000 
people, more severe symptoms have been reported including shortness of breath, wheezing, hives, 
and lowering of blood pressure. You should not receive gadolinium if you previously had an 
allergic reaction to it.  You will be asked about such allergic reactions before gadolinium is given.
People with kidney disease are at risk for a serious reaction to gadolinium contrast called 
“nephrogenic systemic fibrosis (NSF)”.  This condition always involves the skin and can also 
involve the muscles, joints and internal organs.  NSF has resulted in a very small number of deaths. 
A blood test of your kidney function may be done within the month before an MRI scan with 
gadolinium contrast. You will not receive gadolinium for a   research MRI scan if your kidney 
function is below the safe level. Most of the gadolinium contrast leaves the body in the urine.  
However, the FDA has issued a safety alert that indicates small amounts of gadolinium may remain 
in the body for months to years. The effects of the retained gadolinium are not clear. At this time, 
retained gadolinium has not been linked to health risks in people whose kidneys work well. Some 
types of gadolinium contrast drugs are less likely to remain in the body than others. In this study, 
we will use the gadolinium contrast drugs that are less likely to remain in the body, whenever 
possible. We will also give you additional information called a “Medication Guide.” Upon request, 
we will give you individual information about retained gadolinium we see on your study.
Risks of Lumbar Puncture
The lumbar puncture may cause pain at the site where the needle goes in and the spinal fluid is 
taken.  There is a small risk of infection or bleeding.  After the lumbar puncture you may get a 
headache.  About a third of adults report a headache after an LP. To minimize the risk of a 
headache, the doctor will use a small needle and may prescribe bed rest for one or more hours 
after the procedure.  If a headache occurs, it is usually mild and can be controlled by bed rest, 
drinking lots of fluids and a pain pill, such as acetaminophen.  Rarely, the headache is severe 
and may require additional treatment with a “blood patch”.  In this procedure, a small amount of 
your own blood is injected into the lumbar puncture site.  This procedure is generally effective 
in stopping the headache.  A rare but serious complication of a LP, if it is done when the pressure 
inside the head is higher than normal (such as when a brain tumor is present), is known as 
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medullary herniation which can result in death.  Increased intracranial pressure is very unlikely 
to be present.  The LP will not be done if there are any clinical indications that you have increased 
intracranial pressure, a skin infection in the lower back area, or bone malformation of the lower 
back (including severe scoliosis) which would make a LP difficult.
To minimize these risks, the lumbar puncture procedure will be performed by a medical 
professional specifically trained to do this procedure.
Urine Collection
There is no physical risks involved with urine collection.
POTENTIAL BENEFITS OF PARTICIPATION
The aim of this study is to see if this treatment will cause your tumors to shrink. We do not know 
if you will receive personal, medical benefit from taking part in this study. The potential benefits 
could include shrinking of your tumor or lessening of your symptoms, such as pain, that are caused 
by the cancer. We do know that the information from this study will help doctors learn more about 
EPOCH-R as a treatment for aggressive lymphoma. We do not know if you will benefit from 
taking part in this study, although the knowledge gained from this study may help future patients 
diagnosed with lymphoma.
ALTERNATIVE APPROACHES 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:
1. Other combination drug regimens and other schedules of the same drugs used in this study.  
For example, a chemotherapy called CHOP given in the conventional manner would be 
suitable standard therapy for your condition.
2. Treatment with single drugs.  This is known to produce brief responses of a few months' 
duration in many patients but to have little beneficial effect in long-term control of the disease.
3. Radiation (X-ray) treatments.  This can stop tumor growth in particular locations, such as bone, 
abdomen, and other sites but is not successful in controlling the disease overall unless the 
disease is very localized at the start of therapy. 
4. Surgery.   As with radiation, surgery can be successful in removing tumor from particular 
locations but cannot be used successfully to remove all lymphoma cells from the body, since 
the disease is almost always present in multiple locations.  Also, surgery cannot be used against 
tumor in some of the organs most commonly involved by lymphoma, such as the liver or the 
lungs.
5. Waiting, without active therapy.  Although a period of watchful waiting is appropriate 
treatment for some kinds of tumors, in lymphomas similar to yours the disease will often grow 
and spread rapidly if no treatment is administered.
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IRB APPROVAL DATE: 05/02/2021


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
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STOPPING THERAPY 
Your doctor may decide to stop your therapy for the following reasons:

if he/she believes that it is in your best interest

if your disease comes back during treatment

if you have side effects from the treatment that your doctor thinks are too severe

if new information shows that another treatment would be better for you
In this case, you will be informed of the reason therapy is being stopped.
You can stop taking part in the study at any time. However, if you decide to stop taking part in the 
study, we would like you to talk to the study doctor and your regular doctor first.
If you decide at any time to withdraw your consent to participate in the trial, we will not collect 
any additional medical information about you. 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.
BLOOD COLLECTION FOR RESEARCH
You may be asked to donate a small amount of blood for research. If you agree to this, you will 
have blood collected for research before, during and after you complete treatment. The amount 
of blood collected will be kept within the safe range set by the Clinical Center. The blood 
collected is exclusively for research purposes and will not benefit you. 
USE OF SPECIMENS AND DATA FOR FUTURE RESEARCH 
To advance science, it is helpful for researchers to share information they get from studying human 
samples.  They do this by putting it into one or more scientific databases, where it is stored along 
with information from other studies. A researcher who wants to study the information must apply 
to the database and be approved.  Researchers use specimens and data stored in scientific databases 
to advance science and learn about health and disease.  
We plan to keep some of your specimens and data that we collect, use them for future research and 
share them with other researchers. We will not contact you to ask about each of these future uses.  
These specimens and data will be stripped of identifiers such as name, address or account number, 
so that they may be used for future research on any topic and shared broadly for 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.
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IRB APPROVAL DATE: 05/02/2021


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
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File in Section 4: Protocol Consent (1)
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CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
PAYMENT
Will you receive any type of payment for taking part in the study?
You will not receive compensation for participation in this study. 
REIMBURSEMENT
Will you receive reimbursement or direct payment by NIH as part of your participation?
Some NIH Clinical Center studies offer reimbursement or payment for travel, lodging or meals 
while participating in the research. The amount, if any, is guided by NIH policies and guidelines.
On this study, the NCI will cover the cost for some of your expenses.  Some of these costs may 
be paid directly by the NIH and some may be reimbursed after you have paid. Someone will 
work with you to provide more information.
COSTS
Will taking part in this research study cost you anything? 
NIH does not bill health insurance companies or participants for any research or related clinical 
care that you receive at the NIH Clinical Center. 
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.
CONFLICT OF INTEREST(COI) 
The National Institutes of Health reviews NIH staff researchers at least yearly for conflicts of 
interest.  This process is detailed in a COI Guide.  You may ask your research team for additional 
information or a copy of the COI Guide.  Investigators 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.
Investigators working on this study may have up to $15,000 of stock in the companies that make 
products used in this study.  This is allowed under federal regulations and is not a conflict of 
interest.
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PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
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File in Section 4: Protocol Consent (1)
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CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
CLINICAL TRIAL REGISTRATION AND RESULTS REPORTING 
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.
CONFIDENTIALITY PROTECTIONS PROVIDED IN THIS STUDY  
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 NIH 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 researchers conducting this study and the NIH follow applicable laws and policies to keep 
your identifying information private to the extent possible.  However, there is always a chance 
that, despite our best efforts, your identity and/or information about your participation in this 
research may be inadvertently released or improperly accessed by unauthorized persons.
In most cases, the NIH will not release any identifiable information collected about you without 
your written permission.  However, your information may be shared as described in the section of 
this document on sharing of specimens and data, and as further outlined in the following sections. 
Further, the information collected for this study is protected by NIH under a Certificate of 
Confidentiality and the Privacy Act. 
Certificate of Confidentiality
To help us protect your privacy, the NIH Intramural Program has received a Certificate of 
Confidentiality (Certificate). With this certificate, researchers may not release or use data or 
information about you except in certain circumstances.  
NIH researchers must not share information that may identify you in any federal, state, or local 
civil, criminal, administrative, legislative, or other proceedings, for example, if requested by a 
court.  
The Certificate does not protect your information when it:  
1. is disclosed to people connected with the research, for example, information may be used 
for auditing or program evaluation internally by the NIH; or 
2. is required to be disclosed by Federal, State, or local laws, for example, when information 
must be disclosed to meet the legal requirements of the federal Food and Drug 
Administration (FDA); 
3. is for other research;
4. is disclosed with your consent. 
The Certificate does not prevent you from voluntarily releasing information about yourself or your 
involvement in this research. 
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PATIENT IDENTIFICATION
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The Certificate will not be used to prevent disclosure to state or local authorities of harm to self or 
others including, for example, child abuse and neglect, and by signing below you consent to those 
disclosures. Other permissions for release may be made by signing NIH forms, such as the Notice 
and Acknowledgement of Information Practices consent.
Privacy Act
The Federal Privacy Act generally protects the confidentiality of your NIH medical records we 
collect under the authority of the Public Health Service Act.  In some cases, the Privacy Act 
protections differ from the Certificate of Confidentiality.  For example, sometimes the Privacy Act 
allows release of information from your medical record without your permission, for example, if 
it is requested by Congress. Information may also be released for certain research purposes with 
due consideration and protection, to those engaged by the agency for research purposes, to certain 
federal and state agencies, for HIV partner notification, for infectious disease or abuse or neglect 
reporting, to tumor registries, for quality assessment and medical audits, or when the NIH is 
involved in a lawsuit.  However, NIH will only release information from your medical record if it 
is permitted by both the Certificate of Confidentiality and the Privacy Act.
POLICY REGARDING RESEARCH-RELATED INJURIES  
The NIH 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 NIH, the NIH Clinical Center, or the Federal 
Government. However, you have the right to pursue legal remedy if you believe that your injury 
justifies such action.
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, Mark 
Roschewski, M.D., Building 10, Room 4N115, mark.roschewski@nih.gov, 240-760-6183. You 
may also call the NIH Clinical Center Patient Representative at 301-496-2626, or the NIH Office 
of IRB Operations at 301-402-3713, if you have a research-related complaint or concern.
CONSENT DOCUMENT 
Please keep a copy of this document in case you want to read it again.
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PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
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File in Section 4: Protocol Consent (1)
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CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
Adult Research Participant: I have read the explanation about this study and have been given the opportunity 
to discuss it and to ask questions. I consent to participate in this study.
Signature of Research Participant
Print Name of Research Participant
Date
Legally Authorized Representative (LAR) for an Adult Unable to Consent: I have read the explanation 
about this study and have been given the opportunity to discuss it and to ask questions. I am legally authorized 
to make research decisions on behalf of the adult participant unable to consent and have the authority to provide 
consent to this study. As applicable, the information in the above consent was described to the adult participant 
unable to consent who agrees to participate in the study.
Signature of LAR
Print Name of LAR
Date
Parent/Guardian of a Minor Participant: I have read the explanation about this study and have been given 
the opportunity to discuss it and to ask questions. I give permission for my child to take part in this study.
Signature of Parent/Guardian
Print Name of Parent/Guardian
Date
Signature of Parent/Guardian 
Print Name of Parent/Guardian
Date
Assent: I have had this study explained to me in a way that I understand, I have been given the opportunity to 
discuss it, and I have had the chance to ask questions. I agree to take part in this study.
Assent of Minor: 
Signature of Minor
Print Name of Minor
Date
Investigator:
Signature of Investigator
Print Name of Investigator
Date
Witness to the oral short-form consent process only: 
Witness:
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PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
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CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
Signature of Witness*
Print Name of Witness
Date
*NIH ADMINISTRATIVE SECTION TO BE COMPLETED REGARDING THE USE OF AN 
INTERPRETER:
An interpreter, or other individual, who speaks English and the participant’s preferred language facilitated
the administration of informed consent and served as a witness. The investigator obtaining consent may not 
also serve as the witness.
An interpreter, or other individual, who speaks English and the participant’s preferred language facilitated
the administration of informed consent but did not serve as a witness. The name or ID code of the person 
providing interpretive support is:
.
IRB NUMBER: 93C0133
IRB APPROVAL DATE: 05/02/2021