Conditions: Lymphoma
Keywords: contiguous stage II grade 3 follicular lymphoma noncontiguous stage II grade 3 follicular lymphoma stage I grade 3 follicular lymphoma stage III grade 3 follicular lymphoma stage IV grade 3 follicular lymphoma AIDS-related diffuse large cell lymphoma contiguous stage II adult diffuse large cell lymphoma noncontiguous stage II adult diffuse large cell lymphoma stage I adult diffuse large cell lymphoma stage III adult diffuse large cell lymphoma stage IV adult diffuse large cell lymphoma AIDS-related immunoblastic large cell lymphoma contiguous stage II adult immunoblastic large cell lymphoma noncontiguous stage II adult immunoblastic large cell lymphoma stage I adult immunoblastic large cell lymphoma stage III adult immunoblastic large cell lymphoma stage IV adult immunoblastic large cell lymphoma AIDS-related peripheral/systemic lymphoma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 43
Healthy volunteers: no

Brief summary:
RATIONALE: Drugs used in chemotherapy work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as rituximab, can block cancer growth in different ways. Some find cancer cells and help kill them or carry cancer-killing substances to them. Others interfere with the ability of cancer cells to grow and spread. Giving combination chemotherapy together with rituximab may kill more cancer cells.

PURPOSE: This phase II trial is studying how well giving combination chemotherapy together with rituximab works in treating patients with newly diagnosed AIDS-related B-cell non-Hodgkin's lymphoma.

Detailed description:
OBJECTIVES:

Primary

* Determine the complete response rate (complete response and complete response unconfirmed) in patients with newly diagnosed, AIDS-related B-cell non-Hodgkin's lymphoma treated with doxorubicin hydrochloride liposome, rituximab, cyclophosphamide, vincristine, and prednisone (DR-COP).
* Determine the duration of response (relapse-free survival) in patients treated with this regimen.
* Determine the median survival time of patients treated with this regimen.
* Determine rate of bacterial, fungal, and opportunistic infections in patients treated with this regimen.

Secondary

* Determine, preliminarily, the relationship between MDR-1 expression in tumor tissue and response to therapy in patients treated with this regimen.
* Determine, preliminarily, any relationship between response and survival and BCL-2 expression in tumor tissue in patients treated with this regimen.
* Determine any relationship between development of bacterial, fungal, and/or opportunistic infections and baseline CD4 lymphocyte count, HIV-1 RNA level, and quantitative immunoglobulin levels, or changes in quantitative immunoglobulin levels over time in patients treated with this regimen.
* Compare the results of positron emission tomography (PET) scanning with traditional CT scans in predicting response to therapy in these patients.
* Examine the relationship between chemotherapeutic drug levels and receipt of specific antiretroviral and/or anti-infective medications in these patients.
* Examine the mortality and the causes of death in patients treated with this regimen.
* Determine event-free survival at 1 year.

OUTLINE: This is a nonrandomized, multicenter study.

Patients receive doxorubicin hydrochloride liposome IV over 90 minutes, rituximab IV over 5-7 hours, cyclophosphamide IV over 1 hour, and vincristine IV over 1-2 minutes on day 1 and oral prednisone on days 1-5. Patients also receive filgrastim (G-CSF), sargramostim (GM-CSF), or pegfilgrastim beginning on day 3 and continuing until blood counts recover. Treatment repeats every 21-28 days for up to 8 courses in the absence of disease progression or unacceptable toxicity.

Patients undergo laboratory/biomarker studies at baseline and after every 2 courses of chemotherapy. Tissue is examined by immunohistochemistry for BCL-2, Ki67, and MDR-1, along with other markers.

After completion of study treatment, patients are followed periodically for 3 years.

PROJECTED ACCRUAL: A total of 44 patients will be accrued for this study.

Arms:
arm 1: Single arm interventional study: all subjects receive DR-COP regimen.

Interventions: intervention 1: filgrastim intervention 2: pegfilgrastim intervention 3: rituximab intervention 4: sargramostim intervention 5: cyclophosphamide intervention 6: pegylated liposomal doxorubicin hydrochloride intervention 7: prednisone intervention 8: vincristine sulfate intervention 9: immunohistochemistry staining method intervention 10: laboratory biomarker analysis
Intervention descriptions: intervention 1: Supportive therapy: GF therapy with G-CSF, GM-CSF, or pegfilgrastim will be used in all patients, beginning on Day 3 of each cycle, until post nadir of blood counts from each chemotherapy cycle. intervention 2: GF therapy with G-CSF, GM-CSF, or pegfilgrastim will be used in all patients, beginning on Day 3 of each cycle, until post nadir of blood counts from each chemotherapy cycle. intervention 3: 375 mg/m2 IV Day 1 of each cycle intervention 4: GF therapy with G-CSF, GM-CSF, or pegfilgrastim will be used in all patients, beginning on Day 3 of each cycle, until post nadir of blood counts from each chemotherapy cycle. intervention 5: 750 mg/m2 IV Day 1 of each cycle intervention 6: 40 mg/m2 IV Day 1 of each cycle intervention 7: 100 mg PO Days 1-5 of each cycle intervention 8: 1.4 mg/m2 IV Day 1 (2.0 mg maximum) of each cycle intervention 9: tissue specimen collected at baseline intervention 10: tissue specimen collected at baseline

Protocol document:
Prot_SAP_001.pdf: 
 
 
 
AIDS MALIGNANCY 
CLINICAL TRIALS CONSORTIUM 
 
 
 
AMC PROTOCOL #047: 
A Phase II Trial of Doxil, Rituximab, Cyclophosphamide, 
Vincristine, and Prednisone (DR-COP) in Patients with Newly 
Diagnosed AIDS-associated B-Cell Non-Hodgkin’s Lymphoma 
 
A Multi-Center Trial of the AIDS Malignancy  
Clinical Trials Consortium (AMC)  
 
 
Sponsored by: 
National Cancer Institute 
Division of Cancer Treatment and Diagnosis 
 
 Pharmaceutical 
Support Provided by: 
 
Ortho Biotech Clinical Affairs, LLC 
 Protocol Chair: 
Alexandra M. Levine, M.D. 
 
 Protocol Co-chair: 
Anil Tulpule, M.D. 
 
 
Version 6.0 
January 21, 2011 
NCI Version Date: January 21, 2011 
 


AMC PROTOCOL SIGNATURE PAGE 
 
I,                           , Principal Investigator at site            , agree to conduct and follow this protocol: 
AMC Protocol #047 - A Phase II Trial of Doxil, Rituximab, Cyclophosphamide, Vincristine, 
and Prednisone (DR-COP) in Patients with Newly Diagnosed AIDS-Associated B-Cell Non-
Hodgkin’s Lymphoma (Version 6.0, 01/21/2011), as written according to AMC, NCI and FDA 
guidelines. I understand that no deviations from the above protocol may be made without written 
permission from the Protocol Chair(s). 
 
 
_________________________________ 
_____________________ 
 
Signature 
Date (mm/dd/yyyy) 
 
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TABLE OF CONTENTS 
AMC PROTOCOL SIGNATURE PAGE .........................................................................................ii 
PROTOCOL ROSTER ......................................................................................................................vi 
STUDY SCHEMA .............................................................................................................................vii 
1.0 
...................................................................................1 
BACKGROUND AND RATIONALE
1.1 
.......................................................1 
Role of Highly Active Anti-Retroviral Therapy (HAART) in Acquired Immune 
Deficiency Syndrome (AIDS)-Related Lymphoma
1.2 
...............................................................1 
Response to Therapy and MDR-1 Expression
1.3 
......................................................................................................................1 
Addition of Rituximab to Combination Chemotherapy in Patients with AIDS-Related 
Lymphoma
1.4 
...................................................................................2 
Occurrence of Infectious Death Among HIV-Infected Patients Treated with 
Rituximab-Containing Regimens
1.5 
.........................................................................................................2 
Dose-Adjusted Etoposide, Vincristine Doxorubicin, Prednisone, Cyclophosphamide 
(EPOCH) Regimen
1.6 
........................................................................................................3 
Use of Liposomal Preparations of Anthracycline with Standard Agents in AIDS-
Related Lymphoma
1.7 
.............................................................................5 
Rationale for Exploratory Use of Positron Emission Tomography (PET) Scans as Part 
of Staging and Response Evaluations
1.8 
......................6 
Rationale for Study of BCL-2 Expression in AIDS-Related Lymphoma
1.9 
............................................................................................6 
Rationale for Current Study
2.0 
..........................................................................................................................8 
OBJECTIVES
2.1 
..........................................................................................................8 
Primary Endpoints
2.2 
......................................................................................................8 
Secondary Endpoints
3.0 
.....................................................................................................................9 
STUDY DESIGN
3.1 
.......................................................................................................9 
Treatment Summary
3.2 
........................................................................................................9 
Treatment Regimen
3.3 
..............................................................................................................10 
Study Duration
4.0 
........................................................................................................11 
STUDY POPULATION
4.1 
..........................................................................................................11 
Inclusion Criteria
4.2 
.........................................................................................................12 
Exclusion Criteria
4.3 
...............................................................................13 
Number of Patients to be Enrolled
4.4 
.......................................................................................13 
Patient Enrollment Procedure
5.0 
.......................................................................................................15 
STUDY PROCEDURES
5.1 
...................................................................................15 
Screening/Baseline Evaluations
5.2 
..........................................................................16 
Evaluations During Treatment Period
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5.3 
................................................................................................17 
Evaluation of Response
5.4 
...........................................................18 
Follow-Up Evaluations (Month 3 and Beyond)
5.5 
..........................................................19 
Disease Progression Evaluations/Off-Treatment
6.0 
...........................................................................20 
PHARMACEUTICAL INFORMATION
6.1 
.............................................................................................................................20 
Doxil
6.2 
.....................................................................................................................22 
Rituximab
6.3 
.............................................................23 
Cyclophosphamide (Cytoxan ) (NSC-26271)
®
6.4 
....................................................................................................................25 
Prednisone
6.5 
....................................................................................................................26 
Vincristine
7.0 
...........................................................................................................28 
DRUG TREATMENT
7.1 
.....................................................................................................28 
Drug Administration
7.2 
.......................................................................................................................28 
Schedule
7.3 
..........................................................................28 
Prevention of Tumor Lysis Syndrome
7.4 
..........................................................................................................29 
CNS Prophylaxis
7.5 
......................................................................................................29 
Supportive Therapy
7.6 
.....................................................................................................30 
Duration of Therapy
7.7 
...........................................................................30 
Criteria for Removal from Treatment
8.0 
....................................................................................................31 
DOSE MODIFICATIONS
8.1 
.......................................31 
Decision to Re-Treat at Day 21 Versus Day 28 of the Cycle
8.2 
...................................................................................................31 
Hematologic Toxicity
8.3 
...........................................................................................32 
Non-Hematologic Toxicity
9.0 
.................................................35 
CRITERIA FOR TREATMENT DISCONTINUATION
9.1 
.................................................................................................35 
Permanent Withdrawal
10.0 
.............................36 
ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS
10.1 
......................................................................................36 
Adverse Event Characteristics
10.2 
...............................................................................................37 
Expedited AE Reporting
10.3 
.........................................................................39 
Expedited Reporting to Ortho Biotech
10.4 
................................................................................39 
Routine Adverse Event Reporting
10.5 
..................................................................................................39 
Secondary AML/MDS
11.0 
.........................................................................................40 
EVALUATION OF RESPONSE
11.1 
...................................................................................................40 
Response Assessment
11.2 
.................................................................................................40 
Definition of Response
12.0 
.................................................................................43 
STATISTICAL CONSIDERATIONS
12.1 
................................................................................................................43 
Study Design
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12.2 
..........................................................................................................43 
Statistical Design
12.3 
...............................................................................................43 
Statistical Analysis Plan
13.0 
.........................................44 
PATIENT CONSENT AND ETHICAL CONSIDERATIONS
13.1 
...........................................................................................44 
Institutional Review Board
13.2 
.........................................................................................................44 
Informed Consent
13.3 
.................................................................................................44 
Women and Minorities
14.0 
......................................................................................................................45 
REFERENCES
 
APPENDIX I:  
Schedule Of Assessments ...................................................................................48 
APPENDIX II:  
Performance Status Scale....................................................................................50 
APPENDIX III:  
Common Terminology Criteria For Adverse Events (CTCAE) .........................51 
APPENDIX IV:  
Model Informed Consent ....................................................................................52 
APPENDIX V:  
AIDS and Cancer Specimen Resource (ACSR)..................................................65 
APPENDIX VI:  
Informed Consent Form Research Study AIDS and Cancer Specimen Resource 
(ACSR)................................................................................................................68 
APPENDIX VII:  Handling of Tissue..............................................................................................70 
APPENDIX VIII:  AMC Data Safety Monitoring Plan.....................................................................72 
APPENDIX IX:  
Drug Distribution Guidelines..............................................................................75 
 
 
 
 
  


 
 
PROTOCOL ROSTER 
AMC-047 
A Phase II Trial of Doxil, Rituximab, Cyclophosphamide, Vincristine, and Prednisone (DR-
COP) in Patients with Newly Diagnosed AIDS-Associated B-Cell Non-Hodgkin’s Lymphoma 
 
 
Protocol Chair: 
Statistician: 
Alexandra M. Levine, M.D. 
Jeannette Y. Lee, Ph.D. 
City of Hope National Medical Center 
University of Arkansas for Medical Sciences 
1500 East Duarte Road 
4301 W. Markham, #781 
Needleman 213 
Little Rock, Arkansas 72205-7199 
Duarte, California 91010 
Tel: (501) 526-6712 
Phone: 626-471-7213 
Fax: (501) 526-6729 
Fax: 626-471-7200 
E-mail: jylee@uams.edu 
Email: alevine@coh.org 
 
 
 
Protocol Co-Chair: 
Data Operations/ Management: 
Anil Tulpule, M.D. 
AMC Operations Center 
USC School of Medicine 
The EMMES Corporation 
Norris Cancer Hospital 
401 N. Washington St., Suite 700 
1443 East Lake Ave., MS-34, Rm 3461 
Rockville, MD  20850 
Los Angeles, CA  90089 
Phone: 301-251-1161 
Phone: 323-865-3927 
Fax: 240-238-2842 
Fax: 323-865-0060 
Email: amcpm@emmes.com 
Email: Tulpule_a@ccnt.hsc.usc.edu 
 
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AMC #047 (Version 6.0) 01/21/2011 
 
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STUDY SCHEMA 
 
A Phase II Trial of Doxil, Rituximab, Cyclophosphamide, Vincristine, and Prednisone (DR-
COP) in Patients with Newly-Diagnosed AIDS-Associated B-cell Non-Hodgkin’s Lymphoma 
(NHL) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cycle 1 Until Study Completion 
 
Doxil 40 mg/m2 IV Day 1 
*Rituximab 375 mg/m2 IV Day 1 
Cyclophosphamide 750 mg/m2 IV Day 1 
Vincristine 1.4 mg/m2 IV Day 1 (2.0 mg maximum) 
Prednisone 100 mg PO Days 1-5 
 
*If use of rituximab on Day 1 of Cycle 1 is felt to be a potential problem in terms of patient safety (i.e., high tumor burden or presence of circulating lymphoma 
cells in the peripheral blood), the treating physician is asked to call the Pricipal Investigator  to discuss possible omission of rituximab in Cycle 1. 
 
** Repeat Chemotherapy cycles every 21-28 days (see section 8.1 of the protocol) 
REGISTRATION 
Chemotherapy Cycles 1-2 
Staging 
Discontinue protocol therapy. 
Follow-up for 2 years. 
Complete Response (CR) 
Chemotherapy Cycles 5-6 
Chemotherapy Cycles 7-8 
Discontinue protocol therapy. 
Follow-up for 2 years. 
Discontinue protocol therapy. 
Follow-up for 2 years. 
Progressive Disease (PD) or 
Stable disease 
Partial Response (PR) 
Discontinue protocol therapy. 
Follow-up for 2 years. 
Chemotherapy Cycles 5-6 
Staging 
CR
PR 
Chemotherapy Cycles 3-4 


 
1.0 
BACKGROUND AND RATIONALE 
 
1.1 
Role of Highly Active Anti-Retroviral Therapy (HAART) in Acquired Immune 
Deficiency Syndrome (AIDS)-Related Lymphoma 
The use of HAART has been associated with a marked improvement in overall survival for 
patients with AIDS-related lymphoma, such that median survival times now approach those 
achieved in HIV-negative patients with de novo aggressive lymphoma.1-6 Nonetheless, while 
HAART has clearly been associated with prolonged survival, it is currently unclear if 
HAART must be given concomitantly with chemotherapy or immediately thereafter.2,7 
 
1.2 
Response to Therapy and MDR-1 Expression 
It has been hypothesized that suboptimal responses to chemotherapy observed in some 
patients with AIDS-related lymphoma may be due to tumor cell resistance, mediated by the 
protein product of multi-drug resistance 1 (MDR-1), p-glycoprotein (P-gp). MDR-1 gene 
expression has been correlated with clinical resistance to chemotherapy, mediated through 
overexpression of P-gp, a 170-kd plasma glycoprotein, which acts as a unidirectional, drug 
efflux pump, resulting in decreased intracellular drug accumulation.8-10 In lymphoma that is 
unrelated to human immunodeficiency virus (HIV), the majority of studies have 
demonstrated MDR-1 expression in less than 20% of patients at the time of initial diagnosis, 
with an increase to more than 50% at the time of relapse.11,12 By contrast, in a population of 
50 patients with newly-diagnosed AIDS-related lymphoma, Tulpule et al. demonstrated that 
tissues from 33 patients (66%) expressed MDR-1 at lymphoma diagnosis.13 Of importance, 
this group had a significantly lower complete remission (CR) rate when compared with 
MDR-1 negative patients. Thus, an abnormally high rate of MDR-1 expression in patients 
with AIDS-related lymphoma may serve as another explanation for the low response rates 
observed in these individuals. Of interest, protease inhibitors may serve as both substrates 
and inducers of MDR-1, thus providing a potential explanation for the divergence of MDR-1 
expression profiles in patients with HIV-related or de novo aggressive lymphoma.14,15 
 
1.3 
Addition of Rituximab to Combination Chemotherapy in Patients with AIDS-Related 
Lymphoma 
Coiffier and colleagues demonstrated a significant advantage to the addition of rituximab to 
the cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) regimen in elderly 
patients (> 60 years) with newly-diagnosed diffuse large B-cell lymphoma (DLBCL), with a 
20% improvement in CR rate, as well as median overall survival times.16,17 The 
improvements in overall survival seen with R-CHOP (rituximab-CHOP) have been verified 
with longer follow-up as well. These results have been confirmed by other groups, in both 
younger and older patients, and in population-based studies. In patients with AIDS-related 
lymphoma, the use of rituximab with chemotherapy has also resulted in improved outcomes 
in terms of higher CR rates, and decreased likelihood of death due to lymphoma.18,19 Thus, in 
a trial of CHOP versus R-CHOP conducted in approximately 200 subjects by the AIDS 
Malignancy Clinical Trials Consortium (AMC), while no statistically significant differences 
in CR rates were apparent between the two treatment groups, better tumor control was 
evident in the rituximab treated group in terms of CR rates, progression-free survival, and 
rate of death due to lymphoma. The failure of this AMC trial to document a statistically 
significant advantage in the rituximab-treated patients may be related to the fact that the 
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AMC trial was not adequately powered to detect differences at the 20% level, as were 
demonstrated by Coiffier and colleagues in their study of approximately 400 subjects, which 
clearly demonstrated a statistically significant advantage for rituximab-treated patients in 
terms of tumor control.17,19 The infusional cyclophosphamide/doxorubicin/etoposide (CDE) 
regimen with HAART has been studied in several sequential trials conducted in patients with 
newly-diagnosed AIDS-related lymphoma.20 The addition of rituximab to CDE resulted in 
marked improvements in both CR rate and overall survival, when compared with patients 
treated with CDE and HAART alone.18 These data would, again, indicate an advantage to the 
use of rituximab along with chemotherapy in patients with AIDS-related lymphoma. 
 
1.4 
Occurrence of Infectious Death Among HIV-Infected Patients Treated with Rituximab-
Containing Regimens 
In the AMC trial of CHOP versus R-CHOP in patients with newly-diagnosed AIDS-related 
lymphoma, a statistically increased rate of infectious death was documented in patients 
treated in the R-CHOP arm.19 Nonetheless, the rates of Grade 4 neutropenia (<500/mm3), or 
febrile neutropenia were not statistically different in the two treatment groups, although the 
R-CHOP-treated patients tended to have more neutropenia. While full data were not available 
on the entire patient cohort, quantitative immunoglobulin levels also appeared similar in the 
two treatment arms. Of interest, the infectious deaths in the AMC trial occurred primarily 
among patients with CD4 cells <50/mm3, which is a known risk factor for infectious death in 
HIV-infected patients without underlying lymphoma.21 Thus, if patients with CD4 <50/mm3 
were removed from the analysis, no difference in the rate of infectious death was apparent in 
the CHOP versus R-CHOP treated patients.19 The risk of infectious death after receipt of 
rituximab-containing chemotherapy thus remains somewhat controversial in patients with 
AIDS-related lymphoma, and additional data is clearly indicated to help to explain the 
findings to date. This would include a careful assessment of CD4 cell count, absolute 
neutrophil count (ANC), and quantitative immunoglobulin levels at baseline and throughout 
therapy, with an assessment of any relationship between these variables and the development 
of intercurrent infection. Additionally, based upon the AMC data, it would seem prudent to 
employ prophylactic antibiotics as well as hematopoietic growth factors (G-CSF or GM-
CSF) in patients with AIDS-related lymphoma undergoing chemotherapy who have severe 
underlying immune deficiency. 
 
1.5 
Dose-Adjusted Etoposide, Vincristine Doxorubicin, Prednisone, Cyclophosphamide 
(EPOCH) Regimen 
The dose-adjusted EPOCH regimen (da-EPOCH) was initially tested in a single center, Phase 
II study at the National Cancer Institute (NCI), in which 39 patients were accrued.7 In this 
study, HAART therapy was withheld until completion of the 6 months of chemotherapy. A 
CR rate of 74% was achieved. At a median follow-up of 53 months, disease-free survival was 
92%, while overall survival was 60%. In patients with CD4 cell counts >100/mm3 at 
diagnosis, CR was achieved in 87%, while 53-month overall survival was 87%. In contrast, 
56% of patients with CD4 cells <100/mm3 at diagnosis achieved CR, and 53-month survival 
was only 16%. During the course of chemotherapy, the median CD4 cells fell by 187 
cells/mm3 (range +19--973 cells/mm3), while HIV-1 viral load increased a median of 0.83 
log10 (range -0.28-+4.12). While no patient experienced an opportunistic infection (OI) during 
EPOCH therapy, three patients developed OI at 5, 8 and 13 weeks after completion of 
chemotherapy.7 
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The EPOCH regimen was further tested in a multi-institutional clinical trial as part of the 
NCI-sponsored AMC. While full results are pending at this time, the preliminary results have 
recently been analyzed.  In this trial (AMC #034), the AMC trial added rituximab to EPOCH, 
given either concomitantly (R-EPOCH) or sequentially (EPOCH followed by rituximab). 
Early data are as follows 22:   
 
 
Rituximab +EPOCH 
EPOCH followed by Rituximab 
Number 
40 
40 
Median CD4 cell count 
198/uL 
188/Ul 
Age adjusted IPI, score 2 to 3 
54% 
60% 
Stage III/IV 
85% 
73% 
CR/CR u 
24 (60%) 
15 (37%) 
95% confidence intervals 
(43%, 75%) 
(23%,54%) 
 
While the outer limit of the confidence intervals for R-EPOCH include a CR rate of 75%, 
still, our multi-institutional data do not yet confirm the expected CR rate of 74% as originally 
described by Little et al from the NCI 7.   
 
Additionally, the AMC data on R-CHOP versus CHOP (AMC protocol #010) did not 
confirm the potential of achieving a CR rate as high as 75%.  Thus, with 99 patients 
randomized to R-CHOP and 50 to CHOP alone, the CR+ CRu rate for R-CHOP was 57.6%, 
while that for CHOP was 47% 19 
 
While Levine et al demonstrated a 75% CR +CRu rate in 24 patients treated with liposomal 
anthracycline (Myocet) plus COP 25, again, these data come from a small, single institutional 
trial (see Section 1.6, below), and have not been confirmed in a multi-center setting. 
 
With these facts in mind, we believe it is appropriate to target a complete remission rate of 
60% or more, as indicative of success for this currently proposed DR-COP regimen. We will 
also evaluate event-free survival at one year, looking for an increase in median EFS from 12 
months to 18 months as a marker of success. Of interest, the current AMC #034 study (see 
table above) do indicate a potential superiority of concomitant rituximab as opposed to the 
sequential use of this agent along with EPOCH.22 
 
1.6 
Use of Liposomal Preparations of Anthracycline with Standard Agents in AIDS-Related 
Lymphoma 
Doxorubicin hydrochloride (doxorubicin) (Myocet™, Caelyx®, Doxil®) is one of the most 
active agents in the therapy of patients with aggressive lymphoma.16 However, doxorubicin is 
a substrate for P-gp, the protein product of MDR-1.12,14 In vitro studies have demonstrated 
that liposomal encapsulation of doxorubicin (e.g., Doxil) can overcome excessive drug efflux 
due to MDR-1 over-expression.23,24 Doxil is doxorubicin encapsulated in long-circulating 
STEALTH® liposomes. Liposomes are microscopic vesicles composed of a phospholipid 
bilayer that are capable of encapsulating active drugs. The STEALTH liposomes of Doxil are 
formulated with surface-bound methoxypolyethylene glycol (MPEG), a process often 
referred to as pegylation, to protect liposomes from detection by the mononuclear phagocyte 
system (MPS) and to increase blood circulation time.  
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A Phase I/II trial of liposomal doxorubicin in combination with standard agents vincristine, 
cyclophosphamide, and prednisone (COP) was recently reported by Levine and colleagues in 
a group of 24 patients with newly-diagnosed AIDS-related lymphoma.25 Median CD4 count 
at study entry was 112/mm3, and median HIV-1 ribonucelic acid (RNA) level in plasma was 
93,650 copies/cc in the 20 patients with detectable virus. A CR rate of 75% was achieved, 
with PR in 13% (overall response [OR] rate of 88%). The median duration of CR is in excess 
of 15.6 months (range 1.7-43.5+ months). At last follow-up, median survival had not been 
reached for the group as a whole, and overall survival was 58% at 1 year from start of 
chemotherapy. Effective HIV viral control during chemotherapy was associated with 
significantly improved survival, but CR rates were attained independent of HIV viral control. 
Of interest, the regimen was equally effective in both MDR-1 positive and negative cases, 
suggesting that the efficacy of the regimen was related to the ability of liposome encapsulated 
doxorubicin to overcome excessive drug efflux due to MDR-1 over-expression.25 
Additional use of liposomal doxorubicin 
 
In a separate study by Zaja, et al.26, thirty untreated patients, median age 69 years (range 60 - 
75 years), with diffuse large B-cell lymphoma (B-DLCL) were treated with a pegylated 
liposomal doxorubicin (PL-doxorubicin) modified CHOP-rituximab regimen. PL-
doxorubicin 30 mg/m2, was given in combination with standard dosage of prednisone, 
vincristine, cyclophosphamide, rituximab (according to CHOP-R regimen) every 21 days for 
six courses. Cardiac toxicity was evaluated by mean of echocardiography for left ventricular 
ejection fraction (LVEF) evaluations and serum troponin-I levels. Overall response and 
complete response rates were 76% and 59%. Projected two year event free survival and 
overall survival are 65.5% and 68.5%. No treatment-related mortality was documented. 
WHO grade III-IV neutropenia and thrombocytopenia were 86% and 3%. Extra-
hematological III-IV toxicity was represented, respectively, by a single case of infection, 
mucositis, and bleeding. LVEF evaluations and the troponin levels did not show significant 
changes over the course of the treatment. One patient with a previous history of atrial 
fibrillation experienced a single episode of arrhythmia. None of the patients developed 
palmar-plantar erythrodysesthesia. This regimen appears an active regimen for the treatment 
of elderly patients with B-DLCL. The replacement of conventional doxorubicin with PL-
doxorubicin seems to be associated with a negligible incidence of extra-hematological 
toxicity, in particular cardiac and infectious complications. 26 
 
In another trial by Visani et al.27, subjects received a regimen consisting of Day 1: 
cyclophosphamide 750 mg/m2, PL-doxorubicin, 40 mg/m2, vincristine 1.4 mg/m2, prednisone 
100 mg p.o. (Days 1 – 5); rituximab 375 mg/m2 on Day 15 of every cycle; granulocyte 
colonystimulating factor (G-CSF) from Day 10 to Day 14. Therapy was repeated every 21 
days for six cycles. Complete and partial remission were assessed as the overall response. 
Toxicity was evaluated according to the WHO criteria. Thirteen patients were treated; 12 
(92%) completed the six courses and were assessable for response. A dose reduction (25%) 
was carried out in two cases (1 frail, 1 relapsed-refractory), due to their extremely altered 
clinical condition. Seven patients (53%) obtained complete remission, five (31%) partial 
remission, for an overall response rate of 84%. No major toxicity (WHO grade III/IV) 
occurred. Only one patient delayed therapy for grade II hematological toxicity. After a 
median follow-up of 18 months (range 8 – 22 months), seven patients are in continuous 
complete remission (53%), three (23%) in partial remission, one in stable disease, whereas 
only two patients progressed.27 
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PL-Doxorubicin has also been associated with a lower risk of cardiotoxocity than 
conventional formulations of doxorubicin, allowing the use of higher cumulative doses.28 In a 
recent Phase II study by Tsavaris, 25 patients aged over 70 years (median 79, range 75-82 
years) with aggressive NHL (International Prognostic Index (IPI) -2, 12 (48%); IPI-3, 10 
(40%); IPI-4, 3 (12%)) received CHOP with PL-doxorubicin. A complete response was 
achieved in 13 (52%) patients and a partial response in 12 (48%) patients, which was 
maintained for at least 12 months. The median time to progression was 26 months (range 14-
>42) and median overall survival was 32 months (range 26-48). No Grades III/IV toxicity 
occurred; adverse events included neutropenia, anaemia, nausea and vomiting, diarrhoea and 
constipation in 16-29% of the cycles. Pegylated liposomal doxorubicin showed as an 
effective and well-tolerated component that may be substituted for doxorubicin in the 
CHOPC (cyclophosphanide, doxorubicin, vincristine, prednizolone) regimen for the 
treatment of aggressive NHL in elderly people.28 
 
A separate prospective, Phase II study for patients with DLBCL analyzed the feasibility of a 
regimen (CCOP) that includes pegylated liposomal doxorubicin (Caelyx) plus vincristine, 
cyclophosphamide and prednisone in patients with DLBCL above the age of 60 years. Thirty-
three patients, with a median age of 74 years, were enrolled in the study. The overall 
response rate was 64% (49% complete remissions and 15% partial remissions). The 
estimated one-year overall and event-free survivals were 55% (95% CI, 38-72) and 45% 
(95%CI, 28-62), respectively. The only relevant toxicity was neutropenia, which reached 
Grades 3/4 in 21 cases (64%). These results suggest that CCOP appears to be an acceptable 
alternative for elderly patients with DLBCL, and randomized trials against a conventional 
doxorubicin-containing regimen are justified.29 
 
1.7 
Rationale for Exploratory Use of Positron Emission Tomography (PET) Scans as Part 
of Staging and Response Evaluations 
Over the years, there have been problems with the criteria that are currently in use for 
evaluating the response to lymphoma therapy.30,31 A designation of “complete remission 
unconfirmed” (CRu) has been suggested and employed in recent years. The designation of 
“CR” has been given when the following conditions were met at the conclusion of therapy: 
(a) 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); (b) 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 diameter after treatment, or by >75% in the 
sum of the products of the greatest diameters (SPD); and (c) the spleen, if enlarged before 
therapy on the basis of a Computed Axial Tomography (CT) scan, must have decreased in 
size, and must not be palpable upon physical examination. In addition to these criteria, the 
designation of “Cru” has been made in the following circumstances: (a) a residual lymph 
node mass >1.5 cm in greatest transverse diameter present at the time of response evaluation, 
that has regressed by more than 75% in the SPD (individual nodes that were previously 
confluent must have regressed by >75% in their SPD compared with the size of the original 
mass); and (b) indeterminate bone marrow results at the time of re-biopsy, as indicated by 
increased number or size of lymphoid aggregates without cytologic or architectural atypia. 
Despite this definition, the designation of “Cru” has been unclear, with inconsistent 
definitions in various studies. Furthermore, “Cru” has not included definitions for response in 
extranodal sites, with the exception of the bone marrow. “Cru” has been used to describe 
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responses in the treatment of Hodgkin’s disease, although it was really designed and tested 
for use in evaluating responses in DLBCL or aggressive lymphomas. Additionally, “Cru” 
depends upon technical mechanisms of staging that are outdated at the present time. For 
example, the CT scan, initially, was not considered a part of routine restaging, while single 
photon emission computed tomography (SPECT) gallium scan was. There are no data 
available on flow cytometry in bone marrow analysis that can more accurately identify 
isolated areas of marrow involvement.  
 
For all of the reasons discussed above, a specific study group, International Harmonization 
project (IHP) of the Competence Network of Malignant Lymphoma, led by Bruce Cheson 
from the United States, was recently developed to assess the current criteria for staging and 
response criteria in patients with NHL.30 This group has concluded that positron emission 
tomography (PET) scanning should be used to define response in DLBCL and NHL, and in 
all types of lymphomas, for studies in which response rate is the endpoint. If a patient was 
PET-positive for disease at baseline, and subsequently had negative findings on the CT scan 
at the end of therapy, or had a negative PET scan at the time of reevaluation, the patient was 
considered to be in CR. If, on the other hand, the patient was PET-negative at diagnosis or 
PET scanning was not done at time of diagnosis, and if the CT scan improved by 75%, but 
there is still residual disease, patients were regarded as having achieved a PR. Therefore, the 
category of “Cru” would cease to exist. There are multiple issues that need to be addressed in 
these new criteria, including the issue of when a restaging PET scan is to be performed. 
Furthermore, there are no data on the validity of PET restaging in patients with AIDS-related 
lymphoma. Since this area is currently one in which significant change is expected over the 
next few years, we will employ PET scanning as part of the current study, if feasible in terms 
of patient insurance coverage. Results of PET scanning will be used in an exploratory fashion 
to determine the validity and role of this procedure in assessing response of patients with 
AIDS-related aggressive lymphoma. 
 
1.8 
Rationale for Study of BCL-2 Expression in AIDS-Related Lymphoma 
Mornier and colleagues have demonstrated that presence of BCL-2 expression in lymphoma 
tissue of de novo lymphoma, unassociated with HIV, was correlated with decreased 
likelihood of receiving benefit from the addition of rituximab along with the CHOP 
regimen.17,32-33 The precise prevalence of BCL-2 expression in AIDS-related lymphomas is 
not well studied, although Little et al. from NCI reported approximately 13% BCL-2 
positivity in their study of 39 patients treated with EPOCH.7 It will be of interest to determine 
the prevalence of BCL-2 expression in larger numbers of patients with AIDS-related 
lymphoma to determine the role of this molecular marker, if any, in predicting outcome to 
therapy employing chemotherapy, with or without the addition of rituximab. 
 
1.9 
Rationale for Current Study 
In this study, we wish to employ a regimen of HAART,34 along with pegylated anthracycline 
(Doxil), Rituximab, and standard agents cyclophosphamide, vincristine, prednisone (DR-
COP), using a Phase II design, in order to determine the potential efficacy and toxicity of the 
approach in a multi-institutional setting. In this regard, initial Phase II results of the EPOCH 
regimen, and of a liposomal anthracycline regimen with standard agents, have suggested 
similar outcomes, with CR rates of 74 and 75%, respectively.7,25 Nonetheless, while results of 
EPOCH when used in a multi-institutional setting are only preliminary at this time (see 
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Section 1.5 above), initial AMC data indicate that the CR rate of 75% will not be achieved 
with the back-bone EPOCH regimen.22 Furthermore, such confirmation has not yet been 
accomplished for use of conventional regimens in which doxorubicin has been replaced with 
a liposomal or pegylated anthracycline (Doxil). Nonetheless, early results do suggest possible 
equivalency with these two approaches. If Phase II results are found to be similar to those 
reported by AMC for R-EPOCH treated patients, AMC plans to move forward with a Phase 
III, randomized trial of DR-COP versus R-EPOCH in patients with newly-diagnosed AIDS-
related lymphoma. Alternatively, if results from DR-COP are clearly inferior to those 
reported for EPOCH, the AMC will proceed forward with EPOCH as our platform for future 
study. 
 
The importance of the question being addressed relates to practical aspects of therapy. While 
results from the EPOCH and R-EPOCH trials have been encouraging, the regimen is difficult 
to employ, requiring a 4-day continuous infusion, administered primarily in the hospital, 
monthly, and for as long as 6 months. If similar results could be achieved with a less complex 
regimen that did not require the continuous infusion of chemotherapeutic agents, the resulting 
regimen would clearly be more cost-effective, and easier, in a practical sense, for patients, 
healthcare providers, and the healthcare system in general. The current protocol seeks to 
obtain information on the results of DR-COP in patients with newly-diagnosed, CD20+, 
aggressive lymphoma. If results are acceptable (CR rate > 60%), the regimen will be carried 
forward in formal Phase III testing against R-EPOCH. 


 
2.0 
OBJECTIVES 
2.1 
Primary Endpoints 
2.1.1 
To determine the complete response rate (CR + Cru) to DR-COP in patients with 
newly-diagnosed AIDS-related lymphoma. 
 
2.1.2 
To determine the duration of response (DR) (relapse-free survival) of patients treated 
with DR-COP. 
 
2.1.3 
To determine the median survival time of patients treated with DR-COP. 
 
2.1.4 
To determine rate of bacterial, fungal and opportunistic infections in patients treated 
with DR-COP. 
 
2.2 
Secondary Endpoints 
2.2.1 
To determine, preliminarily, the relationship between MDR-1 expression in tumor 
tissue and response to therapy. 
 
2.2.2 
To determine, preliminarily, any relationship between response and survival, and 
BCL-2 expression in tumor tissue. 
 
2.2.3 
To determine any relationship between development of bacterial, fungal and/or 
opportunistic infections and baseline CD4 lymphocyte count, HIV-1 RNA level, and 
quantitative immunoglobulin levels, or with changes in quantitative immunoglobulin 
levels over time. 
 
2.2.4 
To examine, in exploratory fashion, the results of PET scanning when compared with 
traditional CT scans in predicting response to therapy in patients with AIDS-related 
lymphoma. 
 
2.2.5 
To examine the cause(s) of subject death. 
 
2.2.6 
To examine event-free survival (EFS) at one year. 
 
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3.0 
STUDY DESIGN 
3.1 
Treatment Summary 
This is a standard Phase II trial in which patients with newly-diagnosed AIDS-related 
lymphoma will receive DR-COP, given every 21 to 28 days. Data on tumor response will be 
collected, as well as serial data on CD4 cell counts, HIV-1 RNA levels, and quantitative 
immunoglobulin levels in an attempt to decipher those factors that may be operative in terms 
of prediction of intercurrent infection and/or death from infection. 
 
Patients will be evaluated by physical examination, complete blood count (CBC), routine 
serum chemistries, lactate dehydrogenase (LDH), HIV viral RNA, T cell subsets, and 
immunoglobulin levels at Baseline, and after every two cycles of chemotherapy. CT scans 
will be performed at study entry, after Cycle 2, 4, and 6, and 1 month after completion of all 
therapy. Additionally, PET/CT, PET or gallium scans will be performed at the same time 
intervals, if feasible in terms of patient insurance coverage. Patients will be followed for 
immunologic and virologic parameters every 2 months during year 1 post chemotherapy, and 
every 6 months during years 2 and 3 post chemotherapy. Additionally, patients will be 
followed for survival and DR for 3 years posttherapy. 
 
All patients will be on HAART (the specific agents are at the discretion of the treating 
investigator, but should be in accordance with the current International AIDS-Society 
guidelines). (See Section 7.5.6) 
 
All eligible patients receiving at least one cycle of DR-COP chemotherapy will be evaluable 
for toxicity and response. 
 
3.2 
Treatment Regimen 
DR-COP: 
 Doxil 40 mg/m2 intravenously (IV), Day 1. 
 Rituximab 375 mg/m2, slow IV infusion, Day 1, beginning with Cycle 1. 
 Cyclophosphamide 750 mg/m2 IV, Day 1.  
 Vincristine 1.4 mg/m2 IV (total dose not to exceed 2 mg), Day 1. 
 Prednisone 100 mg orally (PO), Days 1-5 of each cycle. 
 
BSA is to be recalculated at the start of each cycle. Doses of Doxil, rituximab, 
cyclophosphamide, and vincristine will be based upon the subject’s BSA. With any 
change of weight within 10% of baseline, drug dosing will be maintained at the baseline 
level. Doses of chemotherapy are to be adjusted only if a subject’s weight has changed 
more than 10% from baseline or prior dose. 
 
Repeat DR-COP cycles every 21 to 28 days. One cycle is 21 to 28 days, depending upon 
recovery from any hematologic or non-hematologic toxicity, as specified in Section 8.1. 
 
Central Nervous System (CNS) Prophylaxis: 
Mandated per protocol in patients who meet the following criteria: lymphomatous 
involvement of bone marrow, testis, sinuses, or epidural regions; stage IV disease; 
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and/or two or more extra-nodal sites of disease. One of the following regimens will be 
required: intrathecal (IT) depocyte, IT cytarabine, or IT methotrexate. The specific 
regimen will be at the discretion of the primary oncologist. 
 
Supportive Therapy: 
Growth Factor (GF) therapy with G-CSF, GM-CSF, or pegfilgrastim will be used in all 
patients until post nadir of blood counts from each chemotherapy cycle, beginning on 
Day 3 of each cycle. 
 
Use of erythropoietic factors is left up to the discretion of the Investigator. 
 
Prophylaxis against Pneumocystis carinii is required, with the specific regimen at the 
discretion of the treating physician. 
 
Prophylaxis against other common OI is encouraged, dependent upon the patient’s CD4 
cell count at study entry, and at the discretion of the treating physician. 
 
Use of prophylactic oral quinalones is required for patients with CD4 cell counts  
≤ 100/mm3 at study entry, for those whose CD4 counts fall to ≤ 100/mm3 during 
therapy, or for those patients who have experienced a fall in ANC to <500/mm3 during 
treatment. In patients with CD4 counts >100/mm3, use of prophylactic antibiotics is 
strongly encouraged at the discretion of the treating physician. Patients with active HBV 
(surface antigen positive) are strongly encouraged to receive anti-HBV therapy. 
 
HAART Therapy: 
All patients will be on HAART (the specific agents are at the discretion of the treating 
investigator, but should be in accordance with the current International AIDS-Society 
guidelines). Antiretroviral therapy that is currently available on an expanded access 
basis will be allowed during the treatment regimen, but use of experimental 
antiretroviral agents will not be allowed. Zidovudine and zidovudine-containing 
regimens (including Combivir® and Trizivir®) will be prohibited, due to known marrow 
suppressive effects of zidovudine. 
 
3.3 
Study Duration 
The total duration of this trial includes 18 months for patient accrual, and 3 years for full 
therapy and follow-up. 
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4.0 
STUDY POPULATION 
 
4.1 
Inclusion Criteria 
4.1.1 
Previously untreated, histologically or cytologically documented B-cell NHL. The 
following histologies are eligible: follicular large-cell (Grade 3), DLBCL, 
immunoblastic lymphoma, plasmablastic lymphoma, primary effusion lymphoma. 
 
4.1.2 
Lymphoma must be CD20+. Please note: If only a subset of tumor cells are CD20+, 
the subject will still be eligible for study entry. 
 
4.1.3 
Documented HIV infection. Documentation may be serologic (enzyme-linked 
immunosorbent assay [ELISA], western blot), culture, or quantitative polymerase 
chain reaction (Q-PCR) or Branched deoxyribonucleic acid (bDNA) assays. Prior 
documentation of HIV seropositivity is acceptable. 
 
4.1.4 
All stages of disease. 
 
4.1.5 
Measurable or non-measurable tumor parameter(s). Non-measurable tumor 
parameters are defined as not having bidimensional measurements (e.g., gastric or 
marrow involvement), but can be followed for response by other diagnostic tests such 
as gallium, PET imaging and/or bone marrow biopsy. 
 
4.1.6 
Age ≥ 18 years. 
 
4.1.7 
Karnofsky Performance Status (KPS) ≥ 50% (Eastern Cooperative Oncology Group 
[ECOG] Performance Score 0, 1, or 2). 
 
4.1.8 
Able to give signed informed consent. 
 
4.1.9 
Adequate hepatic function: bilirubin ≤ 2.0 mg/dL (unless elevated secondary to 
lymphomatous involvement of liver or biliary system, or due to other HIV 
medications [e.g., indinavir, tenofavir, or atazanavir]. For patients whose bilirubin 
measures >3.0 mg/dL due to hepatic involvement, the initial dose of Doxil will be 
decreased by 50%, and the initial dose of vincristine will be omitted. Serum glutamic-
oxaloacetic transaminase (SGOT) < 5X upper limit of normal. 
 
4.1.10 Adequate renal function: creatinine < 2.0 mg/dL, or creatinine clearance  
≥ 60 ml/min, unless secondary to renal involvement by lymphoma. 
 
4.1.11 Adequate 
hematologic 
function: 
granulocytes/ANC 
>1000/mm3, 
platelets 
>75,000/dL (unless these parameters are abnormal secondary to lymphomatous 
involvement of bone marrow, or due to HIV-related thrombocytopenia). All patients 
must cease colony-stimulating factor (CSF) therapy at least 24 hours prior to 
institution of Cycle 1 chemotherapy. 
 
4.1.12 Left ventricular ejection fraction (LVEF) that is at or above the lower institutional 
limits of normal, as assessed by Multiple Gated Acquisition (MUGA) scan or 
echocardiogram within the 6 weeks prior to registration.  
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4.1.13 Concurrent radiation, with or without steroids, for emergency conditions secondary to 
lymphoma (i.e., CNS tumor, cord compression, etc.) will be permitted. 
 
4.1.14 Female patients must have a negative pregnancy test within 72 hours of entering into 
the study. Both men and women will be included and, if of child bearing potential, 
must agree to use adequate methods of contraception for the duration of the 
treatment. Women must avoid pregnancy, and men must avoid fathering children 
while in the study, and for 6 months following the last study drug treatment. 
 
4.1.15 Concurrent effective HAART treatment of HIV with any licensed agents, or any 
agent available on an expanded access program, is required at study entry. A specific 
level of HIV-1 RNA in plasma is not required for protocol entry. However, when the 
HIV-1 viral load analysis becomes clinically available, if the HIV viral load is ≥ 
50,000 copies/cc, the HAART regimen is to be modified to a patient-specific 
alternative regimen as decided by the primary treating physician. Concurrent therapy 
with zidovudine or a zidovudine-containing regimen (including combivir and 
Combivir and Trizivir) will be prohibited until 2 months following the completion of 
chemotherapy as part of this protocol. 
 
4.1.16 Patients already receiving erythropoietin or G-CSF are eligible for participation, 
although GF therapy must be discontinued at least 24 hours prior to receiving 
chemotherapy. 
 
4.2 
Exclusion Criteria 
4.2.1 
Presence of second active tumor, other than non-melanomatous skin cancer, 
carcinoma in situ of the cervix, or Kaposi’s sarcoma (KS) that does not require 
systemic therapy. 
 
4.2.2 
Primary CNS lymphoma, including parenchymal brain or spinal cord lymphoma. 
 
4.2.3 
Presence of leptomeningeal disease (positive cerebral spinal fluid [CSF] for 
lymphoma) or presence of metastatic disease to brain in terms of any mass lesion. 
 
4.2.4 
Pregnant women or nursing mothers. 
 
4.2.5 
KPS <50% (ECOG Performance Score > 3). 
 
4.2.6 
Expected survival < 2 months. 
 
4.2.7 
Unable to comply with the requirements of the protocol, or unable to provide 
adequate informed consent in the opinion of the Principal Investigator.  
 
4.2.8 
Serious, ongoing, non-malignant disease or infection, which, in the opinion of the 
Investigator and/or the sponsor, would compromise other protocol objectives. 
 
4.2.9 
Major surgery, other than diagnostic surgery, occurring 4 weeks prior to study entry. 
 
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4.2.10 Rituximab therapy within the 12 months prior to study entry. Patients treated with 
rituximab >12 months prior to study registration are eligible only if it was given for 
indications other than the treatment of aggressive lymphoma. 
 
4.2.11 Prior cytotoxic chemotherapy or radiotherapy for this lymphoma, except as outlined 
in Section 4.1.13. 
 
4.2.12 History of cutaneous or mucocutaneous reactions, or diseases in the past, due to any 
cause, severe enough to cause hospitalization or an inability to eat or drink for >2 
days. This exclusion relates to the long-term possibility of severe cutaneous or 
mucocutaneous reactions to rituximab that might occur at increased frequency in 
patients who have had severe skin disease or reactions in the past. 
 
4.2.13 Use of zidovudine as part of the HAART regimen. 
 
4.2.14 Any acute, inter-current infection that may interfere with planned protocol treatment. 
Patients with mycobacterium avium will not excluded from study entry. 
 
4.2.15 Myocardial infarction (MI) within 6 months prior to study entry, New York heart 
Association (NYHA) Class II or greater heart failure, uncontrolled angina, severe 
uncontrolled ventricular arrhythmias, clinically significant pericardial disease, or 
electrocardiographic evidence of acute ischemic or active conduction system 
abnormalities. 
 
4.2.16 Inadequate hepatic function: Bilirubin >2.0 mg/dl (unless elevated secondary to 
lymphomatous involvement of liver or biliary system or due to other HIV 
medications such as indinavir, tenofavir, or atazanavir). 
 
4.2.17 Inadequate renal function: Creatinine >2.0 mg/dl, or creatinine clearance <60 cc/min, 
unless secondary to renal involvement by lymphoma 
 
4.2.18 Inadequate cardiac function: Left ventricular cardiac ejection fraction that is less than 
the lower institutional limits of normal, as assessed by nuclear scan or 
echocardiogram obtained within 6 weeks prior to registration. 
 
4.2.19 Inadequate pulmonary function: Presence of shortness of breath at rest, with arterial 
PO2 of <70 or pulse oximeter derived O2 saturation <94% on room air, unless due to 
lymphomatous involvement of the lungs. 
 
4.3 
Number of Patients to be Enrolled 
A one-stage design will be employed, enrolling a total of 40 evaluable patients. 
 
4.4 
Patient Enrollment Procedure 
This study will be available for enrollment at all AMC sites. Each site must have this 
protocol approved by their Institutional Review Board (IRB) and be registered with the AMC 
Operations Center before they may enroll patients. 
 
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After it has been determined that a patient is eligible and an informed consent has been 
signed by the patient, the patient must be registered on-line via the AMC AdvantageEDCSM 
Internet Data Entry System. Enrollment and data collection will occur via the AMC Internet 
Data Entry System. 
 
The participating site will ensure the patient meets all eligibility criteria prior to completing 
the protocol-specific eligibility checklist. Patients will be enrolled on-line via the AMC 
Internet Data Entry System no more than one week prior to the initiation of treatment 
(enrollment one day prior to, or on the day of treatment is strongly encouraged). Once the 
eligibility checklist is submitted and eligibility is confirmed, a system generated confirmation 
email will be sent to the enroller upon successful completion of the patient enrollment. If the 
on-line system is inaccessible, the site should notify the AMC Operations Center (via e-mail 
at amcpm@emmes.com or phone at 301-251-1161) for further instructions. 
 
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5.0 
STUDY PROCEDURES 
 (See Appendix I, Schedule of Evaluations) 
 
5.1 
Screening/Baseline Evaluations 
Unless otherwise specified, the following evaluations must be performed within 4 weeks 
prior to patient registration: 
 
5.1.1 
Medical history, including history of nadir CD4 count, if available; history of current 
and past anti-retroviral regimens, if available; and history of any prior AIDS-defining 
conditions. Date of initial lymphoma diagnosis is required, with a copy of the 
pathology report in the medical record. Presence of systemic “B” symptoms should 
be noted, as well as other symptoms of NHL. History of drug allergies should be 
ascertained. Current concomitant medication list, including all anti-retroviral, anti-
viral, antibiotics and opportunistic prophylaxis. 
 
5.1.1.1 
A drug diary should be initiated and maintained, documenting all 
medications being taken by the study subject. 
 
5.1.2 
Physical examination, including performance status (see Appendix II; Performance 
Status Scale), vital signs (weight, height, body surface area), neurological 
examination, careful measurement of all palpable, peripheral lymph nodes and 
measurement of other sites of disease present. 
 
5.1.3 
CT scan or Magnetic Resonance Imaging (MRI) of chest, abdomen and pelvis. 
 
5.1.4 
PET, PET/CT or gallium scan to document active sites of lymphomatous disease. 
However, if the patient’s insurance or third party will not cover the costs for these 
tests, omission of these exams will not be considered a protocol violation. The 
PET/CT scan will substitute for separate CT and PET scans, if PET/CT is performed. 
 
5.1.5 
Electrocardiogram (ECG). 
 
5.1.6 
Laboratory tests, including: 
5.1.6.1 
CBC with differential and platelet count (within 2 weeks prior to patient 
registration) 
 
5.1.6.2 
Serum chemistries: glucose, blood urea nitrogen (BUN), creatinine, total 
bilirubin, alkaline phosphatase (ALP), LDH, total protein, albumin, serum 
glutamic oxaloacetic transaminase and/or aspartate aminotransferase 
(SGOT and/or AST), serum glutamic pyruvic transaminase and/or alanine 
aminotransferase (SGPT and/or ALT) and calcium (within 2 weeks prior to 
patient registration) 
 
5.1.6.3 
Serum pregnancy test for women of childbearing potential (within 72 hours 
prior to Cycle 1 chemotherapy). 
 
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5.1.1.4 
Bone marrow biopsy or aspirate for histology and determination of percent 
bone marrow involvement (within 6 weeks prior to patient registration). 
Unilateral bone marrow biopsy/aspirate is allowed, with an aggregate core 
length of 2 cm, either from one site or bilateral sites. If feasible, a portion of 
the bone marrow biopsy and aspirate will be sent for cytogenetic analysis.  
 
5.1.6.5 
HIV-1 RNA viral load (evaluated at the local laboratory) 
 
5.1.6.6 
CD4 and CD8 cells 
 
5.1.6.7 
Quantitative serum immunoglobulin levels (IgG, IgA, IgM) 
 
5.1.6.8 
Assessment for Hepatitis C (hepatitis C virus [HCV] antibody) and 
Hepatitis B (hepatitis B surface antigen [HbSAg] and hepatitis B surface 
antibody [HbSAb]), in all patients. 
 
5.1.7 
Skin test (Delayed Cutaneous Hypersensitivity [DCH]) for Mycobacterium 
tuberculosis. 
 
5.1.8 
Determination of LVEF by MUGA scan or echocardiogram. Patients will not be 
enrolled if LVEF is below institutional lower limits. 
 
5.1.9 
Lumbar puncture with routine studies and cytology. IT chemotherapy may be injected 
at the time of initial staging lumbar puncture (see Section 7.4). 
 
5.1.10 Central pathology review: All specimens will be reviewed by a panel of pathologists 
and must be submitted within 30 days of study enrollment. 
 
5.1.11 Optional donation to the AIDS and Cancer Specimen Resource (ACSR). (See 
Appendix V for instruction on shipping samples). 
 
5.1.12 MDR-1 determination on lymphoma tissue (to be sent to central laboratory for 
testing. [See Appendix VII for central laboratory information]). 
 
5.1.13 Blood culture for Mycobacterium avium in all patients with fever at the time of 
presentation. 
 
5.2 
Evaluations During Treatment Period 
5.2.1 
Prior to each cycle of DR-COP chemotherapy: 
 
5.2.1.1 
History, to include completion of drug diary. 
 
5.2.1.2 
Physical examinations, including performance status and vital signs. 
 
5.2.1.3 
Laboratory tests including: 
 
CBC with differential and platelet count 
 
Serum chemistries: glucose, BUN, creatinine, total bilirubin, ALP, 
LDH, total protein, albumin, SGOT, SGPT and calcium 
 
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Adverse events (AEs) are to be recorded on an ongoing basis and on 
appropriate source documents at the clinical site and in the patient's case 
report form (CRF). The onset of new AEs as defined in Section 10.0 will 
be documented in the patient's CRF. In addition, any transfusions of blood 
and/or blood products are to be recorded in the patient’s CRF. 
 
In the event that a Grade 3 or 4 hematologic toxicity occurs at any time, 
blood samplings for follow-up evaluations should be performed as 
clinically indicated until the abnormality is resolved. 
 
5.2.2 
After Cycles 2, 4 and 6 of DR-COP chemotherapy: 
 
5.2.2.1 
CD4 and CD8 cells. 
 
5.2.2.2 
HIV-1 viral load by Q-PCR or bDNA (evaluated at the local laboratory). 
 
5.2.2.3 
Quantitative immunoglobulins (IgG, IgA, IgM). 
 
5.2.2.4 
HBV and/or HCV viral load in patients with HBV surface antigen 
positivity, or HCV antibody positivity at baseline, respectively. 
 
5.3 
Evaluation of Response 
5.3.1 
After Cycles 2, 4 and 6 of DR-COP chemotherapy: 
 
5.3.1.1 
CT or MRI scan. 
 
5.3.1.2 
PET, PET/CT or gallium scan to document active sites of lymphomatous 
disease. However, if the patient’s insurance or third party will not cover 
the costs for these tests, omission of these exams will not be considered a 
protocol violation. The PET/CT scan will substitute for separate CT and 
PET scans, if PET/CT is performed. 
 
5.3.1.3 
Repeat bone marrow biopsy after Cycle 4 if result of initial biopsy 
indicated that bone marrow is involved with lymphoma. 
 
5.3.1.4 
Repeat of any other test that demonstrated lymphomatous involvement at 
the Baseline evaluation. 
 
5.3.1.5 
History and physical examination. 
 
5.3.2 
One month after completion of chemotherapy: 
 
5.3.2.1 
CT or MRI scan. 
 
5.3.2.2 
PET, PET/CT or gallium scan to document active sites of lymphomatous 
disease. However, if the patient’s insurance or third party will not cover 
the costs for these tests, omission of these exams will not be considered a 
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protocol violation. The PET/CT scan will substitute for separate CT and 
PET scans, if PET/CT is performed. 
5.3.2.3 
Repeat bone marrow aspirate and biopsy if results of initial biopsy 
indicated that bone marrow is involved with lymphoma. 
 
5.3.2.4 
Repeat of any other test that demonstrated lymphomatous involvement 
prior to protocol treatment. 
 
5.3.2.5 
History and physical examination. 
 
5.4 
Follow-Up Evaluations (Month 3 and Beyond) 
5.4.1 
Post treatment Follow-up Period 
 
The following will be performed/collected at 2-month intervals for 1 year post 
completion of protocol chemotherapy, and at 6-month intervals for an additional 2 
years (total follow-up is 3 years). In those instances in which a third party payer 
denies payment for some or all of these laboratory analyses, absence of these test 
results will not be considered a protocol violation.  
 
In participants who attain CR, laboratory and other evaluations will be performed in 
the manner outlined below in Sections 5.4.1.1-5.4.1.10.  
 
Participants who attain PR after 6 cycles, or SD after 4 cycles will come off treatment 
at that point, and will be followed in the usual manner as outlined in Sections 5.4.1.1-
5.4.1.10 until progression or an alternative anti-cancer therapy is begun. From that 
point on, the subject will be followed for survival alone.  
 
5.4.1.1 
Interim medical history. 
 
5.4.1.2 
Serious adverse events (SAEs), as well as any new or worsening drug-
related AEs (see Section 10.0 and Appendix III, Common Terminology 
Criteria for Adverse Events [CTCAE]. 
 
5.4.1.3 
Quantitative serum immunoglobulins (IgG, IgA, IgM).  
 
5.4.1.4 
HIV-1 RNA levels.  
 
5.4.1.5 
CD4 and CD8 cells.  
 
5.4.1.6 
Physical examination, including performance status and vital signs.  
 
5.4.1.7 
Serum chemistries: glucose, BUN, creatinine, total bilirubin, ALP, LDH, 
total protein, albumin, SGOT, SGPT and calcium at Month 6 and Month 
12 for the first year post treatment, and every 6 months thereafter during 
years 2 and 3 post treatment. 
 
5.4.1.8 
CBC with differential and platelet count.  
 
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5.4.1.9 
Restaging of disease and Response Evaluation by physical examination. It 
is recommended that restaging of disease by CT scan or MRI be done 
every 6 months for the first year, and every 6 months for years 2 and 3 
post-treatment. 
 
5.4.1.10 In patients with HBV surface antigen positivity and/or HCV antibody 
positivity at baseline, HBV and/or HCV viral load will be determined at 2-
month intervals after completion of therapy for a period of one year. 
 
5.5 
Disease Progression Evaluations/Off-Treatment 
Patients who develop disease progression during the treatment period and who do not begin 
other anti-cancer therapy will continue to be followed for routine safety and efficacy for a 
total of 12 weeks following completion of protocol treatment and followed for vital status for 
3 years post-treatment. 
 
5.5.1 
Tests to be Performed when a Patient is Determined to have Disease Progression or is 
Removed from Treatment for any Reason. 
 
The following tests will be performed within 4 weeks after a patient has demonstrated 
clinical progression of disease. These tests do not have to be repeated if they were 
performed within 7 days prior to documentation of disease progression: 
 
5.5.1.1 
Tumor assessment (if patient is removed from the study for a cause other 
than progressive disease). 
 
5.5.1.2 
Interim medical history and physical examination, including performance 
status and vital signs. 
 
5.5.1.3 
CBC with differential and platelet count. 
 
5.5.1.4 
Quantitative serum immunoglobulins (IgG, IgA, IgM). 
 
5.5.1.5 
HIV-1 RNA levels. 
 
5.5.1.6 
CD4 and CD8 cells. 
 
5.5.1.7 
Serum chemistries: glucose, BUN, creatinine, total bilirubin, ALP, LDH, 
total protein, albumin, SGOT, SGPT and calcium. 
 
5.5.1.8 
Follow-up of all ongoing, related AEs until resolved or determined to be 
permanent. 
 
5.5.1.9 
In patients with HBV surface antigen positivity and/or HCV antibody 
positivity at baseline, HBV and/or HCV viral load. 
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6.0 
PHARMACEUTICAL INFORMATION 
6.1 
Doxil 
6.1.1 
Description 
Doxil is a formulation of doxorubicin, encapsulated in long-circulating STEALTH 
liposomes for IV administration. 
 
Doxil was designed to enhance the efficacy and reduce the dose-limiting toxicities of 
doxorubicin by altering the plasma pharmacokinetics (PK) and tissue distribution of 
the drug. Preclinical results show that Doxil prolongs the systemic circulation of 
doxorubicin leading to higher concentrations of the drug in tumors and resulting in a 
reduction in tumor mass and prolonged survival. 
 
6.1.2 
Human Toxicology 
The most extensive experience with Doxil to date has been reported in patients with 
AIDS-related KS. The most common AEs associated with Doxil in KS studies have 
been leukopenia, anemia, nausea, asthenia, thrombocytopenia, fever, alopecia, 
increased ALP, vomiting, diarrhea, and stomatitis. 
 
6.1.3 
Pharmacology 
Several animal and human studies have been conducted to define the PK of Doxil. 
Plasma PK studies have been evaluated in 42 patients with AIDS-related KS who 
received single doses of 10 or 20 mg/m2 IV Doxil administered over 30 minutes. 
Results from this study showed that Doxil displayed linear (dose proportional) PK. 
Disposition occurred in two phases after Doxil administration, with a relatively short 
first phase (5 hours) and a prolonged second phase (52 hours), that accounted for the 
majority of the area-under the curve (AUC). 
 
6.1.4 
Formulation 
The vial contains 2.0 mg/mL doxorubicin hydrochloride, unless specified otherwise on 
the label. The volume of Doxil to be administered will be based upon the dose specified 
in the protocol. 
 
Take the appropriate volume of Doxil up into a sterile syringe. Aseptic technique must 
be strictly observed since no preservative or bacteriostatic agent is present in Doxil. 
Each vial is single-use only. 
 
Dilute the Doxil in Dextrose 5% In Water for Injection, USP (D5W). For doses > 12 mg 
and < 90 mg, dilute in 250 mL of D5W. For doses > 90 mg, dilute in 500 mL D5W. 
Once Doxil has been diluted, it must be refrigerated at 2-8º C and administered within 8 
hours of mixing. Ordinarily, the drug can be administered intravenously over 1 hour. 
However, because of occasional acute reactions to the first dose, the initial infusion can 
be administered more slowly if necessary (see Section 6.1.6). 
 
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6.1.5 
Storage and Stability 
Store Doxil in a refrigerator at 2-8º C. Avoid freezing. Doxil is supplied in vials as a 
liquid. Each vial contains 20 mg doxorubicin hydrochloride. Do not use if a precipitate 
or foreign matter is present. Do not use if vial seal is breached. 
 
6.1.6 
Administration 
In patients with solid tumors and other malignancies, Doxil should be administered 
intravenously over 90 minutes. Rapid infusion may increase the risk of infusion-related 
reactions. In some patients, the reaction resolves by slowing the rate of infusion. To 
minimize the risk of infusion-related reactions, it is recommended that the first infusion 
of Doxil should be as follows: 
 
10 mL over first 10 minutes 
 
20 mL over next 10 minutes 
 
40 mL over next 10 minutes 
 
Then, complete the infusion over a total of 90 minutes. 
 
If no infustion-related reactions are noted with the initial infusion, subsequent infusions 
will occur at a rate of 1 mg/minute. 
 
Do not administer Doxil as a bolus injection or an undiluted solution. Doxil should be 
considered a vesicant and precautions should be taken to avoid extravasation. During IV 
administration of Doxil, extravasation may occur with or without an accompanying 
stinging or burning sensation, and even if blood returns well on aspiration of the 
infusion needle. If any signs or symptoms of extravasation have occurred, the infusion 
should be immediately terminated and restarted in another vein. Doxil must not be given 
by intramuscular (IM) or subcutaneous (SC) route. 
 
Parenteral drug products should be inspected visually for particular matter and 
discoloration prior to administration, whenever solution and container permit. 
 
6.1.7 
Supplier 
Doxil will be provided by Ortho Biotech Clinical Affairs, LLC (Ortho Biotech), and will 
be free of charge. 
 
Drug ordering and distribution procedures for Doxil will be posted on the AMC 
Operations Center web site (www.amcoperations.com) and are also listed in Appendix 
IX. 
 
6.1.8 
Handling and Disposal 
Doxil should not be mixed with other drugs until specific compatibility data are 
available. The presence of any bacteriostatic agent, such as benzyl alcohol, may cause 
precipitation of Doxil. 
 
Caution should be exercised in handling Doxil solution. The use of gloves is 
recommended. If Doxil comes into contact with skin or mucosa, immediately wash 
thoroughly with soap and water. 
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Doxil should be handled and disposed of in a manner consistent with other anti-cancer 
drugs. 
 
6.2 
Rituximab 
6.2.1 
Clinical Formulation 
Rituximab is a mouse/human antibody. The antibody is produced by a Chinese 
hamster ovary transfectoma. Rituximab will be provided to the clinical sites packaged 
in 10 mL (100 mg) and 50 mL (500 mg) pharmaceutical grade glass vials at a 
concentration of 10 mg/mL. 
 
Storage: Rituximab for clinical use should be stored in a secure refrigerator at 2-8º C. 
 
6.2.2 
Reconstitution and Dilution of Rituximab 
The antibody should be diluted with normal saline (NS) to allow for a maximal 
concentration of rituximab to equal 1 mg/mL. The final preparation should be 
administered through a 0.22 micron in-line filter, although the specifics of 
administration will be left to the discretion of the individual Investigator, based upon 
the details required at each Institution. Caution should be taken during the preparation 
of the drug, as shaking can cause aggregation and precipitation of the antibody. 
 
6.2.3 
Product Administration 
In calculating body surface area (BSA), actual height and weight should be used. 
There will be no downward adjustment to “ideal” weight. Dosage calculations for all 
treatments will be calculated using the patient’s body surface area as determined 
during the screening evaluation, with re-assessment on Day 1 of each new cycle. 
 
6.2.4 
Dose and Schedule 
Rituximab will be administered as an IV infusion at 375 mg/m2 based upon the 
patient’s BSA calculated during the baseline evaluation for cycle 1. BSA is to be 
recalculated at the start of each cycle. The dose of rituximab will be adjusted at the 
start of each cycle only if a subject’s weight has changed more than 10% from 
baseline or prior dose. 
 
6.2.5 
Method of Administration 
CAUTION: DO NOT ADMINISTER AS AN IV PUSH OR BOLUS. 
 
Rituximab infusions will be administered to patients in either an outpatient or 
inpatient clinic setting, as clinically indicated. Oral premedication (acetaminophen 
and diphenhydramine hydrochloride) may be administered 30-60 minutes prior to 
starting each infusion of rituximab. A peripheral or central IV line will be established. 
The initial dose rate at the time of the first rituximab infusion should be 12.5 
mg/hour. If no toxicity is seen, the dose rate may be escalated gradually (50 mg/hour 
increments at 30-minute intervals) to a maximum of 300 mg/hour. If the first dose of 
rituximab is well-tolerated, the starting flow rate for the administration of additional 
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doses will be 100 mg/hour and increased gradually (100 mg/hour increments at 30 
minute intervals) not to exceed 400 mg/hour. 
 
Patients may experience transient fever and rigors with infusion of chimeric anti-
CD20 antibody. When these side effects are noted, the antibody infusion should be 
temporarily discontinued, the patient should be observed and the severity of the side 
effects should be evaluated. The patient should be treated according to the best 
available local practices and procedures. Following observation, when the patient’s 
symptoms improve, the infusion should be continued, initially, at half of the previous 
rate (see table below). Upon resolution of all side effects, and in the judgment of the 
Investigator, the patient’s dose may be gradually escalated (50 mg/hour increments at 
30-minute intervals) to a maximum rate of 300 mg/hour. Following the antibody 
infusion, the IV line should be kept open for medications, as needed. If there are no 
complications, the IV line may be discontinued after one hour of observation. If 
complications occur during the rituximab infusion, the patient should be observed for 
two hours after the completion of the infusion, as per the recommendations at each 
individual Institution. 
 
6.2.6 
Human Antichimeric Antibody Response (HACA) 
Both HACA and human antimouse antibody (HAMA) were monitored in the early 
trials of rituximab. None of the 67 patients tested developed a HAMA response. Of 
355 patients in seven trials, three had a detectable HACA response (<0.9%). The 
HACA responses were transient and present at very low concentrations (<120 
ng/mL). None of the three patients had clinical or laboratory abnormalities associated 
with a HACA response. The presence of a positive HACA response did not affect 
tolerability or preclude retreatment with rituximab. 
 
6.2.7 
Supplier 
Rituximab is commercially available. 
 
6.3 
Cyclophosphamide (Cytoxan®) (NSC-26271) 
6.3.1 
Description 
2-[bis (2-chloroethyl) amino] tetrahydro-2H-1, 3, s-oxazophosphorine 2- oxide 
monohydrate. Cyclophosphamide is biotransformed principally in the liver to active 
alkylating metabolites which crosslink to tumor cell DNA. The active metabolite, 
hydroxycyclophosphamide, is produced by hepatic microsomal enzymes. It acts by 
substituting an alkyl group for the hydrogen atoms of certain organic compounds, 
primarily DNA, which produces breaks in the DNA molecule and cross-linking of its 
twin strands. These changes interfere with the DNA replication and the transcription 
of RNA. 
 
6.3.2 
Human Toxicology 
Toxicity from cyclophosphamide includes bone marrow suppression which usually 
occurs 10 to 12 days after administration, nausea, vomiting, anorexia, abdominal 
discomfort, diarrhea, stomatitis, hemorrhagic colitis, jaundice, reversible alopecia, 
hemorrhagic cystitis which can frequently be prevented with increased hydration, 
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hematuria, ureteritis, tubular necrosis, fibrosis of the bladder, cardiac toxicity, which 
may potentiate doxorubicin-induced cardiotoxicity, rare anaphylactic reaction, skin 
rash, hyperpigmentation of the skin and nails, interstitial pulmonary fibrosis, and 
cross sensitivity with other akylating agents. Treatment with cyclophosphamide may 
cause significant suppression of the immune system. 
 
Second malignancies, most frequently of the urinary bladder and hematologic 
systems have been reported when cyclophosphamide is used alone or with other 
antineoplastic drugs. It may occur several years after treatment has been 
discontinued. It interferes with oogenesis and spermatogenesis and may cause 
sterility in both sexes which is dose- and duration-related. It has been found to be 
teratogenic, and women of childbearing potential should be advised to avoid 
becoming pregnant. Increased myelosuppression may be seen with chronic 
administration of high doses of phenobarbital. Cyclophosphamide inhibits 
cholinesterase activity and potentiates effect of succinylcholine chloride. If patient 
requires general anesthesia within 10 days after cyclophosphamide administration, 
the anesthesiologist should be alerted. Adrenal insufficiency may be worsened with 
cyclophosphamide. Cyclophosphamide is excreted in breast milk and it is advised 
that mothers discontinue nursing during cyclophosphamide administration. The 
occurrence of acute leukemia has been reported rarely in patients treated with 
anthracycline/alkylator combination chemotherapy. 
 
6.3.3 
Pharmacology 
Cyclophosphamide is activated principally in the liver by a mixed function 
microsomal oxidase system. PO administration is well-absorbed, with bioavailability 
>75%. Five to 25% of unchanged drug is excreted in the urine. Several active and 
inactive metabolites have been identified with variable plasma protein binding. There 
appears to be no evidence of clinical toxicity in patients with renal failure, although 
elevated levels of metabolites have been observed. 
 
6.3.4 
Formulation 
Cyclophosphamide is supplied in 100 mg, 200 mg, 500 mg, 1 gram and 2 gram vials 
as a white powder. The drug should be reconstituted with Sterile Water for Injection, 
USP (SWI), and may be diluted in either NS or D5W. 
 
6.3.5 
Storage and Stability 
The reconstituted drug is stable for 24 hours at room temperature and for 6 days 
under refrigeration. Tablets are stable at room temperature. 
 
6.3.6 
Administration 
The drug should be diluted in approximately 150 cc of NS or D5W and infused 
intravenously. An added dose of IV fluids may help prevent bladder toxicity. 
 
6.3.7 
Supplier 
The drug is commercially available for purchase through a third party.  
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6.4 
Prednisone 
6.4.1 
Description 
Prednisone is a glucocorticoid rapidly absorbed from the gastrointestinal (GI) tract. 
 
6.4.2 
Toxicology 
Possible AEs associated with the use of prednisone are: fluid and electrolyte 
disturbances, congestive heart failure in susceptible persons, hypertension, euphoria, 
personality changes, insomnia, mood swings, depression, exacerbation of infection, 
exacerbation or symptoms of diabetes, psychosis, muscle weakness, osteoporosis, 
vertebral compression fractures, pancreatitis, esophagitis, peptic ulcer, dermatologic 
disturbances, convulsions, vertigo and headache, endocrine abnormalities, ophthalmic 
changes, and metabolic changes. Some patients have experienced itching and other 
allergic anaphylactic or other hypersensitivity reactions. Withdrawal from prolonged 
therapy may result in symptoms including fever, myalgia and arthralgia. Phenytoin, 
phenobarbital and phedrin enhance metabolic clearance of corticosteroids. 
 
6.4.3 
Pharmacology 
Natural and synthetic glucocorticoids are readily and completely absorbed from the 
GI tract. Prednisone is very slightly soluble in water. Glucocorticoids have salt-
retaining properties. The anti-inflammatory property of this drug is its ability to 
modify the body's immune system. On the other hand, glucocorticoids suppress the 
body's response to viral as well as bacterial infections. Equivalent doses are as 
follows: 
 
Dexamethasone 
Prednisolone 
Methyl- 
Hydrocortisone 
Cortisone 
 
Prednisolone 
──────────────────────────────────────────────────────── 
0.75 mg 
 
5 mg 
 
4 mg 
20 mg 
25 mg 
 
 
6.4.4 
Formulation 
Prednisone is available in 2.5 mg, 5 mg, 10 mg, 20 mg and 50 mg tablets. 
 
6.4.5 
Storage and Stability 
Prednisone should be stored at room temperature. 
 
6.4.6 
Administration 
Prednisone will be administered orally. 
 
6.4.7 
Supplier 
Prednisone is commercially available and should be purchased by third party. 
 
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6.5 
Vincristine 
6.5.1 
Chemistry 
Vincristine is one of the vinca-alkaloids and is extracted from the plant 
Cantharanthus roseus (Vinca rosea). This drug appears to produce the arrest of 
mitosis in animal cells by interfering with microtubule function. 
 
6.5.2 
Human Toxicology 
The primary toxic effects of vincristine are neurological with paresthesia, weakness, 
muscle wasting, motor difficulties, including difficulty walking and slapping gait, 
loss of deep tendon reflexes, sensory loss, neuritic pain, paralytic ileus, bladder atony, 
and constipation. Rarely, it produces myelosuppression. Other side effects may 
include alopecia, allergic reactions (including rare anaphylaxis, rash and edema), jaw 
pain, hypertension, hypotension, nausea, vomiting, diarrhea, fever, and headache. 
 
6.5.3 
Pharmacology 
After IV administration, a triphasic serum decay pattern follows with half-lives of 5 
minutes, 2-3 hours and 85 hours. The range of terminal half-life is 19-155 hours. 
Excretion is 80% in the feces and 10-20% in the urine. The liver is the major 
excretory organ in humans and animals, and biliary obstruction causes increased 
toxicity in man. 
 
6.5.4 
Formulation 
The concentration of vincristine contained in all vials and disposable syringes is 1 
mg/mL. 
 
6.5.5 
Drug Interactions 
The simultaneous PO and IV administration of phenytoin and antineoplastic 
chemotherapy combination, that includes vincristine, has been reported to induce 
blood levels of the anticonvulsant and to increase seizure activity. Vincristine should 
not be diluted in solutions that raise or lower the pH outside the range of 3.5 to 5.5. 
 
6.5.6 
Storage and Stability 
Vincristine should be stored under refrigeration. Once reconstituted, the drug should 
be used within 1 week if stored at room temperature, or 2 weeks if refrigerated. 
Protect from light. Depending on the manufacturer, the product may contain a 
preservative. If the product being used contains a preservative, the vial may be used 
longer than 1 or 2 weeks. Please refer to the individual manufacturer's package insert 
for more information. Parenteral drug products should be inspected visually for 
particulate matter and discoloration prior to administration. 
 
6.5.7 
Administration 
Vincristine should be administered through a freely-running IV. If vincristine 
extravasates, it produces a severe local reaction with skin slough.  
 
CAUTION: FATAL IF GIVEN INTRATHECALLY. FOR IV USE ONLY. 
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6.5.8 
Supplier 
Vincristine is commercially available and should be purchased through a third party. 


 
7.0 
DRUG TREATMENT 
7.1 
Drug Administration   
Cycles 1 through study completion 
Doxil 
40 mg/m2 IV Day 1 
Rituximab* 
375 mg/m2 IV Day 1 
Cyclophosphamide 
750 mg/m2 IV Day 1 
 
 
Vincristine 
1.4 mg/m2 IV Day 1 (2.0 mg maximum) 
 
 
Prednisone 
100 mg PO Days 1-5 
 
 
* If use of rituximab on Day 1 of Cycle 1 is felt to be a potential problem in terms of patient 
safety (i. e., high tumor burden or presence of circulating lymphoma cells in the peripheral 
blood), the treating physician is asked to call the Protocol Chair to discuss possible omission 
of rituximab in Cycle 1. Steroid pre-treatment for rituximab is allowed during Cycle 1. 
 
BSA is to be recalculated at the start of each cycle. Doses of Doxil, rituximab, 
cyclophosphamide, and vincristine will be based upon the subject’s BSA. With any change of 
weight within 10% of baseline, drug dosing will be maintained at the baseline level. Doses of 
chemotherapy are to be adjusted only if a subject’s weight has changed more than 10% from 
baseline or prior dose. 
 
7.2 
Schedule 
Chemotherapy cycles will be repeated every 21 to 28 days, depending upon blood counts and 
recovery from other toxicity (see Section 8.1). Chemotherapy cycles will be given every 21 
days as long as the following criteria are met: 
 
ANC ≥ 1000/mm3. 
 
Platelet count is ≥ 75,000/mm3. 
 
Grade < 2 Hand Foot Syndrome (HFS), and absence of other severe skin reactions of grade 
2 or more. 
 
Recovery to Grade ≤ 1 non-hematologic toxicity. 
 
If these criteria are not achieved by Day 21, the next cycle will begin on Day 28, as specified in 
Section 8.0. A minimum of six cycles, or two doses beyond documentation of CR (for a 
maximum of 8 cycles), will be administered. 
 
7.3 
Prevention of Tumor Lysis Syndrome 
 
Specific methods to prevent or treat tumor lysis syndrome will be at the discretion of the 
investigator. Aggressive IV hydration and urinary alkalization are suggested, as is use of 
allopurinol, as follows: 
 
7.3.1 
Allopurinol, 600 mg (PO or IV, per Investigator discretion) should be given 24-48 hours 
prior to onset of chemotherapy, and thereafter, should be given at 300 mg/day, for at 
least 7 days following administration of the first cycle of chemotherapy. 
 
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7.3.2 
Precautionary hospitalization is recommended for patients who have a high tumor 
burden, or who experience severe infusional reaction due to rituximab, that do not 
resolve after discontinuation or completion of the infusion. 
 
7.4 
CNS Prophylaxis 
CNS Prophylaxis will be mandated per protocol for patients who meet the following criteria: 
lymphomatous involvement of bone marrow, testis, sinuses, or epidural regions; stage IV 
disease; > 2 extra-nodal sites of lymphomatous disease. Specific regimen will be at the 
discretion of the primary oncologist. One of the following three regimens is recommended:  
 
7.4.1 
Cytarabine, 50 mg IT on Day 1 of each DR-COP cycle, for a total of 4 doses. 
 
7.4.2 
Methotrexate, 12 mg IT on Day 1 of each DR-COP cycle, for a total of 4 doses. 
 
7.4.3 
Depocyt, 50 mg IT, on Day 1 of each cycle of DR-COP, for a total of 4 doses. 
 
7.5 
Supportive Therapy 
7.5.1 
GF therapy with G-CSF, GM-CSF, or pegfilgrastim will be used in all patients, 
beginning on Day 3 of each cycle, until post nadir of blood counts from each 
chemotherapy cycle. 
 
7.5.2 
Use of erythropoietic factors is left up to the discretion of the individual Investigator.  
 
7.5.3 
Prophylaxis against Pneumocystis carinii is required. All patients will receive 
prophylaxis with either trimethoprim-sulfamethoxazole (160 mg/800mg, at least three 
times weekly), dapsone (100 mg daily), or inhaled pentamidine or alternative PCP 
prophylaxis (should the other methods not be feasible or are contraindicated). 
 
7.5.4 
Prophylaxis against other common opportunistic infections is encouraged, dependent 
upon the patient’s CD4 cell count at study entry, and at the discretion of the treating 
physician. 
 
7.5.5 
Patients who meet the following criteria are required to receive oral quinolone 
prophylaxis during DR-COP chemotherapy, lasting throughout the period of 
neutropenia. Patients who do not meet these criteria may still receive antibiotic 
prophylaxis, at the discretion of the individual’s physician. 
 
7.5.1.1 
A baseline CD4 count ≤ 100/uL: prophylaxis should be given in all 
chemotherapy cycles. 
 
7.5.1.2 
A CD4 cell count that decreases to ≤ 100/dL during therapy: prophylaxis 
should be given in all subsequent cycles. 
 
7.5.1.3 
Nadir neutrophil count of <500/uL occurring in a previous or current 
cycle: prophylaxis may begin immediately if the patient is severely 
neutropenic, and the prophylactic quinolone should be used in all 
subsequent cycles. 
 
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7.5.1.4 
A nadir neutrophil count of <1000/uL associated with fever of at least 
100.4º F, occurring in a previous cycle: prophylaxis should be given in all 
subsequent cycles. Patients with neutropenia and fever during a current 
cycle should be hospitalized and receive broad-spectrum antibiotic 
therapy. 
 
7.5.6 
HAART Therapy: All patients will be on HAART (the specific agents are at the 
discretion of the treating investigator, but should be in accordance with the current 
International AIDS-Society guidelines). Antiretroviral therapy available on an expanded 
access basis will be allowed, while experimental anti-retroviral agents will not be 
allowed. Zidovudine and zidovudine-containing regimens (including Combivir and 
Trizivir) will be prohibited, due to the known marrow suppressive effects of zidovudine. 
 
7.5.7 
Patients with active HBV infection (HBV surface antigen positive) are strongly 
encouraged to receive anti-HBV therapy. 
 
7.6 
Duration of Therapy 
7.6.1 
At the completion of Cycles 2, 4 and 6, and, if applicable, 8, all initially abnormal 
diagnostic tests should be repeated to document response to therapy. 
 
7.6.1.1 
If after four cycles of therapy, CR or PR has been documented, therapy 
will continue. If stable or progressive disease (PD) has been documented, 
the patient will be withdrawn from protocol therapy. 
 
7.6.1.2 
In patients who achieve a complete response after Cycle 4, two additional 
cycles of treatment will be administered for a maximum of six cycles. 
Chemotherapy will then be considered complete.  
 
7.6.1.3 
If PR has occurred after Cycle 4, treatment will be continued for a total of 
six cycles, at which time a restaging evaluation will be performed. If CR is 
then confirmed after Cycle 6, two additional cycles of DR-COP 
chemotherapy will be given, for a total of 8 cycles (see 7.6.1.2). If only 
stable disease persists after four cycles, or only PR persists after six cycles, 
the patient will come off treatment. 
 
7.7 
Criteria for Removal from Treatment 
7.7.1 
PD. 
 
7.7.2 
CR; six cycles of therapy for partial responders; or four cycles of therapy for patients 
with stable disease. 
 
7.7.3 
Severe toxicity, defined as grade 4 toxicity that is not resolved in a clinically 
satisfactory manner. 
 
7.7.4 
Patient request. 
 
7.7.5 
Investigator decision. 


 
8.0 
DOSE MODIFICATIONS 
8.1 
Decision to Re-Treat at Day 21 Versus Day 28 of the Cycle 
8.1.1 
The next planned cycle of DR-COP chemotherapy will be given on Day 21 of the cycle, 
provided that the following criteria are met: 
 
ANC ≥ 1000/mm3 
 
Platelet count ≥ 75,000/mm3 
 
HFS or other severe skin reactions recovered to < Grade 2 
 
Non-hematologic toxicity recovered to ≤ Grade 1 
 
8.1.2 
If these criteria above are not met, the next planned cycle of DR-COP will be given on 
Day 28, unless toxicity has not yet recovered at that time (see section 8.2). 
 
8.2 
Hematologic Toxicity 
8.2.1 
Day 1 Counts 
8.2.1.1 
If ANC <1000/mm3 or platelets <75,000/mm3, delay up to 2 weeks (to 
Day 42) until ANC and platelets have increased above these levels. 
Treatment with G-CSF or pegfilgrastim is encouraged. 
 
8.2.1.2 
If by Day 42, ANC remains between 750-999/mm3, and/or the platelet 
count 
remains 
between 
50,000/mm3-75,000/mm3, 
doses 
of 
cyclophosphamide and Doxil will be reduced by 25%. 
 
8.2.1.3 
If, by Day 42, ANC is <750/mm3, and/or the platelet count is 
<75,000/mm3, the patient will be removed from protocol. 
 
8.2.1.4 
Dose-reduction of 25% for cyclophosphamide and Doxil will be employed 
on the cycle following that in which the doses were initially reduced by 
25%. However, if, ANC remains ≥ 1000/mm3, and platelet count remains 
≥ 75,000/mm3 on Day 1 of the subsequent cycle, doses of 
cyclophosphamide and Doxil may be increased to 100% again. 
 
8.2.1.4.1 
If, in the discretion of the Investigator, the regimen is too toxic 
to the patient (e.g., ANC <1000/mm3 which has been 
prolonged, but resolved by Day 42; or intercurrent infection 
with ANC <1000/mm3 on more than one occasion while on 
protocol therapy; or more than one dose delay while on 
protocol therapy, the dose of liposomal doxorubicin may be 
decreased by 25% in subsequent cycles. 
 
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8.3 
Non-Hematologic Toxicity 
8.3.1 
Neurological 
Neurotoxicity 
Vincristine Dose 
Moderate paresthesias  (inability to button) 
50% dose 
Inability to walk on heels or obstipation 
No vincristine 
Ambulation difficulties 
No vincristine 
 
8.3.2 
Renal 
Creatinine Clearance < 40 cc/min  
 
 
Drug 
Reduce 
 
Vincristine 
25%  
 
8.3.3 
Hepatic 
If direct bilirubin >2.5 mg/ 
 
 
Drug 
Reduce 
 
Vincristine 
25% 
 
Doxil 
25% 
 
 
8.3.4 
HFS Guidelines for Doxil Dose Adjustment: 
HAND FOOT SYNDROME (HFS) 
Week after Dose 
Toxicity Grade 
3 
4 
6 
1 
(mild erythema, 
swelling, or 
desquamation not 
interfering with daily 
activities) 
Redose unless 
patient has experienced 
a previous Grade 3 or 4 
skin toxicity in which 
case wait an additional 
week 
Redose unless 
patient has experienced a 
previous Grade 3 or 4 
skin toxicity in which 
case wait an additional 
week 
Redose at 25% dose 
reduction; return to 4 
week interval 
or withdraw patient per 
investigator’s 
assessment 
2 
(erythema, 
desquamation, or 
swelling interfering 
with, but not precluding 
normal physical 
activities; small blisters 
or ulcerations less than 
2 cm in diam.) 
Delay dosing up to 2 
weeks or until 
resolved to Grade 0-1 
 
Delay dosing an 
additional week until 
resolved to Grade 0-1. 
If no prior Grade 3-4 
HFS, continue treatment 
at previous dose and 
return to original dose 
interval. If patient 
experienced previous 
Grade 3-4 toxicity, 
continue treatment with 
a 25% dose reduction 
and return to original 
dose interval 
 
Redose at 25% dose 
reduction; return to 4 
week interval 
or withdraw patient per 
investigator’s 
assessment 
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HAND FOOT SYNDROME (HFS) 
Week after Dose 
Toxicity Grade 
3 
4 
6 
3 
(blistering, ulceration, 
or swelling interfering 
with walking or normal 
daily activities; cannot 
wear regular clothing) 
Delay dosing up to 2 
weeks or until 
resolved to Grade 0-1 
 
Delay dosing an 
additional week until 
resolved to Grade 0-1. 
Decrease dose by 25% 
and return to original 
dose interval 
 
Withdraw patient 
4 
(diffuse or local process 
causing infectious 
complications, or a bed 
ridden state or 
hospitalization) 
Delay dosing up to 2 
weeks or until 
resolved to Grade 0-1 
 
Delay dosing an 
additional week until 
resolved to Grade 0-1. 
Decrease dose by 25% 
and return to original 
dose interval 
 
Withdraw patient 
 
8.3.5 
Stomatitis Guidelines for Doxil Dose Adjustment: 
STOMATITIS 
Week after Dose 
Toxicity Grade 
3 
4 
6 
1 
(painless ulcers, 
erythema, or mild 
soreness) 
Redose unless 
patient has 
experienced a previous 
Grade 3 or 4 skin 
toxicity in which case 
wait an additional 
week 
Redose unless  
patient has experienced a 
previous Grade 3 or 4 
skin toxicity in which 
case wait an additional 
week 
Redose at 25% dose 
reduction; return to 4 
week interval 
or withdraw patient per 
investigator’s 
assessment 
2 
(painful erythema, 
edema, or ulcers, but 
can eat) 
Delay dosing up to 2 
weeks or until 
resolved to Grade 0-1 
 
Delay dosing an 
additional week until 
resolved to Grade 0-1. 
If no prior Grade 3-4 
HFS, continue treatment 
at previous dose and 
return to original dose 
interval. If patient 
experienced previous 
Grade 3-4 toxicity, 
continue treatment with 
a 25% dose reduction 
and return to original 
dose interval 
 
Redose at 25% dose 
reduction; return to 4 
week interval 
or withdraw patient per 
investigator’s 
assessment 
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STOMATITIS 
Week after Dose 
Toxicity Grade 
3 
4 
6 
3 
(painful erythema, 
edema, or ulcers, but 
cannot eat) 
Delay dosing up to 2 
weeks or until 
resolved to Grade 0-1 
 
Delay dosing an 
additional week until 
resolved to Grade 0-1. 
Decrease dose by 25% 
and return to original 
dose interval  
Withdraw patient 
4 
(requires parenteral or 
enteral support) 
 
Delay dosing up to 2 
weeks or until 
resolved to Grade 0-1 
 
Delay dosing an 
additional week until 
resolved to Grade 0-1. 
Decrease dose by 25% 
and return to original 
dose interval 
 
Withdraw patient 
 
8.3.6 
Bladder Toxicity 
Cyclophosphamide-related cystitis, whether symptomatic or manifested only by 
otherwise unexplained microhematuria, will be treated by temporarily withholding 
the drug, vigorous hydration, and re-induction of cyclophosphamide when symptoms 
remit, or in 7 days in the case of asymptomatic microhematuria. 
 
8.3.7 
Skin Toxicity 
Patients who have evidence of clinically significant skin rash, or oral/pharyngeal 
mucositis attributed to rituximab should have rituximab discontinued, with no further 
use of the agent. Please contact the Protocol Chair if this circumstance occurs. 
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9.0 
CRITERIA FOR TREATMENT DISCONTINUATION 
9.1 
Permanent Withdrawal 
After enrollment, the patient will be permanently withdrawn from study treatment for any of 
the following reasons: 
9.1.1 
Patients developing a life-threatening infection will have chemotherapy interrupted until 
the infectious process has cleared. The subject will be withdrawn from study treatment 
only if chemotherapy has been held for more than 6 weeks (Day 42).  
 
9.1.2 
Chemotherapy delays for more than 6 weeks (Day 42), for any reason. 
 
9.1.3 
Severe toxicities, defined as grade 4 toxicity that is not resolved in a satisfactory 
manner. 
 
9.1.4 
Progressive lymphoma at any time while on study. 
 
9.1.5 
Voluntary withdrawal. 
 
9.1.6 
The Investigator has the right to remove subjects from study for clinical reasons, which 
he or she believes to be life-threatening or resulting in significant morbidity to the 
subject 


 
10.0 
ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS 
AE monitoring and reporting is a routine part of every clinical trial. The following list of AEs 
(Section 10.1) and the characteristics of an observed AE (Section 10.2) will determine 
whether the event requires expedited reporting (via Adverse Event Expedited Reporting 
System [AdEERS] and to Ortho Biotech) in addition to routine reporting (via Clinical Trials 
Monitoring Service [CTMS] or Clinical Data Update System [CDUS]). 
 
10.1 
Adverse Event Characteristics 
10.1.1 CTCAE term (AE description) and grade: The descriptions and grading scales found 
in the NCI CTCAE will be utilized for AE reporting. CTCAE version 3.0 will be 
utilized for AE reporting until June 30, 2011.  CTCAE version 4.0 will be utilized 
beginning July 1, 2011.  All appropriate treatment areas should have access to a copy of 
the CTCAE version 3.0 and 4.0. A copy of the CTCAE version 3.0 and 4.0 can be 
downloaded from the CTEP web site (http://ctep.cancer.gov). The document “CTEP, 
NCI Guidelines: Adverse Event Reporting Requirements for NCI Investigational 
Agents” (sections 2 and 3) clearly outlines reporting criteria. 
 
10.1.2 ADVERSE EVENT (AE): Any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom or disease temporally associated with the use of 
a medical treatment of procedure regardless of whether it is considered related to the 
medical treatment or procedure (attribution of unrelated, unlikely, possible, probable, or 
definite). 
 
10.1.3 LIFE-THREATENING AE: Any adverse drug experience that places the patient or 
subject, in the view of the investigator, at immediate risk of death from the reaction as it 
occurred, i.e., it does not include a reaction that, had it occurred in a more severe form, 
might have caused death. 
 
10.1.4 SERIOUS ADVERSE EVENT (SAE): Any adverse drug experience occurring at any 
dose that results in any of the following outcomes: death, a life-threatening adverse drug 
experience, inpatient hospitalization, or prolongation of existing hospitalization, a 
persistent or significant disability/incapacity, or a congenital anomaly/birth defect. 
Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
medical judgment, they may jeopardize the patient or subject and may require medical 
or surgical intervention to prevent one of the outcomes listed in this definition. 
 
Please note for hospitalization – All hospitalizations (or prolongation of existing 
hospitalization) for medical events equivalent to CTCAE Grade 3, 4, 5 must be 
reported regardless of the requirements for Phase of study, expected or unexpected, 
and attribution. For example, do not report an admission for PK sampling, but do 
report an admission for an MI. For this study, hospitalization for expedited AE 
reporting purposes is defined as an inpatient hospital stay equal to or greater than 24 
hours. A hospital visit where a patient is admitted for observation or minor treatment 
(e.g., hydration) and released in less than 24 hours would not meet the requirements 
for hospitalization. 
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10.1.5 TOXICITY: Toxicity is a term NOT clearly defined by regulatory organizations. 
Toxicity has been described as an adverse event that has an attribution of possibly, 
probably or definitely related to investigational treatment. To minimize confusion the 
NCI would recommend that the term toxicity NOT be utilized for adverse event 
reporting purposes. 
 
10.1.6 UNEXPECTED AE: Any AE that is not listed in available sources including the 
package insert, the Investigator’s Brochure, or the protocol. 
 
10.1.7 Adverse Event Expedited Reporting System (AdEERS): An electronic system for 
expedited submission of AE reports. 
 
10.1.8 ATTRIBUTION: The determination of whether an AE is related to a medical 
treatment or procedure. Attribution categories: 
Definite – The AE is clearly related to the investigational agent(s). 
Probable – The AE is likely related to the investigational agent(s). 
Possible – The AE may be related to the investigational agent(s). 
Unlikely – The AE is doubtfully related to the investigational agent(s). 
Unrelated – The AE is clearly NOT related to the investigational agent(s). 
 
10.2 
Expedited AE Reporting 
10.2.1 Expedited AE reporting for this study must use AdEERS, accessed via the CTEP home 
page (http://ctep.cancer.gov). The reporting procedures to be followed are presented in 
the CTEP, NCI Guidelines: Adverse Event Reporting Requirements which can be 
downloaded from the CTEP home page (http://ctep.cancer.gov). These requirements are 
briefly outlined in the table below (Section 10.3.3). 
 
In the rare occurrence when internet connectivity is lost, an AE report may be 
submitted using CTEP's Adverse Event Expedited Report-Single Agent or Multiple 
Agent paper template (available at http://ctep.cancer.gov) and faxed to the AMC 
Operations Center at 240-238-2842. A 24-hour notification is to be made to AMC by 
telephone at 301-251-1161, only when internet connectivity is disrupted. Once 
internet connectivity is restored, an AE report submitted on a paper template, or a 24-
hour notification phoned in, must be entered electronically into AdEERS by the 
original submitter at the site. 
 
10.2.2 AdEERS is programmed for automatic electronic distribution of reports to the following 
individuals: Study Coordinator of the Lead Organization, Principal Investigator, and the 
local treating physician. AdEERS provides a copy feature for other e-mail recipients. 
 
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10.2.3 Expedited Reporting Requirements for AEs that occur within 30 Days of Last Protocol 
Treatment 
 
1 
2 
2 
3 
3 
4 & 5 
4 & 52 
Unexpected 
Expected 
 
Unexpected 
and  
Expected 
Unexpected Expected 
with  
Hospitalization
without 
Hospitalization
with 
Hospitalization
without 
Hospitalization 
Unexpected
Expected 
Unrelated 
Unlikely 
Not  
Required 
Not  
Required 
Not  
Required 
10 Calendar
Days 
Not  
Required 
10 Calendar
Days 
Not  
Required 
10 Calendar
Days 
10 Calendar
Days 
Possible 
Probable 
Definite 
Not  
Required 
10 Calendar 
Days 
Not  
Required 
10 Calendar
Days 
10 Calendar
Days 
10 Calendar
Days 
Not  
Required 
24-Hour; 
5 Calendar 
Days 
10 Calendar
Days 
1Adverse events with attribution of possible, probable, or definite that occur greater than 30 days after the last dose of treatment 
require reporting as follows: 
24-hour notification followed by complete report within 5 calendar days for: 
 
Grade 4 and Grade 5 unexpected events 
Complete SAE report within 10 calendar days: 
 
Grade 3 unexpected events with hospitalization or prolongation of hospitalization 
 
Grade 5 expected events 
2Although 24-hour notification is not required for death clearly related to progressive disease, a full report is required as outlined in the table. 
 
 
December 15, 2004 
10.2.3.1 
Note: All deaths on study require both routine and expedited reporting 
regardless of causality. Attribution to treatment or other cause must be 
provided. 
10.2.3.2 Expedited AE reporting timelines defined: 
“24 hours; 5 calendar days”– The investigator must initially report the AE 
via AdEERS, according to the procedures outlined in section 10.3.1, 
within 24 hours of learning of the event, and followed by a complete AE 
report submitted via AdEERS within 5 calendar days of the initial 24-hour 
report. Use the NCI protocol number and protocol-specific patient ID 
assigned during trial registration on all reports. 
 
“10 calendar days”– A complete AdEERS report on the AE must be 
submitted within 10 calendar days of the Investigator learning of the event. 
Use the NCI protocol number and protocol-specific patient ID assigned 
during trial registration on all reports. 
 
Any medical event equivalent to CTCAE Grade 3, 4, or 5 that precipitates 
hospitalization (or prolongation of existing hospitalization) must be 
reported regardless of attribution and designation as expected or 
unexpected with the exception of any events identified as protocol-specific 
expedited AE reporting exclusions. 
 
Any event that results in persistent or significant disabilities/incapacities, 
congenital anomalies, or birth defects must be reported via AdEERS 
according to the guidelines as described above. 
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10.3 
Expedited Reporting to Ortho Biotech 
All SAEs regardless of relationship or severity must be reported to Ortho Biotech within 24 
hours of the investigational staff’s knowledge. Please fax all reports to the attention of Khalid 
Mamum at: 
 
SAE Fax (Ortho Biotech Clinical Affairs, LLC): 908-541-4565 
 
10.4 
Routine Adverse Event Reporting 
AEs reported through AdEERS must also be reported in routine study data submissions. 
Routine reporting of all AEs attributed to therapy, regardless of grade, should be reported. 
 
10.5 
Secondary AML/MDS 
All cases of acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and acute 
lymphocytic leukemia (ALL) that occur in patients on or following treatment on NCI-
sponsored chemotherapy protocols must be reported to the AMC Operations Center using the 
NCI/CTEP Secondary AML/MDS Report Form. This form can be downloaded from the 
CTEP web site (http://ctep.cancer.gov). Refer to the CTEP, NCI Guidelines: Adverse Event 
Reporting Requirements (available at http://ctep.cancer.gov) for additional information about 
secondary AML/MDS reporting.  
 
The following must be submitted within 30 days of an AML/MDS/ALL diagnosis occurring 
after treatment for cancer on an NCI-sponsored trial: 
 
A completed NCI/CTEP Secondary AML/MDS Report Form (do not use AdEERS); 
 
A copy of the pathology report confirming the AML/MDS/ALL; and 
 
A copy of the cytogenetics report (if available). 
 
The AMC Data Coordinator will forward copies to the Investigational Drug Branch 
(IDB) of the NCI CTEP. 


 
11.0 
EVALUATION OF RESPONSE 
All patients will be evaluated for clinical response by physical examination following each 
chemotherapy cycle, and by imaging studies at the conclusion of the second cycle of 
chemotherapy, and every second cycle thereafter. 
 
11.1 
Response Assessment 
Response is currently assessed on the basis of clinical, radiologic, and pathologic (e.g., bone 
marrow) criteria. 
11.1.1 CT scans remain the standard for evaluation of nodal disease. Thoracic, abdominal, and 
pelvic CT scans will be performed for restaging even if those areas were not initially 
involved because of the unpredictable pattern of recurrence in NHL. MRI scans may be 
used instead of CT scans, at the discretion of the Investigator. 
 
11.1.2 A bone marrow aspirate and biopsy should only be performed to confirm a CR if they 
were initially positive or if it is clinically indicated by new abnormalities in the 
peripheral blood counts or blood smear. 
 
11.2 
Definition of Response 
11.2.1 CR requires the following:  
11.2.1.1 
Complete disappearance of all detectable clinical and radiographic 
evidence of disease and disappearance of all disease-related symptoms if 
present before therapy, and normalization of those biochemical 
abnormalities (e.g., LDH) definitely assignable to NHL. 
 
11.2.1.2 
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). 
 
11.2.1.3 
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 diameter after treatment, or by more than 75% in 
the sum of the products of the greatest diameters (SPD). 
 
11.2.1.4 
The spleen, if considered to be enlarged before therapy on the basis of a 
CT scan, must have decreased in size and must not be palpable on 
physical examination. 
 
11.2.1.5 
Similarly, other organs considered to be enlarged before therapy due to 
involvement by lymphoma, such as liver and kidneys, must have 
decreased in size. 
 
11.2.1.6 
If the bone marrow was involved by lymphoma before treatment, the 
infiltrate must be cleared on repeat bone marrow aspirate and biopsy of 
the same site. 
 
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11.2.1.7 
For exploratory analyses alone, related to the use of PET scans:  With 
residual nodal or extra-nodal masses on CT scan, greater than 1.5 cm in 
greatest transverse diameter that have regressed by more than 75% in the 
SPD; with individual nodes that were previously confluent, but have now 
regressed by more than 75% in their SPD compared with the size of the 
original mass on CT scan; or with indeterminate bone marrow biopsy, 
indicating increased number or size of lymphoid aggregates without 
cytologic or architectural atypia, a designation of CR will be made, if an 
initial PET, PET/CT or gallium scan was performed, was positive in these 
areas, and has now converted to negative at the time of assessment of 
tumor response.  
 
11.2.2 CR unconfirmed (CRu) includes those patients who fulfill criteria 11.2.1.2 and 11.2.1.3 
above, but with one or more of the following features: 
11.2.2.1 
A residual lymph node mass greater than 1.5 cm in greatest transverse 
diameter that has regressed by more than 75% in the SPD. Individual 
nodes that were previously confluent must have regressed by more than 
75% in their SPD compared with the size of the original mass. 
 
11.2.2.2 
Indeterminate bone marrow (increased number or size of aggregates 
without cytologic or architectural atypia). 
 
11.2.2.3 
For exploratory analyses alone, related to the use of PET scans: Patient 
has had staging and restaging with CT scans, but has not undergone PET 
scanning, PET/CT scanning or gallium scanning at Baseline, or 
underwent these studies, which were negative at baseline. 
 
11.2.3 PR requires the following: 
11.2.3.1 
>50% decrease in SPD of the six largest dominant nodes or nodal masses. 
These nodes or masses should be selected according to the following 
features: (a) they should be clearly measurable in at least two 
perpendicular dimensions, (b) they should be from as disparate regions of 
the body as possible, and (c) they should include mediastinal and 
retroperitoneal areas of disease whenever these sites are involved. 
 
11.2.3.2 
No increase in the size of the other nodes, the liver, or the spleen. 
 
11.2.3.3 
Splenic and hepatic nodules must regress by at least 50% in the SPD. 
 
11.2.3.4 
With the exception of splenic and hepatic nodules, involvement of other 
organs is considered assessable, and not measurable, disease. 
 
11.2.3.5 
Bone marrow assessment is irrelevant for determination of a PR because 
it is assessable, and not measurable, disease; however, if positive, the cell 
type should be specified in the report (e.g., large-cell lymphoma or low-
grade lymphoma, [i.e., small, lymphocytic small cleaved, or mixed small 
and large cells]). 
 
11.2.3.6 
No new sites of disease. 
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11.2.3.7 
For exploratory analyses alone, related to the use of PET scans: If patient 
has had a Baseline PET, PET/CT scan or gallium scan which was 
positive, and has residual PET, PET/CT or gallium positivity in sites of 
prior disease, PR will be designated if the above size criteria are met in 
terms of CT scan findings, and CRu will be designated if PET, PET/CT 
or gallium scans have returned to normal (negative), and the above size 
criteria are met in terms of CT scan findings. 
 
11.2.4 Stable disease is defined as less than a PR (see above) but is not a progressive disease 
(see below). 
 
11.2.5 Progressive disease (PD, non-responders) requires the following: 
11.2.5.1 
50% increase from nadir in the SPD of any previously identified 
abnormal node for PRs or non-responders. 
 
11.2.5.2 
Appearance of any new lesion during or at the end of therapy. 
 
11.2.6 Recurrent disease is defined as the appearance of tumor following documentation of a 
complete remission. 
 
11.2.7 Time to response is defined as time from the first dose of chemotherapy until 
documentation of first response.  
 
11.2.8 Time to progression is defined as time from initiation of chemotherapy to 
documentation of first progression.  
 
11.2.9 Response duration is defined as the time from first documentation of response to 
documentation of first progression. 
 
11.2.10 Event free survival (EFS) is defined as time from initiation of chemotherapy to 
documentation of first progression or death. 


 
12.0 
STATISTICAL CONSIDERATIONS 
12.1 
Study Design 
This will be a non-randomized, single arm, Phase II study. 
 
12.2 
Statistical Design 
A sample size of 40 evaluable patients will be sufficient to test the null hypothesis that the 
complete response (CR + CRu) rate is 0.40 against the alternative hypothesis that it is 0.60 at 
the one-sided 0.10 significance level with power of 0.87.35 It is anticipated that 44 patients 
will be enrolled to allow for a 10% drop-out rate.  
 
12.3 
Statistical Analysis Plan 
Descriptive statistics will be used to summarize the patient population with respect to 
demographic features and baseline clinical characteristics.  
 
Binomial proportions and their 95% confidence intervals will be used to describe the 
complete response (CR + CRu) rate and the overall response rate. The Kaplan-Meier method 
will be used to describe the duration of response, EFS and overall survival time. Binomial 
proportions will be used to estimate the proportion of patients who experience bacterial, 
fungal or opportunistic infections. 
 
Fisher’s exact rate will be used to evaluate the relationship between mdr-1 expression and 
BCL-2 expression with response. The Cox proportional hazards model will be used to 
evaluate the relationship between response and survival. The Wilcoxon rank sum test will be 
used to compare patients who develop a bacterial, fungal and/or opportunistic infection with 
those who do not with respect to baseline CD4 lymphocyte count, HIV-1 RNA level, 
quantitative immunoglobulin levels or changes in quantitative immunoglobulin levels. 
 
To evaluate the role of PET scanning in predicting disease response, exploratory analyses 
will be done to evaluate the concordance between CT and PET for those patients and 
evaluations when both imaging modalities are used. Observations within a patient at different 
timepoints will be considered independent events for the purposes of the exploratory 
analyses. McNemar’s chi-square test will be used to compare the two modalities with respect 
to whether or not response criteria have been met by each modality. 
 
Causes of death for those patients who died will be summarized using a frequency table. 
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13.0 
PATIENT CONSENT AND ETHICAL CONSIDERATIONS 
All institutional and Federal regulations concerning informed consent will be fulfilled. A 
patient consent form will be used for this study, and must be approved by the IRB. 
 
13.1 
Institutional Review Board 
This study must have the approval of a properly constituted Hospital Ethics Committee, 
Regional Ethics Committee or other IRB. 
 
AEs must also be reported to the IRB by the investigator. 
 
13.2 
Informed Consent 
The principles of informed consent described in Food and Drug Administration (FDA) 
regulations (21 CFR part 50) must be followed. IRB approval of the protocol and the 
informed consent form must be given in writing. 
 
The AMC Operations Center must receive a copy of the letter of approval from the IRB, 
which specifically approves the protocol and informed consent, before patient enrollment. 
The IRB must also approve any significant changes to the protocol and documentation of this 
approval must be sent to the sponsor. Records of all study review and approval documents 
must be kept on file by the investigator and are subject to FDA inspection during or after 
completing of the study. Adverse events must be reported to the IRB. The IRB should receive 
notification of completion of the study. The investigator will maintain an accurate and 
complete record of all submissions made to the IRB, including a list of all reports and 
documents submitted. 
 
13.3 
Women and Minorities 
This is a study being conducted by the NCI-sponsored AMC. Each participating site within 
the AMC and the AMC as a whole are required to assure that the participation of women and 
minority subjects reflects the percentage representation of these populations in their 
geographic region and, for the AMC, the United States as a whole. As such, it is expected 
that the representation of subjects on this trial will reflect the constitution of the respective 
populations. 
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14.0 
REFERENCES 
 
1. Besson, C; Gouybar, A; Gabarre, J et al:  Changes in AIDS related lymphoma since the 
era of highly active antiretroviral therapy.  Blood 2001; 98; 2339-2344. 
2. Antinori, A; Cingolani, A; Alba, L et al:  Better response to chemotherapy and prolonged 
survival in AIDS related lymphomas responding to highly active antiretroviral 
therapy.  AIDS 2001: 15: 1483-91. 
3. Hoffmann, C; Wolf, E; Fatkenheuer, G et al:  Response to highly active anti-retroviral  
therapy strongly predicts outcome in patients with AIDS related lymphoma.  AIDS 
2003; 17: 1521-29. 
4. Palella, FJ; Delaney, KM; Moorman, AC et al:  Declining morbidity and mortality among 
patients with advanced human immunodefieicncy virus infection.  N Engl J Med 
1998: 338: 653-60. 
5. Lim, ST; Karim, R; Nathwani, GN; Tulpule, A; Espina,B; Levine, AM:  AIDS related 
Burkitt’s lymphoma versus diffuse large cell lymphoma in the pre-HAART and 
HAART eras:  Significant differences in survival with standard chemotherapy.  J Clin 
Oncol 2005: 23: 4430-4438. 
6. Mocroft, A; Ledergerber, B; Katlama, B et al:  Decline in the AIDS and death rates in the 
EuroSIDA study:  an observational study.  Lancet 2003: 362: 22-29. 
7. Little, RF; Pittaluga, S; Grant, N et al:  Highly effective treatment of acquired 
immunodeficiency syndrome-related lymphoma with dose adjusted EPOCH:  impact 
of antiretroviral therapy suspension and tumor biology.  Blood 2003; 101: 4653-4659. 
8. Ueda, K; Coswell, MM; Gottesman, MM et al:  The mdr1 gene, responsible for 
multidrug-resistance, codes for p-glycoprotein.  Biochem Biophys Res Commun 
1986; 141: 956-62. 
9. Pastan,I; Gottesman,MM:  Multidrug resistance.  Annu Rev Med 1991; 42: 277. 
10. Hamada, H; Tsuruo, T:  Purification of the 170 to 180 kilodalton membrane glycoprotein 
associated with multidrug resistance.  J Biol Chem 1997; 263: 1454-8. 
11. Yuen, AR; Sikic, BI:  Multidrug resistance in lymphoma.  J Clin Oncol 1994; 12: 2453-9. 
12. Miller, TP; Grogan, TM; Dalton, WS et al:  P=glycoprotein expression in malignant 
lymphoma and reversal of clinical drug resistance with chemotherapy plus high dose 
verapamil.  J Clin Oncol 1991; 9: 17-24. 
13. Tulpule, A; Sherrod, A; Dharmapala, D et al:  Multidrug resistance (MDR-1) expression 
in AIDS related lymphomas.  Leukemia Research 2002: 26: 121-127. 
14. Lee, CG; Gottesman, MM; Cardarelli, CO et al:  HIV-1 protease inhibitors are substrates 
for the MDR-1 multidrug transporter.  Biochemistry 1998: 37: 3596-601. 
15. Kim, RB; Fromm, MF; Wandel, C et al:  The drug transporter P-glycoprotein limits oral 
absorption and brain entry of HIV-1 protease inhibitors.  J Clin Invest 1998: 1091: 
289-294. 
 
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16. McKelvey, EM; Gottlieb, JA; Wilson, HE et al: Hydroxyldaunomycin (Adriamycin) 
combination chemotherapy in malignant lymphoma.  Cancer 1976.  38: 1484. 
17. Coiffier, B; Lepage, E; Briere, J et al:  CHOP chemotherapy plus Rituximab compared 
with CHOP alone in elderly patients with diffuse large B cell lymphoma.  N Engl J 
Med 2002: 346: 235-42. 
18. Spina, M; Jaeger, U; Sparano, JA et al:  Rituximab plus infusional cyclophosphamide, 
doxorubicin and etoposide in HIV associated non-Hodgkin lymphoma:  pooled 
results from 3 phase 2 trials.  Blood 2005; 105: 1891-97. 
19. Kaplan, LD; Lee, JY; Ambinder, RF et al:  Rituximab does not improve clinical outcome 
in a randomized phase 3 trial of CHOP with or without Rituximab in patients with 
HIV associated non-Hodgkin’s lymphoma:  AIDS Malignancies Consortium Trial 
010.  Blood 2005; 106: 1538-1543.   
20. Sparano, JA; Wiernik, PH; Hu, X et al:  Pilot trial of infusional cyclophosphamide, 
doxorubicin and etoposide plus didanosine and filgrastin in patients with human 
iommunodeficiency virus associated non-Hodgkin’s lymphoma.  J Clin Oncol 1996; 
14: 3026-35. 
21. Borg, C; Ray-Coquard, I; Philip, I et al:  CD4 lymphopenia as a risk factor for febrile 
neutropenia and early death after cytotoxic chemotherapy in adult patients with 
cancer.  Cancer 2004; 101: 2675-80. 
22. Sparano, J:  Personal communication.  AMC protocol #034:  EPOCH with concomitant 
versus sequential rituximab in newly diagnosed patients with AIDS lymphoma. 
23. Rahman, A; Husain, SR; Siddiqui, J et al: Liposome mediated modulation of multi-drug 
resistance in human HL-60 leukemia cells.  JCNI 1992; 84: 1909-1915. 
24. Thierry, AR; Vige, D; Coughlin, SS et al:  Modulation of doxorubicin resistance in multi-
drug resistant cells by liposomes  FASEB J 1993; 7: 572-579. 
25. Levine, AM; Tulpule, A; Espina, B et al:  Liposome-encapsulated doxorubicin in 
combination with standard agents (cyclophosphamide, vincristine, prednisone) in 
patients with newly diagnosed AIDS related non-Hodgkin’s lymphoma:  Results of 
therapy and correlates of response.  J Clin Oncol 2004: 22: 2662-2670. 
26. Zaja F, Tomadini V and Zaccaria A et al. CHOP-rituximab with pegylated liposomal 
doxorubicin for the treatment of elderly patients with diffuse large B-cell lymphoma. 
Leuk Lymphoma. 2006 Oct;47(10):2174-80. 
27. Visani et al. Cyclophosphamide, pegylated liposomal doxorubicin, vincristine and 
prednisone (CDOP) plus rituximab is effective and well tolerated in poor 
performancestatus elderly patients with non-Hodgkin's lymphoma. Leuk Lymphoma. 
2005 Mar;46(3):477-9. 
28. Tsavaris N et al. Pegylated liposomal doxorubicin in the CHOP regimen for older 
patients with aggressive (stages III/IV) non-Hodgkin's lymphoma. Anticancer Res. 
2002 May-Jun;22(3):1845-8. 
29. Martino et al. Cyclophosphamide, pegylated liposomal doxorubicin (Caelyx), vincristine 
and prednisone (CCOP) in elderly patients with diffuse large B-cell lymphoma: 
results from a prospective phase II study. Haematologica. 2002 Aug;87(8):822-7. 
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30. Cheson, BD; Pfistner, B; Juweid, ME et al:  Revised response criteria for malignant 
lymphomas.  From the Members of the International Harmonization Project of the 
Competence Newwork Malignant Lymphoma.  Blood 2005; 106; 10a (abstract # 18). 
31. Cheson, BD et al.  J Clin Oncol 1999; 17: 1244. 
32. Mournier, N; Briere, J; Gisselbrecht, C et al:  Rituximab plus CHOP (R-CHOP) 
overcomes bcl-2 associated resistance to chemotherapy in elderly patients with 
diffuse large B cell lymphoma.  J Clin Oncol 2003: 101: 4279-84. 
33. Zucca, E; Bertoni, F; Bosshard, G et al:  Clinical significance of bcl-2 (MBR)/JH 
rearrangement in the peripheral blood of patients with diffuse large B cell 
lymphomas.  Ann Oncol 1996: 7: 1023-27. 
34. Ratner, L; Lee, J; Tang, S et al:  Chemotherapy for HIV associated non-Hodgkin’s 
lymphoma in combination with highly active antiretroviral therapy.  J Clin Oncol 
2001; 19: 2171-78. 
35. Chernick, M.R., Liu, C. Y. The saw-toothed behavior of power versus sample size and 
software solutions: single binomial proportion using exact methods. The American 
Statistician 2002; 56; 149-155. 
36. Lawless, J. Statistical Models and Methods for Lifetime Data, John Wiley and Sons, 
1982. 


 
APPENDIX I: SCHEDULE OF ASSESSMENTS 
 
 
Eligibility/ 
Screening1 
Prior 
to 
Cycle 
1 
Prior 
to 
Cycle 
2 
After 
Cycle 
2 
Prior 
to 
Cycle 
3 
Prior 
to 
Cycle 
4 
After 
Cycle 
4 
Prior 
to 
Cycle 
5 
Prior 
to 
Cycle 
6 
After 
Cycle 
6 
1 Month 
After 
Completion 
of all 
Therapy 
Every 2 
Months for 
1 Year 
After 
Treatment 
Completion
Every 6 
Months 
Thereafte
r for 2 
Additiona
l Years 
Treatment 
Discontinua
t-ion9,12 
 
Clinical Studies: 
  
Informed Consent 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
Lymphoma 
Documentation 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
HIV Documentation 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
Medical History 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Complete Physical Exam 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medication 
Review 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
 
Laboratory Studies: 
 
CBC with differential 
and platelets 
X2 
X 
X 
  
X 
X 
  
X 
X 
  
  
X 
X 
X 
Serum Chemistries 
X2 
X 
X 
  
X 
X 
  
X 
X 
  
  
X7 
 X 
X 
HIV-1 RNA Viral load 
(local lab) 
X 
  
  
X 
  
  
X 
  
  
X 
  
X 
X 
X 
HIV T-cell subsets 
(CD4, CD8) 
X 
  
  
X 
  
  
X 
  
  
X 
  
X 
X 
X 
Quantitative 
Immunoglobulins (IgG, 
IgA, IgM) 
X 
  
  
X 
  
  
X 
  
  
X 
  
X 
X 
X 
Serum pregnancy test 
X3 
X3 
  
  
  
  
  
  
  
  
  
  
  
  
ACSR Donation 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
Hepatitis B (HbSAg, 
HbSAb) and Hepatitis C 
(HCV antibody) 
X 
  
  
X  
  
  
X  
  
  
X  
  
X  
  
X  
MDR-1 determination 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
 
Staging Evaluation: 
 
 
ECG 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
CT or MRI scan: chest, 
abdomen, and pelvis 
X 
  
  
X 
  
  
X 
  
  
X 
X 
X8 
X 
 
 
X 
PET scan, PET/CT, or 
Gallium scan10 
X 
  
  
X 
  
  
X 
  
  
X 
X 
  
  
  
MUGA Scan or 
Echocardiogram 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
Bone Marrow 
X4 
  
  
  
  
  
X6 
  
  
X6 
X6 
  
  
  
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Eligibility/ 
Screening1 
Prior 
to 
Cycle 
1 
Prior 
to 
Cycle 
2 
After 
Cycle 
2 
Prior 
to 
Cycle 
3 
Prior 
to 
Cycle 
4 
After 
Cycle 
4 
Prior 
to 
Cycle 
5 
Prior 
to 
Cycle 
6 
After 
Cycle 
6 
1 Month 
After 
Completion 
of all 
Therapy 
Every 2 
Months for 
1 Year 
After 
Treatment 
Completion
Every 6 
Months 
Thereafte
r for 2 
Additiona
Treatment 
Discontinua
t-ion9,12 
l Years 
Lumbar puncture11 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
Central Pathology 
Review 
X5 
  
  
  
  
  
  
  
  
  
  
  
  
  
1 To be obtained within 4 weeks prior to patient registration, unless otherwise specified 
2 To be obtained within 2 weeks prior to patient registration 
3 To be obtained within 72 hours prior to patient registration and again within 72 hours prior to cycle #1 chemotherapy 
4 To be obtained within 6 weeks prior to patient registration 
5 To be submitted within 30 days of study enrollment 
6 Perform test if marrow was involved prior to treatment 
7 To be performed at month 6 and 12 following treatment and every six months for years 2 and 3 
8 Recommended every 6 months for the 1st year and every six months for years 2 and 3 
9 To be performed within 4 weeks after a subject has demonstrated clinical progression of disease. These tests do not need to be repeated if they were performed 
within 7 days prior to documentation of disease progression. 
10 If allowed by patients insurance company 
11 Intrathecal chemotherapy may be injected at the time of initial staging lumbar puncture. 
12 Tests are not required in participants who attain PR after 6 cycles or SD after 4 cycles once an alternative anti-cancer therapy is begun or disease progression 
has been documented. Patients will be followed for vital status only. 
 
 
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APPENDIX II: PERFORMANCE STATUS SCALE 
 
Karnofsky Performance Scale 
ECOG Performance Status Scale 
Percent 
Description 
Grade 
Description 
100 
Normal, no complaints, no evidence of 
disease. 
90 
Able to carry on normal activity; minor 
signs or symptoms of disease. 
0 
Normal activity.  Fully active, able to carry 
on all pre-disease performance without 
restriction. 
80 
Normal activity with effort; some signs or 
symptoms of disease. 
70 
Cares for self, unable to carry on normal 
activity or to do active work. 
1 
Symptoms, but ambulatory.  Restricted in 
physically strenuous activity, but 
ambulatory and able to carry out work of a 
light or sedentary nature (e.g., light 
housework, office work). 
60 
Requires occasional assistance, but is able 
to care for most of his/her needs. 
50 
Requires considerable assistance and 
frequent medical care. 
2 
In bed <50% of the time.  Ambulatory and 
capable of all self-care, but unable to carry 
out any work activities.  Up and about more 
than 50% of waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
3 
In bed >50% of the time.  Capable of only 
limited self-care, confined to bed or chair 
more than 50% of waking hours. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes progressing 
rapidly. 
4 
100% bedridden.  Completely disabled.  
Cannot carry on any self-care.  Totally 
confined to bed or chair. 
0 
Dead. 
5 
Dead. 
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APPENDIX III: COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS 
(CTCAE) 
 
CTCAE version 3.0 and 4.0 may be downloaded from the NCI CTEP website at: 
http://ctep.cancer.gov/reporting/ctc.html. 
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APPENDIX IV: MODEL INFORMED CONSENT 
 
A Phase II Trial of Doxil, Rituximab, Cyclophosphamide, Vincristine, and  
Prednisone (DR-COP) in Patients with Newly Diagnosed AIDS-Associated B-Cell  
Non-Hodgkin’s Lymphoma 
 
You are being invited to participate in a clinical research study. In order to decide whether you wish 
to be part of this research study, you should understand enough about the possible risks and benefits 
to make an informed decision. This process is known as informed consent. This form summarizes the 
specific information for this study. Your doctor will discuss the details of this study with you. Please 
ask the study doctor or the study staff to explain any words or information that you do not clearly 
understand. You may take an unsigned copy of this consent form home with you, to think about or to 
discuss with family or friends before making your decision. You should be satisfied that all your 
questions are answered before signing this consent form. You will be given a copy of this consent 
form to keep as a record. 
 
WHY IS THIS STUDY BEING DONE?  
 
You are being asked to take part in this research study because you have been diagnosed with non-
Hodgkin’s lymphoma (NHL), a cancer that begins in the lymph glands of the body, and then may spread 
to other areas of the body. Your lymphoma is related to your human immunodeficiency virus (HIV) 
infection.  
 
The current standard treatment for NHL involves drugs called cyclophosphamide, doxorubicin, 
vincristine, prednisone, and rituximab used in a regimen called “R-CHOP.” Using R-CHOP therapy, 
complete disappearance of disease is expected in over 50% of people. As part of this study, one of 
the active drugs in the R-CHOP regimen, doxorubicin, has been placed in a fatty bubble called a 
“liposome”. The reason for placing the drug in the liposome is that there is evidence that the 
liposome is taken up better by the NHL cells, when compared to doxorubicin when it is given 
without the liposome. Liposomal doxorubicin (doxorubicin inside the liposome, also called Doxil) 
has shown similar or better anti-tumor activity against certain cancers, and has also been shown to 
have fewer side effects in some cancer patients. 
 
 
Liposomal doxorubicin is Food and Drug Administration (FDA) approved for ovarian cancer and 
also for patients with an acquired immune deficiency syndrome (AIDS)-related cancer called 
Kaposi’s sarcoma. However, its use in NHL is still investigational. We hope that using liposomal 
doxorubicin (Doxil, the study drug) instead of doxorubicin in the R-CHOP regimen will be better 
at shrinking your tumor, and that you will have reduced side effects. 
 
 
Rituximab is a drug (called a “monoclonal antibody”), which works against certain types of 
lymphoma. Rituximab has been approved by the FDA for use in patients with NHL. Results from a 
recent study in individuals with lymphoma, but without HIV infection, suggested that chemotherapy 
given with rituximab was better than chemotherapy given alone, leading to better increased response 
rates and better increased overall survival. 
 
The purpose of the current study is to see how well liposomal doxorubicin (Doxil) and rituximab 
work in combination with cyclophosphamide, vincristine, and prednisone (DR-COP) in shrinking 
tumors in patients with AIDS-related NHL. The combination of liposomal doxorubicin and rituximab 
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with cyclophosphamide, vincristine, and prednisone (all part of the standard R-CHOP treatment, in 
which only the doxorubicin is given in the liposome) is an experimental treatment, called “DR-COP”. 
 
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY? 
 
Approximately 40 people will take part in this study, nationwide. All people will receive the same 
chemotherapy treatment, DR-COP. 
 
WHAT IS INVOLVED IN THE STUDY? 
 
If you agree to participate and join in this study, the following will occur: 
 
1. Screening Visit 
 
You will need to have the following exams, tests, or procedures done to find out if you are 
eligible and can participate in the study. These exams, tests, or procedures are part of regular 
medical care for your lymphoma and may be done, even if you do not wish to join the study. 
 
 Medical history and complete physical examination. 
◦ Vital signs (blood pressure, heart rate, breathing rate, and temperature) and height/weight will 
be measured. 
◦ Questions to see how much your lymphoma affects your daily life (called performance status 
evaluation). 
◦ Questions to see what medical problems or symptoms you may be having. 
 
 Routine tests on your blood. 
◦ Blood (approximately 1 tablespoon) will be taken and will be used to check your blood cell 
numbers and blood chemicals that tell us how well your liver and kidneys are working, CD4 
and CD8 numbers (the blood cells that are affected by HIV), and the amount of HIV in your 
blood (“viral load”). 
◦ Blood (approximately 2 teaspoons) will also be taken for tests for hepatitis C virus and 
hepatitis B virus. 
◦ A blood test (approximately 1 teaspoon) will be taken to determine if you are pregnant. This 
pregnancy test will be done if you are female, still having periods, and can become pregnant. 
 
 Tests to measure where the lymphoma is in your body, and how big the lymphoma tumors may 
be: 
◦ CT scans (computed tomography, x-ray pictures of the inside of your body using a computer), 
and/or MRI scans (magnetic resonance imaging; pictures of the body which are made using 
magnetic rather than x-ray energy). 
◦ Gallium scan, PET/CT or PET scan (Positron Emission Tomography scan), which measure 
the lymphoma in your body using a small amount of radioactive material. Results of PET 
scanning will be used for research purposes only to determine how well this procedure can 
measure your response to therapy. All PET, PET/CT or gallium scans will be billed to your 
insurance company while you are taking part in this research study. If your insurance company 
does not agree to pay for these scans, you will not be excluded from other procedures included 
in the trial. All PET, PET/CT or gallium scans are optional. 
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◦ Bone marrow biopsy and aspiration (the removal of some cells from the inside of your pelvis 
bone, which is the factory where the cells in the blood are made) so that the doctors can look 
under the microscope to see if there is any lymphoma in the bone marrow. If there is 
lymphoma in your bone marrow when you start the study this test may be repeated again 
during the study to see if the treatment is working. 
◦ Lumbar puncture (the removal of a small sample – about a teaspoon -of the fluid that 
surrounds your spinal cord and brain) to look for lymphoma cells. 
 
The CT, MRI, Gallium, PET, PET/CT, lumbar puncture, and bone marrow biopsy tests will be 
more carefully explained to you by your doctor. You will be asked by your study doctor to sign a 
separate consent form for each of these tests. 
 
 
Tests to measure how well your heart is working. 
◦ 
Electrocardiogram (ECG or EKG– a painless test of how your heart is working). 
◦ 
MUGA (Multi Gated Acquisition) scan. A small amount of a short-lived radioactive 
material is injected into your vein to check the pumping action of your heart. You may be 
asked to sign a separate consent form for this. 
◦ 
Echocardiogram (ECHO) may also be done, instead of the MUGA scan. This is an 
ultrasound of the heart, which uses sound waves to check the pumping action of the heart). 
 
At the screening visit, you will also be asked if you would donate blood or lymphoma tissue to 
the AIDS and Cancer Specimen Bank. You will be given a separate consent form to sign if you 
choose to donate. 
 
2. Study Visits 
 
If the exams, tests, and procedures show that you can be in the study, and you choose to be a part 
of the study, the study treatment will begin. 
 
You will get chemotherapy with five drugs: liposomal doxorubicin (Doxil, the study drug), 
rituximab, cyclophosphamide, vincristine, and prednisone. Each course of treatment is called a 
cycle.  Each cycle of therapy will be repeated every 21 to 28 days for a maximum of 8 cycles.  
The specific chemotherapy drugs will be given in the following way:  
liposomal doxorubicin 
(doxil): 
- will be given by vein (IV) over approximately 2 hours on Day 1 of each cycle 
cyclophosphamide: 
- will be given IV over approximately 1 hour on Day 1 of each cycle 
vincristine: 
- will be given IV over approximately 1 or 2 minutes on Day 1 of each cycle 
prednisone: 
- will be given by mouth as pills, taken in the morning on Days 1 through 5 of 
each cycle 
rituximab: 
- will be given by IV over approximately 5-7 hours on Day 1 of each cycle 
 
For each cycle, you will get the drugs at the clinic or outpatient center.  The treatment will 
probably take all day, since the drugs must be given in order, one after the other. If you are sick 
due to the lymphoma, it is possible that the chemotherapy drugs will be given while you are in 
the hospital.  It is unlikely that you would be admitted to the hospital for the only purpose of 
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getting the chemotherapy, but this may occur if you have any problems or side effects from the 
chemotherapy. 
 
 
Before each cycle of treatment, you will: 
 
 
Have a complete physical examination. 
◦ Vital signs (blood pressure, heart rate, breathing rate, and temperature) and height/weight will 
be measured. 
◦ Questions to see how much your disease affects your daily life (performance status 
evaluation). 
 
Have routine blood laboratory tests (approximately 1 tablespoon) to check your blood cell 
numbers and blood chemicals. 
 
Be asked about any side effects you may be having and any medical illnesses or symptoms that 
you may have had since your last visit. 
 
After every 2 cycles, you will also have: 
 
Blood tests related to your HIV (viral load, CD4 and CD8 cells). 
 
CT or MRI scans. 
 
Gallium, PET, or PET/CT scans (optional). 
 
Repeat of any of the tests done for the screening visit that showed lymphoma. 
 
After cycle 4, you will also have: 
 
A bone marrow biopsy if your first biopsy showed lymphoma cells 
 
3. End of Treatment Visit 
 
The total length of time for treatment on this study is approximately 5 ½ to 7 ½ months.  One 
month after your last chemotherapy, you will have the following tests to check how much 
lymphoma, if any, you have: 
 
CT or MRI scans. 
 
Gallium, PET, or PET/CT scans (optional). 
 
A bone marrow biopsy if your first biopsy showed lymphoma cells. 
 
Repeat of any of the tests done for the screening visit that showed lymphoma. 
 
4. Follow-up Visits 
 
You will be asked to come back to the clinic for follow-up visits. For the first year after the end 
of chemotherapy, you will have tests, exams, and procedures to check your cancer every 2 
months. After one year, you will be asked to return every 6 months for a total of 3 years 
following the end of your chemotherapy. At these visits the following will be done: 
 
Complete physical examination, including: 
◦ 
Vital signs (blood pressure, heart rate, breathing rate, and temperature) and height/weight 
will be measured. 
 
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◦ 
Questions to see how much your disease affects your daily life (performance status 
evaluation). 
 
Assessment of any side effects you may be having, or any medical illnesses or symptoms that 
you may have had since your last visit. 
 
Routine laboratory blood testing to check your blood cell numbers, blood chemicals that tell us 
how well your liver and kidneys are working, CD4 and CD8 numbers (the blood cells that are 
affected by HIV), and HIV level. 
 
Tests to measure your lymphoma (every 6 months, even in the first year, for a total of 3 years 
from the end of your chemotherapy). 
◦ 
CT scans and/or MRI 
◦ 
Gallium scan, PET/CT or PET scans (optional) 
 
5. Other Medications You May Need 
 
You must take antiretroviral therapy (called HAART) in order to treat your HIV infection during 
the chemotherapy. However, you must not take HAART medicine containing zidovudine, such as 
Combivir® or Trizivir®. Your study doctor will discuss this with you. 
 
You must receive prophylaxis (preventive treatment) for Pneumocystis carinii pneumonia (PCP), 
a common pneumonia in persons with immune deficiency). 
 
You may get chemotherapy given directly into the central nervous system (CNS) as a preventive 
treatment. The drugs would be injected into the fluid surrounding the brain and spinal cord 
(called intrathecal chemotherapy). This is done to kill small numbers of cancer cells that may be 
in the brain and spinal cord, even though the numbers are so small that no cancer has actually 
been detected there.  Your doctor will talk with you about whether or not you will need this 
preventive therapy given into the spinal fluid.  
 
You must be given medicines to help increase your white blood cell number. Your doctor will 
discuss the specific treatments with you, which consist of injections given under the skin 
(subcutaneous) in an attempt to prevent the lowering of white blood cells, which commonly 
occurs with chemotherapy. If necessary, you may also be given medicines by injection under the 
skin to help increase your red blood cell number. 
 
You may also be given antibiotics to help prevent infections, especially if your white blood cell 
number is low. 
 
When chemotherapy is started you may be treated with the drug allopurinol to prevent “tumor 
lysis syndrome”. This syndrome may happen when the chemotherapy drugs kill lymphoma cells 
very quickly and cause them to release certain chemicals into the bloodstream, which may cause 
problems with the kidney.  Allopurinol helps to reduce these chemical levels. 
 
WHAT ARE THE POSSIBLE RISKS AND DISCOMFORTS? 
 
While on study, you are at risk for the following side effects that you should discuss with the study 
doctor and/or your regular doctor. Other side effects that are less serious and uncomfortable may also 
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occur. Many side effects go away shortly after the chemotherapy is stopped, but in some cases side 
effects can be serious or long lasting or permanent. 
 
1. Liposomal Doxorubicin 
 
Common side effects are: 
 
Decreased white blood cell counts in the blood, which may increase the risk of fever and 
infection. 
 
Decreased red blood cells (anemia) which may increase the risk of tiredness, fatigue and 
shortness of breath. 
 
Decreased platelets (cells which help blood clotting) which may increase the risk of 
bleeding and/or bruising. 
 
Nausea (upset stomach) 
 
Vomiting 
 
Hair loss (alopecia), or brittle hair 
 
Fever 
 
Diarrhea 
 
Constipation 
 
Belly pain 
 
Weakness 
 
Mucositis (painful sores in your mouth, 
intestines and/or anus) 
 
Skin rash, redness, peeling of the hands and 
feet 
 
Headache 
 
 
Less common: 
 
Acute infusion-related reaction, which may happen during the first drug infusion. Signs of 
this are flushing, shortness of breath, facial swelling, headache, chills, back pain, tightness 
in the chest or throat and a drop in blood pressure. 
 
Rarely: 
 
There have been rare reports of death in patients who develop a body-wide infection as a 
result of decreased white blood cell number. 
 
There has been a report of heart failure and damage and death caused by liposomal 
doxorubicin. 
 
It is possible that liposomal doxorubicin may leak from your blood vessel and damage the 
nearby tissue. Signs of this are a burning sensation and swelling. 
 
Very severe skin reactions have been reported, consisting of redness, swelling, ulcers (skin 
breakdown) and/or pain of the skin, requiring immediate medical attention. Severe reactions 
in the mouth and other mucus membranes, with swelling, ulcerations and pain may occur 
(Stevens-Johnson syndrome), as well as painful rashes and ulcers on the skin (called 
erythema multiforme, or toxic epidermal necrolysis). 
 
2. Cyclophosphamide 
 
Just like liposomal doxorubicin, cyclophosphamide commonly causes belly pain, upset stomach, 
vomiting, diarrhea, hair loss, redness swelling and sores in the mouth, skin rash, and a drop in the 
numbers of white blood cells, red blood cells, and platelets. 
 
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Cyclophosphamide also causes: 
 
Loss of appetite (anorexia) 
 
Kidney problems 
 
Irritation of the large intestine with 
bloody stools 
 
Lung problems 
 
Irritation of the bladder and/or ducts 
connecting it with the kidneys (ureters) with 
bloody urine 
 
Yellow color of the skin and eyes 
(jaundice) 
 
 
Darkening of the skin and nails 
 
 
Heart damage; the combination of cyclophosphamide and liposomal doxorubicin may make 
this more likely or more severe 
 
Infertility in both men and women; if you are a woman of child bearing age your menstrual 
periods may stop either temporarily or permanently. 
 Some people who have received cyclophosphamide developed other cancers of the urinary 
tract or bone marrow (like myelodysplasia or leukemia). This may happen years after the 
treatment has stopped. 
 
3. Vincristine 
 
In common with liposomal doxorubicin and/or cyclophosphamide, vincristine can cause nausea, 
vomiting, constipation, diarrhea, fever, headache, weakness and hair loss. Vincristine may also 
cause: 
 
Numbness and tingling in hands and feet 
 
Nerve pain 
 
Difficulty walking 
 
Loss of normal reflexes 
 
Muscle wasting 
 
Difficulty with balance 
 
Jaw pain 
 
Changes in taste sensation 
 
Decreased bladder control 
 
Change in the ability to see colors 
 
High or low blood pressure 
 
Hearing loss, ringing in the ears 
 
Paralyzed bowel, which results in severe constipation. 
 
Rare allergic reaction (swelling of the face and breathing tube, rash, chills, drop in blood 
pressure, dizziness). 
 
4. Prednisone 
 
Difficulty sleeping 
 
Irritability, nervousness 
 
Slow healing sores 
 
Electrolyte imbalance (abnormal amounts of 
various chemicals in your blood. 
 
Weight gain (especially in the face, 
shoulders and belly) 
 Fluid retention, causing swelling of ankles or 
other areas 
 
Dizziness 
 Headache 
 Development of freckles on the skin 
 Increased risk of infections 
 Changes in personality 
 Feeling of extreme wellbeing 
 
Mood swings 
 Seizures 
 
Severe mental disorder, craziness 
 Brittle bones 
 
Spinal fractures 
 Thin fragile skin 
 
Tendon rupture 
 Increase in blood pressure 
 
Clouding of the eyes (cataracts) 
 Increased eye pressure (glaucoma) 
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 
Inflammation of the pancreas (a small gland that secretes substances such as insulin) 
 
If you are a diabetic, you may need to adjust (increase) the amount of insulin or diabetes pills 
you need to take. 
 
Decreased ability to tolerate carbohydrates (sugars and starches) and development of 
diabetes 
 
Rare: 
 
 
Heart attack 
 
Stroke 
 
Blood vessel disease and other cardiac (heart) abnormalities. 
 Allergic reaction (rash, itching, swelling, severe dizziness, trouble breathing), which could be 
severe and life-threatening 
 
5. Rituximab 
 
Some side effects occur in most individuals treated with rituximab. However, severe side effects 
occur in only 10-20% of people, and usually occur during the actual rituximab infusion (called 
infusion reaction complex). 
 
Common side effects (these effects occur in more than 9% of people taking rituximab): 
 
Fever, chills 
 
Nausea (upset stomach) 
 
Headache 
 
Weakness 
 
Low blood pressure 
 
Angioedema (itchy rash and swelling of areas 
of the skin and mucous membranes, much 
like a serious allergic reaction) 
 
Less common (these effects occur in 3 – 9% of people taking rituximab): 
 
Bronchospasm, which is an abnormal 
narrowing of the windpipe, which can 
cause coughing and wheezing, and 
difficulty in breathing. 
 
Belly (abdominal) pain 
 
Achy joints and muscles 
 
Vomiting 
 
Dizziness 
 Anemia (shortness of breath, weakness 
and fatigue) 
 Congestion  
 
Rare (these effects occur in less than 3% of subjects taking rituximab):  
 
Weakening of certain parts of your immune system, resulting in a greater risk of infections. 
 
Life-threatening skin rashes (mucocutaneous reactions) that could occur many months after 
the end of the chemotherapy treatment. These reactions could occur on the skin, causing 
itching, and swelling, or in the mouth or other mucous membranes (such as the lining of the 
stomach, intestines and mouth), and could be very serious, leading to inability to eat or drink, 
the need to be hospitalized, or even death. 
 
Tumor lysis syndrome (where rapid destruction of lymphoma cells may cause chemical 
abnormalities in the body) has been reported within 12-24 hours after the first rituximab 
infusion. 
 
Infusion reactions (shortness of breath, rash, fever, chills, tightness in the chest and/or low 
blood pressure during the time that the rituximab is given by vein). 
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 
Kidney failure. 
 
Death has been reported due to skin reaction, tumor lysis, infusion reaction complex, hepatitis 
B reactivation, and bowel obstruction and perforation. 
 
In patients with Waldenstrom’s macroglobulinemia, rituximab therapy may cause an 
immediate reaction in your body that may result in the plasma (water part) of the blood 
becoming so thick that it cannot pass through small blood vessels. Blood cells then cannot 
deliver oxygen to where it is needed in your body. This side effect has only been reported in 
patients with a diagnosis of Waldenstrom’s macroglobulinemia.  
 
Rituximab Treatment Risks in Combination with Chemotherapy 
 
Other events have occurred in patients receiving rituximab. The following have occurred in 
patients receiving rituximab in combination with chemotherapy: 
 
In some patients who have hepatitis B virus (HBV), rituximab has caused the infection to 
worsen by reactivating the virus. Severe and sudden hepatitis inflammation of the liver, very 
serious liver disease (including liver failure) and death can occur during, or within several 
months after rituximab treatment. HBV diagnosis in most patients has occurred approximately 
4 months after their first dose of rituximab. Seek immediate medical attention if you develop 
persistent stomach/abdominal pain, dark urine, extreme fatigue, or yellowing eyes and/or skin. 
Treatment with antiviral medication is usually given to control HBV. 
 
There is a report of an increase in fatal infections in HIV-related lymphoma patients when 
rituximab was used in combination with CHOP chemotherapy. 
 
Other viral infections, including JC virus (a virus responsible for an infection of the brain 
and spinal cord), cytomegalovirus (a member of the herpesvirus group, which also includes 
herpes simplex virus and varicella-zoster virus [virus that causes chickenpox]), parvovirus 
B19 (a virus that can decrease or halt the body's production of red blood cells), West Nile 
virus (a virus causing an inflammation to the brain), and hepatitis C have been found in 
patients who have received rituximab in combination with chemotherapy. 
 
Patients have also experienced abdominal pain, bowel obstruction (blockage) and 
perforation (tearing), in some cases leading to death, after receiving rituximab in 
combination with chemotherapy for NHL and diffuse large B-cell lymphoma (DLBCL). 
 
Rituximab Treatment Risks in Other Disease Areas 
 
Rituximab is also used in studies to treat patients with rheumatoid arthritis (RA), a disease 
characterized by inflammation of the joints. Patients with RA are at increased risk for 
cardiovascular (heart) events compared with the general population. Three cardiovascular 
deaths have occurred in RA patients treated with rituximab.  
 
Common side effects in RA studies. (These effects occurred in 2% or more of people taking 
rituximab for RA compared to patients taking placebo, an inactive substance). 
 
abdominal pain 
 
nausea (upset stomach) 
 
anxiety 
 
paresthesia (numbness, tingling of the 
skin) 
 
arthralgia (joint pain) 
 
pruritus (itching) 
 
asthenia (weakness, loss of strength) 
 
pyrexia (fever) 
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 
chills 
 
rhinitis (hayfever) 
 
dyspepsia (indigestion, upset stomach) 
 
throat irritation 
 
hypercholesterolemia 
(high 
blood 
cholesterol) 
 
upper respiratory tract infection 
 
hypertension (high blood pressure) 
 
urticaria (hives) 
 
migraine 
 
 
6. CT-Scans 
 
This research study involves being exposed to radiation from x-rays and CT scans. The amount 
of radiation you will receive from the scans is similar to that of an airline flight across the US. 
The risk from radiation exposure is too small to be measured directly, and is considered low 
when compared with other everyday risks. The study doctor will provide you with a contact 
person if you would like more information about radiation exposure. 
 
7. Drawing Blood 
 
There may be some pain, bleeding, bruising, or infection at the place where the blood tests were 
taken from the vein in your arm. There is also a possibility that you may feel faint when your 
blood is drawn. 
 
8. Lumbar puncture (spinal tap) or bone marrow biopsy/aspirate. 
 
There may be some pain and bleeding at the site of the biopsies, and infection may also occur. 
 
9. Intrathecal (IT) chemotherapy to prevent lymphoma occurring in the brain and spinal cord and 
fluid. 
 
Injection of chemotherapy into the spinal fluid may produce headache, stiff neck, or irritation of 
the lining of the brain.  
 
WHAT ABOUT PREGNANCY? 
 
If you are a woman who could become pregnant during this study, there may be risks to your unborn 
child and to you that are not now known. It is required that you practice birth control if you are 
capable of becoming pregnant during this study. If you are pregnant you may not participate in this 
study, and if you become pregnant you will be removed from the study. A blood or urine test will be 
done before you start this study to test for pregnancy. If you are a man, you and your female partner 
should use an effective method of birth control while you are participating in this study. Both men 
and women should continue to practice an effective method of birth control for at least 6 months after 
your last dose of study drug. Your study doctor will give you information on the ways in which you 
may keep from becoming pregnant.  
 
WHAT ARE THE POSSIBLE BENEFITS OF TAKING PART IN THIS STUDY? 
 
If you agree to take part in this study, there may or may not be a direct medical benefit to you. One 
benefit could be that the treatment works and makes your lymphoma get smaller, or go away 
completely. We cannot promise that you will have a good response or any benefit from being in this 
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study, but we hope the information learned from this study will benefit other patients in the future, 
even if your own lymphoma does not shrink or go away completely.  
 
WHAT OTHER OPTIONS ARE THERE? 
 
If you do not want to join the study, there are other possibilities for treatment.  You could receive 
treatment with other chemotherapy drugs, or other investigational (experimental) drugs. You can 
receive similar drugs (CHOP, using doxorubicin instead of the study drug, liposomal doxorubicin or 
Doxil) with or without rituximab without participating in this study. Another alternative is no further 
therapy. Your doctor can provide detailed information about your disease and the benefits of the 
various treatments available. You should feel free to discuss your disease and your prognosis (likely 
outcome) with the doctor. 
 
WILL YOUR INFORMATION BE KEPT PRIVATE? 
 
The Investigator and the Institutional Review Board (IRB) will keep your records private as far as the 
law allows. Officials of: 
 
The National Cancer Institute (NCI) 
 
The AIDS Malignancy Consortium Operations Center 
 
The EMMES Corporation (AMC Data Management Center) 
 
The Food and Drug Administration (FDA) 
 
The IRB may look at your research records and medical records. Unless otherwise required by 
law, your records will be kept confidential. Information collected will not identify you by name. 
A coded number called a “unique identifier” will be used. We may publish the information from 
this study in journals or present it at meetings. If we do, we will not use your name or any other 
information that could identify who you are. 
 
Medical records that identify you and the consent form you signed will be looked at and/or copied for 
research or regulatory purposes by the sponsor and may be looked at and/or copied for research or 
regulatory purposes by: 
 
FDA 
 
Department of Health and Human Services (DHHS) agencies 
 
IRB 
 
WHAT ARE THE COSTS? 
 
If you take part in this study, your insurance company may not pay for some or all of the procedures, 
treatments, and tests. If that happens, you will need to pay for these procedures, treatments, and tests 
yourself. You will not be responsible for the cost of the drug, liposomal doxorubicin (Doxil), which 
will be provided free of charge by the drug manufacturer, Ortho Biotech Clinical Affairs, LLC 
(Ortho Biotech). 
 
ARE THERE ANY PAYMENTS TO YOU FOR TAKING PART IN THE STUDY? 
 
You will not be paid for taking part in this study. 
 
WHAT HAPPENS IF YOU GET INJURED OR NEED EMERGENCY CARE? 
 
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If you get hurt or sick from taking part in the study, we will give you the medical care you need. You 
must pay for the care. You will not receive any compensation or payment if you get hurt or sick.  
 
WILL YOU RECEIVE NEW INFORMATION ABOUT THIS STUDY? 
 
During the study, we may learn new things about the risks or benefits of being in the study. If we do, 
we will share this information with you. You might change your mind about being in the study based 
on this information. If new information is provided to you, we will ask for your agreement to 
continue taking part in this study. 
 
UNDER WHAT CIRCUMSTANCES CAN YOUR PARTICIPATION BE TERMINATED 
(STOPPED)? 
 
You will be removed from the study for the following reasons: 
 
If you do not follow your doctor’s (the Investigator’s) instructions. 
 
If your disease gets worse. 
 
If you have unacceptable side effects. 
 
If you are unable to complete the necessary testing for the study. 
 
If the sponsor closes the study. 
 
If your chemotherapy treatment is delayed more than 6 weeks. 
If this happens, your doctor (the Investigator) will discuss other options with you. 
 
WHAT ARE YOUR RIGHTS AS A PARTICIPANT AND WHAT WILL HAPPEN IF YOU 
DECIDE NOT TO PARTICIPATE? 
 
Your participation in this study is voluntary. Your decision whether or not to take part will not affect 
your current or future care at this institution. You are not waiving any legal claims or rights. If you 
do decide to take part in this study, you are free to change your mind and stop being in the study at 
any time. However, if you decide to stop participating in the study, we encourage you to talk to the 
research doctor and your regular doctor first. 
 
CERTIFICATE OF CONFIDENTIALITY 
 
To help us protect your privacy, we have obtained a Certificate of Confidentiality from the National 
Institutes of Health. With this Certificate, the researchers cannot be forced to disclose information 
that may identify you, even by a court subpoena, in any federal, state, or local civil, criminal, 
administrative, legislative, or other proceedings. The researchers will use the Certificate to resist any 
demands for information that would identify you, except as explained below. 
 
The Certificate cannot be used to resist a demand for information from personnel of the United States 
Government that is used for auditing or evaluation of federally funded projects or for information 
that must be disclosed in order to meet the requirements of the Federal Food and Drug 
Administration (FDA). 
 
You should understand that a Certificate of Confidentiality does not prevent you or a member of your 
family from voluntarily releasing information about yourself or your involvement in this research. If 
an insurer, employer, or other person obtains your written consent to receive research information, 
then the researchers may not use the Certificate to withhold that information. 
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ARE THERE ANY POTENTIAL CONFLICTS OF INTEREST? 
 
The investigators of this research do not have any financial conflict of interest in the sponsor (Ortho 
Biotech) or in the product (Doxil) being studied.  
 
Your doctor is receiving financial support to pay for research staff to conduct the study. As a 
researcher, the doctor is trying to improve your health condition and conduct good research at the 
same time. You may wish to get a second opinion about your care from another doctor who is not 
involved with this study. You are free to decide not to take part in any studies you may be offered by 
your doctor. 
 
WHOM DO YOU CALL IF YOU HAVE QUESTIONS OR PROBLEMS? 
 
Your participation will be under the care of Dr. _______________ at phone_______________, 
whom you may contact with any questions or concerns regarding your participation. Any questions 
or concerns that you have about study-related injuries should be discussed with the Principal 
Investigator Dr. ______________, who can be reached at phone _____________. If you have any 
questions regarding your rights as a study subject, you may contact the Institutional Review Board 
Office at ___________________________. You will be given a copy of this form to keep. 
 
AGREEMENT:  I have read (or someone has read to me) the information provided above. I have 
been given a chance to ask questions. All my questions were answered. I have decided to sign this 
form in order to take part in this study. 
 
 
_______________________ ______________________ 
__________ 
__________ 
Name of Subject 
Signature 
 
Date Signed 
Time (if consented on  
 
 
 
 
 
 
same day as treatment) 
 
 
_______________________ _______________________ __________ 
__________ 
Name of Witness 
Signature 
 
Date Signed 
Time (if consented on  
 
 
 
 
 
 
 
 
 
 
same day as treatment) 
If applicable: 
I have verbally translated this informed consent document to the study subject. 
 
 
_______________________ _______________________ __________ 
__________ 
Name of Translator 
Signature 
 
Date Signed 
Time (if consented on  
 
 
 
 
 
 
 
 
 
 
same day as treatment) 
 
I have personally explained the research to the subject and answered all questions. I believe that 
he/she understands the information described in this informed consent and freely consents to 
participate. 
 
 
_______________________     _____________________ ________ 
__________ 
Name of Investigator/Person 
Signature 
 
Date Signed 
Time (if consented on  
Obtaining Informed Consent 
same day as treatment) 
 
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APPENDIX V: AIDS AND CANCER SPECIMEN RESOURCE (ACSR) 
 
Specimen Preparation & Shipping Instructions 
 
A. 
COLLECTION 
Consent patient for ACSR donation. Collect 20 cc of whole blood in ACD tubes. 
B. 
SHIPPING 
To ship these specimens, use a diagnostic shipper approved for a volume of at least 30 cc. 
The use of the SAF-T-PAK STP-210 diagnostic cardboard shipper (for category B 
substances) is recommended. These shippers may be ordered at the SAF-T-PAK web site, 
www.saftpak.com. The instructions below are for use with the recommended STP-210 
shipper. If using another federally approved diagnostic shipper, please follow instructions 
provided for that specific shipper. 
To ship bloods, place the tubes into canister of a STP-210 SAF-T-PAK shipper for category 
B substances, wrapping each tube in bubble wrap and using the absorbent paper at the bottom 
of the canister. Each sample tube should be labeled using a sharpie pen (permanent marker) 
with the following information: 
 
AMC Protocol # AMC-047 
 
AMC Patient ID#  
 
Date and time of collection  
 
Specimen type, i.e., WB=Whole Blood, P=Plasma, S=Serum 
 
Specimen purpose: Donation 
Place the lid on the canister and place it inside of the ambient SAF-T-PAK shipper. Fold and 
pack ACSR form inside shipping box. Seal the ambient shipper with cellophane shipping 
tape. Label the ambient shipper with the "UN 3373" diamond shaped label. On one side, in 
black marker write, your name or name of responsible person, date of collection and phone 
number of the person responsible for the package. 
B.1 
Specimen Shipment 
 
Specimens are accepted MONDAY through THURSDAY. Specimens are not 
accepted on Friday. All specimens should be shipped by overnight express (AMC 
Operations Center FedEx account 
 at room temperature to: 
 
ACSR Blood Receiving Lab 
Johns Hopkins Oncology 
1650 Orleans Street, CRB-384 
Baltimore, MD  21231-1000 
TEL: (410) 955-8721 
FAX:  (443) 287-3217 
 
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B.2 
Instructions for Specimens Collected on Friday 
 
PREPARATION OF PLASMA AND MONONUCLEAR CELLS 
It is preferable that separation occurs as soon as possible. If necessary, whole blood in 
acid citrate dextrose (yellow top tube) can be held at room temperature for no more 
than 24 hours. 
 
Materials:  
 
Lymphocyte Separation Medium (LSM Solution, Ficoll-Hypaque - sterile) 
 
15 ml conical centrifuge tubes (sterile) 
 
PBS (sterile) 
 
1, 5 ml and 10 ml serologic pipettes (sterile) 
 
NUNC tubes 
 
Alcohol-saturated, control rate freezer container 
 
DMSO freezing media: 
◦ 
50% Cryoprotective Medium, Cambrex (catalog no.:12-132A) 
◦ 
50% Heat Inactivated Fetal Bovine Serum 
 
Preparation of Plasma Samples  
a. The 7 ml tube of whole blood in acid citrate dextrose should be rotated gently 2 
or 3 times before being centrifuged. Do not transfer before centrifugation.  
b. The cells are separated by centrifugation at 500 g for 10 minutes.  
c. 0.5ml aliquots of plasma are removed and put into 1.5 ml screw top tubes and 
transferred to liquid nitrogen storage. 
 
Peripheral Blood Mononuclear Cell Separation and Freezing  
a. The cells and plasma remaining from the previous step are transferred into a 15 
ml conical tube, capped and re-suspended by gently tapping the bottom of the 
tube.  
b. Sterile PBS should be added to the suspended cells until the final volume is 8 ml; 
invert to mix.  
c. The 8 ml whole blood-PBS mixture should be carefully overlaid onto 4 ml of 
room temperature LSM or Ficoll-Hypaque solution in a sterile 15 ml conical tube. 
A sharp interface should exist between the LSM and the whole blood mixture. (If 
the layer of LSM gets mixed with the blood-PBS, the tube should be gently 
rotated to mix the blood, PBS, and LSM, and transfer to a 50 ml sterile conical 
tube. An equal volume of PBS is added, and the cells are separated at 600 g for 
15 minutes. After removal of LSM-PBS supernatant, return to Step b).  
d. The 15 ml conical tube for 30 minutes at 900 g at room temperature. The 
mononuclear leukocytes (principally lymphocytes and monocytes) will band at 
plasma/LSM interface.  
e. The fluffy white layer just below the plasma layer should be aspirated off, along 
with approximately half of the LSM layer under it, and transferred to an 
appropriately labeled 15 ml sterile conical centrifuge tube. Mix by gentle rotation.  
f. Washed twice in sterile PBS - centrifuge at 500 g for 10 minutes.  
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g. Cell pellet should be mixed well with a gentle finger-tapping action.  
h. Using a 1 ml pipette, the *DMSO freezing mixture should be added drop wise to 
the cell pellet suspension. Gently finger-tap between drops. If the cell pellet is 
small, only 0.5 ml of freezing media is added (and only one aliquot of cells is 
frozen). If the cell pellet is large, up to 4 2 ml of freezing media can be added in a 
drop wise fashion. (Cell densities of 1 - 10 million PBMC/ml are best for 
cryopreservation. If a hemocytometer is available, the optimal concentration is 5 
million PBMC/ml).  
 
* Important-Do not put the DMSO containing media on the cell button all at 
once.  
 
Freeze the cell suspension in 0.5ml aliquots in sterile NUNC vials by placing the 
NUNC tubes in a room temperature, alcohol saturated, control rate freezer container 
and store in the -80°C freezer overnight. Transfer the cell suspension into the liquid 
nitrogen temperature freezer for long-term storage the next working day.  
 
***PLEASE DOUBLE CHECK PACKAGING OF SHIPPER AND DO NOT 
DEVIATE FROM REQUESTED LABELING. ***Shipping frozen aliquots requires 
the use of packaging acceptable for dry ice and Class 9 label with weight of dry ice 
written on package. 
 
Please Note: The shipper will be mailed back to the AMC site. 
 
The STP-210 SAF-T-PAK shipper is a complete kit w/ all trappings, bubble wrap, 
absorbent paper, labels, everything (but to reuse the shipper, you will need new 
labels, wrap, etc). 
 
B.3 
Record of Specimens 
 
This study will track specimens via GlobalTraceSM, a component of the AMC 
AdvantageEDCSM system. The GlobalTrace shipment manifest must accompany all 
specimen shipments. 
 
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APPENDIX VI: INFORMED CONSENT FORM RESEARCH STUDY AIDS AND CANCER 
SPECIMEN RESOURCE (ACSR) 
 
A. INTRODUCTION 
 
You are being asked to donate tissue for research.  Before you decide to be a part of this research 
study, you need to understand the risks and benefits so that you can make an informed decision.  This 
is known as informed consent. 
 
This consent form provides information about the research study, which has been explained, to you. 
Once you understand the study and the tests it requires, you will be asked to sign this form if you 
want to take part in the study.  Your decision to take part in the study is voluntary.  This means that 
you are free to choose if you will take part in the study. 
 
B. PURPOSE 
 
The National Cancer Institute has set up a Bank for tissues and biological fluids from HIV-positive 
and HIV-negative individuals in order to have specimens available for scientists studying 
malignancies associated with HIV disease.  Individuals who have had biopsies to determine a 
malignancy are being asked for permission to store some of the tissue in the Bank.  Only tissue in 
excess of that required for decision making will be given to the Bank.  If it turns out that your 
physician needs more of your tissue for additional studies, the Bank will release all of your tissue 
back to your doctor.  No additional tissues will be taken from your body for the Bank. 
 
In addition, you are requested to donate some of your blood to the Bank so that scientists will also be 
able to look for any deviation in these body fluids that may explain the malignancy. 
 
C. PROCEDURES 
 
You are being asked for consent to place some of the biopsy material in the ACSR.  If you agree to 
allow the ACSR to have some of your tissue, we would also like to: 
 
1. Confidentially obtain some clinical information from your medical records that could be useful to 
research investigators. The report of the information retrieved from your medical record that is 
given to research investigators will not have your name, or include any information which could 
personally identify you. 
 
2. Obtain some blood for the Bank. Up to twenty (20) milliliters of blood will be obtained at your 
next visit to your physician. 
 
If during the course of treatment by your physician, it is necessary to perform any of the following 
procedures for diagnostic reasons, you will be asked, at that time, to consent to having a portion of 
that specimen sent to the Bank.  These requests will not require you to make any additional visits to 
your doctor or have any additional specimens taken just for the Bank.  The Bank will only receive 
part of your specimen, and only what is in excess.  No additional materials will be removed for the 
purposes of the Bank alone.  Samples of interest would include, (but are not limited to): 
 
1.  Spinal fluid. 
2.  Airway washes. 
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3.  Fluid around lungs and intestines. 
4.  Additional biopsy material. 
 
You will not be asked to fill out any forms for any of these specimens. 
 
D. POSSIBLE RISKS 
 
There is a possibility of a bruise and slight pain at the time the blood samples are taken.  There is also 
the possibility of fainting and infection at the site of the blood draw.   
 
E. POSSIBLE BENEFITS 
 
It may be that there will be no direct benefit to you by consenting to allow the Bank to have portions 
of your biopsies and biological fluids.  However, there may be possible benefits to medical 
knowledge and HIV-infected individuals in the future. 
 
F. COSTS 
 
There will not be any additional costs to you for consenting to participate in the AIDS and Cancer 
Specimen Resource. 
 
G. PAYMENT FOR INJURY OR HARM 
 
As the lists of risks shows, taking part in this research study may result in injury or harm to you. In 
the case of injury or illness resulting from this study, emergency medical treatment is available but 
will be provided at the usual charge. No funds have been set aside to compensate you in the event of 
injury. You or your insurance company will be charged for continuing medical care and/or 
hospitalization. (Institution) will not pay for the care. Likewise, (Institution) will not pay you for 
pain, worry, lost income, or non-medical care costs that might occur from taking part in this research 
study.
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APPENDIX VII: HANDLING OF TISSUE 
 
Handling of Tissues: 
 
A paraffin block involved by lymphoma should be submitted to the following address: 
 
Dr. Wayne Tam 
Department of Pathology 
The New York Presbyterian Hospital 
525 E. 68th Street, ST-715 
New York, NY 10021 
Tel:  (212) 746-2442  
Fax:  (212) 746-8173 
 
The submitting Pathology laboratory is also asked to submit the tissue block from involved tissues; a 
total of three 1.0 mm tissue cores from the block will be taken by the Immunopathology Laboratory 
for inclusion in a tissue microarray. The block will be returned to the submitting laboratory within 
one month of receipt. 
 
If the submitting Pathology Department does not agree to submitting the block, we will accept, 
instead, 15 blank tissue sections. 
 
Specimen Accessioning and Tracking: 
 
Upon receipt, each specimen from AMC will receive an Immunopathology Laboratory accession 
number which will be sequential with the other the specimens, including clinical specimens, 
received. This will avoid delays in processing. Specimens belonging to AMC will be so stated under 
“Clinical Information”, and therefore can be easily identified and tracked.  A report will be issued by 
Dr. Chadburn within two days of receipt, with a description and preliminary diagnosis based on the 
microscopic review of H&E-stained sections. This will be followed by “procedure” reports 
describing the results of immunohistochemistry, in situ hybridization (EBER) and molecular analysis 
(if requested or considered informative for final diagnosis), as well as a final report correlating all the 
findings. Average turn-around time for routine immunohistochemistry and in situ hybridization is 
one week. All the reports will be sent by FAX to the Operations Center as well as to the submitting 
physician, and hard copies to both will follow. All information will also be entered into the EMMES 
tissue tracking system. An individual in the laboratory will be specifically designated as data 
coordinator for the AMC. This individual will be responsible for tracking AMC specimens received, 
logging the information in the appropriate data bases, and notifying AMC of specimen status.  He/she 
will be the contact person in the laboratory for any questions AMC may have concerning the status of 
a specific specimen. 
 
Tissue Microarrays: 
 
Tissue microarrays will be constructed from formalin-fixed paraffin-embedded tissues from all the 
cases for which blocks are received. A Beecher tissue microarray instrument (Beecher instruments 
Inc., Sun Prairie, WI) will be used. Each case will be represented by three 1.0 mm tissue cores from 
neighboring areas on the same block. The test samples will be internal.  The controls will consist of a 
lymphoma of known type, Tonsil, spleen and thymus.  Once all the patients are recruited, and all the 
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specimens for the trial are received, the array blocks will be completed and sections will be made 
available to all AMC investigators.   
 
Pathology Review: 
 
Specimens received from AMC will undergo histopathologic diagnosis and classification, 
immunostaining and molecular analysis. Pathologic evaluation will be performed by  
Dr. Chadburn; all interesting, atypical and unusual cases will also be reviewed by Dr. Knowles. 
Molecular analysis will be performed in the Molecular Pathology Laboratory and reported upon by 
Dr. Cesarman.  Specifically, cases will be processed as follows: 
1. Histopathology- Process tissue, pathologist review of H&E and classification. 
2. Immunohistochemistry for lymphoid, proliferation and differentiation antigens, including as 
needed: CD20, CD3, CD79a, CD10, bcl-6. If a lymphoma has histologic features of Hodgkin's 
lymphoma, immunohistochemistry will include CD45, CD20, CD3, CD30, and CD15. For 
DLBCLs we will evaluate germinal center B cell (GC) like vs non GCB-like (BCL-6, CD10, 
MUM1, FoxP1, CD138, IRF4). 
3. Biological correlates. These will be done when the tissue arrays are completed, or using blank 
tissue sections for evaluation of cases not included in the arrays because a block was not 
received. They are as follows: 
a. BCL-2- Immunohistochemistry will be performed, and cases will be classified as positive if 
more than 50% of the tumor cells are found to have clear positivity.  BCL-2 is an anti-
apoptotic gene that had been found to be a prognostic indicator of survival in some DLBL 
cohorts. 
b. Ki67- This is an indicator of cellular proliferation, which will be included as it will provide 
the proliferation index. Cases will be divided into three categories: >90%, 60% to 90% and 
<60%. 
c. MDR-1- Expression of MDR-1 will be evaluated by immunohistochemistry for P-
glycoprotein, as this has been shown by some to be associated with a high probability of 
relapse and poor prognosis. 
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APPENDIX VIII: AMC DATA SAFETY MONITORING PLAN 
 
Monitoring the Progress of Trials and the Safety of Participants 
 
All AMC protocols follow the Cancer Therapy Evaluation Program (CTEP) guidelines for reporting 
of adverse events.  All adverse events that meet the expedited reporting requirements of the National 
Cancer Institute (NCI) are reported to the Investigational Drug Branch (IDB) of the NCI via the 
Adverse Event Expedited Reporting System (AdEERS) web application.  All expedited adverse 
event reports are also required to be submitted to the local Institutional Review Board (IRB) of the 
reporting institution.  If NCI holds the IND or no IND is required for a study, the AMC sites report 
serious adverse events directly to the AMC Operations and Data Management Center (ODMC) via 
AdEERS.  In some instances, the AMC sites may report serious adverse events directly to the 
commercial sponsor holding the IND who will then in turn report to the AMC ODMC.  However, 
most AMC protocol require that sites report all serious adverse events via AdEERS with the AMC 
ODMC forwarding a copy of the report to the sponsor.  Unless an AMC protocol specifies an 
alternate plan for the review and submission of serious adverse events, all serious adverse events 
received by the AMC ODMC will be reviewed by the AMC Medical Monitor at the AMC ODMC 
prior to submission to NCI and the sponsor.  For protocols for which the IDB does not have an 
assigned drug monitor to review serious adverse event reports, in the event of disagreement between 
the reporting physician and the AMC Medical Monitor regarding the attribution of the event to the 
investigational agent(s) (i.e., determination of whether the relationship is unrelated, unlikely, 
possible, probable, or definite), the AMC Medical Monitor will provide the final determination of the 
relationship. 
 
The AMC ODMC provides a listing of serious adverse events to the Protocol Chair and Co-chair(s) 
for review on a regular basis.  The AMC ODMC compiles these events in a tabular format and posts 
them on the password-protected section of the AMC web site.  The AMC web site is accessible to all 
AMC investigators, co-investigators, and their staff. Email notification that this information is 
available on the web site will be sent to all site PIs.  It is the responsibility of each site to provide this 
information to their respective IRBs, if required by their IRB.  For blinded studies, the serious 
adverse events are reviewed and tabulated without treatment assignment. 
 
Accrual summaries for each AMC trial are updated nightly on the password-protected section of the 
AMC web site.  The progress of each AMC trial is reviewed regularly by the Protocol Chair and also 
by the appropriate disease-oriented Working Group during scheduled conference calls.  For phase I 
dose escalation trials, dose escalation (or dose de-escalation) is based on the rules in the protocol and 
the Protocol Chair and Group Statistician determine whether these criteria have been met.  For phase 
II trials, stopping the trial for toxicity or efficacy, or suspending enrollment pending observation of 
responses in a multi-stage phase II trial, is based on meeting criteria stated in the protocol, and the 
Protocol Chair and Group Statistician determine whether these criteria have been met. 
 
For phase III trials, the AMC has formed an independent Data Safety and Monitoring Committee 
(DSMC).  Voting members of the DSMC are physicians, statisticians, and a patient advocate.  All 
voting members are from outside the AMC.  Non-voting members are the NCI scientific project 
officers and an NCI statistician.  The AMC Data Safety and Monitoring Committee reviews AMC 
phase III studies in accordance with the National Cancer Institute’s Policy for Data Safety and 
Monitoring.  Confidential reports of all phase III trials are prepared by the AMC Group Statistician 
with support from the AMC ODMC. A written report containing the current status of each trial 
monitored, and when appropriate, any toxicity and outcome data, are sent to DSMC members by the 
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AMC ODMC allowing sufficient time for DSMC members to review the report prior to the meeting.  
This report addresses specific toxicity concerns as well as concerns about the conduct of the trial.  
The report may contain recommendations for consideration by the DSMC concerning whether to 
close the trial, report the results, or continue accrual or follow-up. 
 
The results of each DSMC meeting are summarized in a formal report sent by the DSMC Chair to the 
Group Chair and AMC ODMC within 1 week of the meeting. The DSMC report contains 
recommendations on whether to close each study reviewed, whether to report the results, and 
whether to continue accrual or follow-up. A primary recommendation (e.g., continue with no change; 
recommended or required modification; stop) must be included in the document. The Group Chair is 
then responsible for notifying the Protocol Chair and relevant Disease-oriented Working Group Chair 
before the recommendations of the DSMC are carried out. In the unlikely event that the Protocol 
Chair does not concur with the DSMC, then the NCI Division Director or designee must be informed 
of the reason for the disagreement.  The Study Chair, relevant Disease-oriented Working Group 
Chair, Group Chair, DSMC Chair and NCI Division Director or designee will be responsible for 
reaching a mutually acceptable decision about the study.  CTEP approval of a formal amendment 
will be required prior to any implementation of a change to the study. 
 
Following a DSMC meeting, a summary of the serious adverse events reported to the DSMC is 
posted to the AMC web site.  It is each site’s responsibility for conveying this information to its IRB. 
 
Plans for Assuring Compliance with Requirements Regarding the Reporting of Adverse Events 
(AE) 
 
For trials monitored by the NCI’s Clinical Data Update System (CDUS), adverse event information 
is transmitted electronically to NCI on a quarterly basis.  For trials monitored by NCI’s Clinical 
Trials Monitoring Service (CTMS), adverse event information is transmitted electronically to NCI 
every two weeks. 
 
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Plans for Assuring that any Action Resulting in a Temporary or Permanent Suspension of an 
NCI-Funded Clinical Trial is Reported to the NCI Grant Program Director Responsible for the 
Grant 
 
In the event that termination of the trial or major modification to the protocol is under consideration, 
the Protocol Chair will convene the AMC Data Coordinator and Disease-oriented Working Group 
Chair by conference call to discuss the options.  For phase I and II trials, the Protocol Chair also has 
the option of asking the AMC DSMC to review the study.  The AMC ODMC will inform the CTEP 
Protocol Information Office (PIO) when studies are temporarily or permanently closed.  The Cancer 
Treatment and Evaluation Program (CTEP) of the National Cancer Institute (NCI) must approve all 
protocol amendments prior to distributing to the AMC sites. 
 
Plans for Assuring Data Accuracy and Protocol Compliance 
 
All study data for AMC clinical trials are entered directly by AMC site staff into AdvantageEDCSM (a 
web-based data entry and enrollment system).  During data entry, the system performs validation 
checks on many fields and performs consistency checks between select fields.  Range checks are 
placed on each field to eliminate entry of out-of-range values.  Edit check programs are run on the 
database on a set schedule to identify and resolve inconsistencies between forms or data collected at 
different points in time.  AMC ODMC staff routinely interacts with site staff to resolve any data 
problems. 
 
In accordance with NCI guidelines, the AMC ODMC conducts monitoring visits at the AMC sites to 
evaluate compliance with regulatory issues, and to review data for specific cases by checking source 
documents.  These reports are sent to the site Principal Investigator and to the NCI.  In the event that 
major violations are identified, sites are asked to provide a plan to correct deficiencies within 30 
days.  If needed, a repeat site visit is conducted.  In the event that a site does not correct deficiencies 
in a pre-determined time frame, the AMC Executive Committee has the option of taking action 
against the site.  Possible actions include, but are not limited to, suspending enrollment of new 
patients to AMC trials until deficiencies are corrected; recommending a decrease in funding to the 
site; and requiring specific training for site investigators or staff members. 
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