Conditions: Epstein Barr Virus Associated Non Hodgkin's Lymphoma Epstein Barr Virus Associated Hodgkin's Lymphoma Post-Transplant Lymphoproliferative Disease
Keywords: EBV+ NHL HL Non Hodgkin's Lymphoma Hodgkin's Lymphoma Epstein Barr Virus Epstein Barr Virus Associated Non Hodgkin's Lymphoma Epstein Barr Virus Associated Hodgkin's Lymphoma Post-Transplant Lymphoproliferative Disease
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 6
Healthy volunteers: no

Brief summary:
By combining a variety of agents that potentiate Zidovudine (ZDV), the investigators hope to induce remission in this generally fatal disease. Most therapies for aggressive B cell lymphomas are based upon intensive chemotherapeutic regimens, expensive modalities (bone marrow transplant, Rituximab), or experimental approaches (gene therapy, cytotoxic T cell infusion) that are difficult to implement in heavily pre-treated patients. Therapy for relapsed aggressive B cell lymphomas is very poor. Even curable lymphomas such as Burkitt Lymphoma (BL) and Hodgkin lymphoma are extremely difficult to treat in relapse and/or after stem cell transplant failure. The investigators propose a novel therapeutic approach that exploits the presence of Epstein-Barr virus (EBV) in lymphomas; antiviral mediated suppression of NF-kB and disruption of viral latency.

Detailed description:

Arms:
arm 1: Combination Chemotherapy for up to six (6) 21-day cycles and Antiviral-Based Therapy:

* Chemotherapy: Up to 6 cycles, 21 days each:

  * Doxorubicin: 20 mg/m2 intravenously (IV) on Day 1 per study protocol;
  * Rituximab: 375mg/m2 (optional) IV on Day 1 per study protocol;
  * Methotrexate: 3.5 gm/m2 IV on Day 2 per study protocol;
  * Leucovorin: 10 mg/m2 IV starting approximately 24 hours after start of Methotrexate infusion, and then 25 mg orally every 6 hours for at least 10 doses per study protocol;
* Antiviral-Based Therapy

  * Zidovudine: Starting 750 mg/m2 IV on Day 2, then 1200 mg orally twice daily for 10 doses per study protocol;
  * Hydroxyurea: 1,000 mg orally twice daily starting Day 2 for a total of 10 doses per study protocol.

Interventions: intervention 1: Doxorubicin intervention 2: Methotrexate intervention 3: Leucovorin intervention 4: Hydroxyurea intervention 5: Zidovudine intervention 6: Rituximab
Intervention descriptions: intervention 1: Doxorubicin 20 mg/m2 intravenously will be administered on Day 1 in patients with systemic (non-primary CNS) lymphoma as per institutional guidelines intervention 2: Methotrexate administered starting on Day 2, per study protocol. intervention 3: Leucovorin administered first intravenously 24 hours after start of Methotrexate infusion, then orally every 6 hours for at least 10 doses, per study protocol. intervention 4: Hydroxyurea administered orally twice daily starting on Day 2, and continuing for a total of 10 doses, per study protocol intervention 5: Zidovudine administered first intravenously on Day 2, and then orally twice daily for 10 doses, per study protocol. intervention 6: Rituximab is optional and will be administered to study participants, per study protocol.

Protocol document:
Prot_SAP_000.pdf: 








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TABLE OF CONTENTS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 
SCHEMA  
 
 
 
 
 
 
 
 
 
 
7 
 
1.0  
BACKGROUND  
 
 
 
 
 
 
8 
 
 
1.1  
Study Disease  
 
 
 
 
 
8 
 
 
1.2  
Rationale  
 
 
 
 
 
 
9 
 
2.0  
OBJECTIVES  
 
 
 
 
 
 
 
9 
 
 
2.1  
Primary Objectives 
 
 
 
 
 
9 
 
 
2.2  
Secondary Objectives  
 
 
 
 
9 
 
3.0  
PATIENT SELECTION 
 
 
 
 
 
10 
 
 
3.1  
Inclusion Criteria  
 
 
 
 
 
10 
 
 
3.2  
Exclusion Criteria 
 
 
 
 
 
11 
 
 
3.3  
Enrollment Procedures 
 
 
 
 
12 
 
4.0  
TREATMENT PLAN 
 
 
 
 
 
12 
 
 
4.1  
Agent Administration  
 
 
 
 
12 
 
 
4.2  
Concurrent Medication 
 
 
 
 
13 
4.3 
Drug Treatment Schedule 
 
 
 
 
14 
 
 
4.4  
Duration of Therapy  
 
 
 
 
14 
 
5.0  
CLINICAL AND LABORATORY EVALUATIONS 
 
15 
 
 
5.1  
Baseline/Pretreatment Evaluation 
 
 
 
15 
 
 
5.2  
Evaluations during Treatment 
 
 
 
16 
 
 
5.3  
Post-treatment Evaluation for Patients Not Receiving 
 
 
 
 
Bone Marrow Transplant 
 
 
 
 
17 
 
 
5.4  
Final Evaluations for Patients Accepted for  
 
 
 
 
Bone Marrow Transplant 
 
 
 
 
18 
 
6.0  
DOSING DELAYS/DOSE MODIFICATIONS 
 
 
18 
 
 
6.1  
Hematologic Toxicity  
 
 
 
 
18 
 
 
6.2  
Non-hematologic Toxicity 
 
 
 
 
18 
 
7.0  
AGENT FORMULATIONS AND PROCUREMENT 
 
19 
 
 
7.1  
Zidovudine 
 
 
 
 
 
 
19 
 
 
7.2  
Doxorubicin  
 
 
 
 
 
20 
 
 
7.3  
Methotrexate  
 
 
 
 
 
21 
 
 
7.4  
Hydroxyurea  
 
 
 
 
 
22 
 
 
7.5  
Leucovorin 
 
 
 
 
 
 
23 
 
 
7.6  
Ritiximab  
 
 
 
 
 
 
24 
 
 
8.0  
CORRELATIVE/SPECIAL STUDIES 
 
 
 
26 
 


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9.0  
MEASUREMENT OF EFFECT 
 
 
 
 
27 
 
 
9.1  
Response Assessment  
 
 
 
 
27 
 
 
9.2  
Definition of Response 
 
 
 
 
27 
 
10.0 
ADVERSE EVENT REPORTING  
 
 
 
30 
 
 
10.1 
Definitions 
 
 
 
 
 
30 
 
 
10.2 
Adverse Event Reporting With Commercial Agents  
31 
 
11.0 
DATA REPORTING  
 
 
 
 
 
32 
 
 
11.1 
Records to Be Kept 
 
 
 
 
 
32 
 
 
11.2 
Role of Data Management 
 
 
 
 
32 
 
12.0 
CRITERIA FOR DISCONTINUATION OF THERAPY 
 
32 
 
 
12.1 
Permanent Withdrawal 
 
 
 
 
32 
 
      12.1 
Permanent Withdrawal Evaluations                
 
32 
 
13.0 
STATISTICAL CONSIDERATIONS 
 
 
 
33 
 
 
13.1 
Overview  
 
 
 
 
 
 
33 
 
 
13.2 
Definitions 
 
 
 
 
 
33 
 
 
13.3 
Study Size and Precision 
 
 
 
 
34 
 
 
13.4 
Statistical Analysis Plan 
 
 
 
 
34 
 
 
13.5 
Correlative Studies 
 
 
 
 
 
36 
 
14.0 
DATA AND SAFETY MONITORING 
 
 
 
37 
 
 
14.1 
Role of the Research Team and DSMC 
 
 
37 
 
 
14.2 
Early Stopping Guidelines 
 
 
 
 
37 
 
 
14.3 
Interim Review of Safety Data 
 
 
 
37 
 
 
14.4 
Study Termination 
 
 
 
 
 
39 
 
15.0 
REFERENCES 
 
 
 
 
 
 
 
40 
 
APPENDICES 
 
Appendix I:   KARNOFSKY PERFORMANCE STATUS 
 
 
 
42 
Appendix II:   STUDY CALENDAR  
 
 
 
 
 
43 
Appendix III: EBV VIRAL LOAD COLLECTION PROCEDURES 
 
 
44 
Appendix IV: MEASUREMENT OF EBV REACTIVATION IN PERIPHERAL  
BLOOD MEMORY B CELLS BEFORE AND AFTER TREATMENT 
 46    
Appendix V: DETERMINING EBV GENE EXPRESSION PATTERN  
AND VIRAL ENCODED KINASES 
 47 
Appendix VI: Forms Submission Table 
 48 
Appendix VII: DRUG DIARY 
 49 
Appendix VIII: MEASUREMENT OF IMMUNE ACTIVATION MARKERS  
AND INFLAMMATION IN PERIPHERAL BLOOD T CELLS BEFORE  
AND AFTER TREATMENT  
 
 




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The epidemiology and pathogenesis of Hodgkin and aggressive non-Hodgkin’s 
lymphoma (NHL) is quite variable.  In developing nations and immune compromised 
populations, the majority of these tumors are associated with Epstein Barr Virus (EBV).  
Although these NHLs share some histologic and molecular features with those that occur 
in the non-immune compromised, there are clear distinctions (1-3).  In the U.S., a large 
percentage of aggressive lymphomas in immunocompromised patients are associated 
with EBV.  This is true for both Acquired Immunodeficiency Syndrome (AIDS) 
associated and post-transplant lymphomas (4, 5).  Recent studies have indicated that a 
substantial genetic heterogeneity in EBV gene expression exists among both Burkitts 
type and Large Cell (Immunoblastic) variants of NHL (8).  Some interesting reports on 
the biology of EBV associated lymphomas suggest that in some cells in these tumors the 
herpes virus is not strictly latent (10).  An important association was made between the 
presence of lytic transcripts or proteins and favorable response to chemotherapy in 
African patients with endemic BL (10).  It is likely that treatment with chemotherapy or 
Zidovudine (ZDV) might enhance the expression of EBV genes and subsequent response 
especially when these approaches are used together (11). 
 
A principal hypothesis that is central to our trial is that high-grade lymphomas associated 
with gamma herpesviruses appear to be dependent on constitutive expression of the 
promiscuous transcription factor nuclear factor kappa B (NF-κB) (16).  Hodgkin and 
Reed-Sternberg (HRS) cells also highly express this transcription factor.  Inhibition of 
NF-κB results in apoptosis of these tumors (17).  In addition, NF-κB appears to play an 
important role in maintaining viral latency (18). Pharmacologic induction of EBV from 
latency can render virus-infected lymphomas susceptible to antiviral nucleoside analogs, 
such as ganciclovir (GCV), and ZDV, which can be readily phosphorylated by the viral-
encoded kinases and serve as highly specific therapeutic agents (19, 20).  We have found 
that ZDV potently induces apoptosis in primary EBV+ BL lines (12).  There is precedent 
for ZDV as an agent with activity in viral lymphomas.  ZDV and Interferon alpha have 
activity in a viral associated malignancy (Human T cell Lymphotropic Virus Type I 
[HTLV-I]) adult T cell leukemia (21).  ZDV exhibits marked activity in certain EBV 
associated lymphomas.  We have recently demonstrated that ZDV inhibits NF-κB and 
induces the EBV lytic cycle (12).  ZDV is phosphorylated by the EBV thymidine kinase 
(EBV TK), a lytic protein.  Therefore, ZDV is unique in its ability to both induce (EBV) 
and kill EBV positive BL cells (22).  Other investigators have demonstrated that the 
conventional chemotherapeutic agents that we will use in this protocol (doxorubicin, 
methotrexate) also induce the EBV lytic program (11, 20).  Our objective is to develop 
therapies for aggressive EBV+ lymphomas with agents that can be easily administered 
especially in immunocompromised patients.  Hydroxyurea enhances phosphorylation of 
ZDV through inhibition of ribonucleotide reductase and methotrexate markedly enhances 
the phosphorylation of ZDV through the inhibition of thymidylate synthesis (23).  Since 
we have demonstrated that ZDV inhibits NF-κB and induces the viral lytic cycle we 
hypothesize that this combination of doxorubicin/methotrexate/ZDV/hydroxyurea will 
be a unique targeted therapy for these poor prognosis EBV positive lymphomas. We 
recently reported a retrospective analysis of 19 patients with aggressive EBV+ non-
Hodgkin’s lymphoma, including 9 cases of AIDS-associated primary central nervous 


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system lymphoma (AIDS-PCNSL) treated with ZDV-based chemotherapy (24). Our 
results demonstrate that high-dose ZDV-methotrexate is efficacious in treating highly 
aggressive systemic EBV+ lymphomas in the upfront setting. In primary EBV+ 
lymphoma cell lines, the combination of ZDV with hydroxyurea resulted in synergistic 
EBV lytic induction and cell death. Further, ZDV-hydroxyurea treatment resulted in 
dramatic responses in patients with AIDS-PCNSL. The combination of ZDV with 
chemotherapy, especially lytic-inducing agents, should be explored further in clinical 
trials for the treatment of EBV-related lymphomas. Both ZDV and methotrexate have 
excellent CNS penetration thus making the combination of these drugs ideal for the 
treatment of lymphomas involving CNS and sanctuary areas.  
 
 
1.2  Rationale 
 
By combining a variety of agents that potentiate ZDV we hope to induce remission in 
aggressive 
EBV-associated 
lymphomas 
such 
as 
those 
occurring 
under 
immunosuppression (i.e. post-transplant) and in the setting of HIV/AIDS. Most therapies 
for aggressive B cell lymphomas are based upon intensive chemotherapeutic regimens, 
expensive modalities (bone marrow transplant, Rituximab), or experimental approaches 
(gene therapy, cytotoxic T cell infusion) that are difficult to implement in heavily pre-
treated and immunocompromised patients. Therapy outcome for HIV-associated PCNSL 
and relapsed aggressive B cell lymphomas is very poor. Even curable lymphomas such as 
Burkitt Hodgkin lymphoma, and NHL, especially in the HIV setting, are extremely 
difficult to treat in relapse and/or after stem cell transplant failure. We propose a novel 
therapeutic approach that exploits the presence of EBV in lymphomas; antiviral mediated 
disruption of viral latency, resulting in EBV reactivation and drug phosphorylation by 
endogenous EBV kinases followed by cell death. This study was originally designed to 
show efficacy in relapsed aggressive EBV-associated lymphomas. However, cooperative 
groups generally exclude patients with central nervous system (CNS) involvement from 
clinical trials.  We have expanded eligibility to include patients with untreated EBV+ CNS 
lymphomas in the upfront setting. 
 
2.0  
OBJECTIVES 
 
2.1 Primary Objectives 
 
The primary objective of this phase II study is to determine efficacy (complete response 
rate) of patients with EBV+ lymphomas presenting with CNS involvement or systemic 
relapse treated with high dose parenteral zidovudine (ZDV), oral hydroxyurea and 
combination chemotherapy with doxorubicin, methotrexate (MTX), and leucovorin. 
 
2.2 Secondary Objectives 
 
2.2.1 Evaluate 1-year overall and failure-free survival of this treatment. 
2.2.2 Assess the toxicity of this treatment regimen. 
2.2.3 Assess the effect of this treatment on HIV viral load and T-cell subsets 
2.2.4 Measure EBV viral load in peripheral blood before, after treatment, and during 


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surveillance in order to correlate the presence of with tumor load and disease status. 
2.2.5 Measure EBV reactivation in circulating peripheral blood memory B-cells before 
and after treatment with chemotherapy/ZDV in order to assess the drug effect on 
EBV latency. 
2.2.6 Determine baseline tumor EBV gene expression profile to assess viral thymidine 
kinases. (BXLF1/vTK and BGLF4/PK), EBV latency pattern (I, II or III) and lytic 
phase. 
2.2.7 Measure immune activation markers and inflammation in peripheral blood in 
response to treatment and EBV reactivation. 
 
3.0  
PATIENT SELECTION 
 
3.1 Inclusion Criteria  
 
3.1.1 Any stage, histologically or cytologically documented intermediate to high grade 
relapsed or refractory EBV+ non-Hodgkin’s or Hodgkin’s lymphoma, or any 
treated or untreated patients with EBV+ lymphoma involving CNS. Patients with 
relapsed 
or 
refractory 
monomorphic 
(monoclonal) 
post-transplant 
lymphoproliferative disease (PTLD) are also eligible. 
3.1.2 Patients who are HIV+ or negative. Documentation of HIV infection can be done 
at any time prior to study entry. Documentation may be serologic (positive ELISA 
and positive Western blot), molecular (positive HIV viral RNA), or other federally 
approved licensed HIV test. Prior documentation of HIV seropositivity is 
acceptable. 
3.1.3 Tumors must be positive for EBV. This may be done either by EBER stain on the 
original tumor or the biopsy of relapsed disease (if performed). Biopsy of relapsed 
disease is desirable but not mandatory. If stains for LMP-1 done outside are 
positive, EBER does not need to be done. 
3.1.4  All patients, except those who have CNS involvement, must have relapsed or 
progressed from at least one previous chemotherapy based regimen. 
3.1.5 Measurable or non-measurable tumor parameter(s). Non-measurable tumor 
parameter(s) is defined as not having bi-dimensional measurements (e.g., gastric or 
marrow involvement), but can be followed for response by other diagnostic tests 
such as gallium scan, PET imaging and/or bone marrow biopsy.   
3.1.6 Age ≥ 18 years.   
3.1.7 Karnofsky performance status (KPS) ≥ 50%/Eastern Cooperative Oncology Group 
(ECOG) Performance Score 0, 1, 2 (See Appendix I). 
3.1.7 Patients must have adequate end organ and bone marrow function as defined below: 
3.1.7.1 Absolute neutrophil count ≥ 1,500 cells/mm3 and platelets ≥ 75,000 
cells/dL unless cytopenias are secondary to lymphomatous involvement 
of bone marrow or due to HIV-related thrombocytopenia.  All patients 
must be off colony stimulating factor therapy at least 24 hours prior to 
institution of Cycle 1 chemotherapy. 
3.1.7.2 Adequate hepatic function:  Serum glutamic-oxaloacetic transaminase 
(SGOT) ≤ 5 times the upper limit of normal.  Total bilirubin ≤ 2.0 mg/dL 
(unless elevated secondary to lymphomatous involvement of liver or 


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biliary system or due to other HIV medications [e.g., indinavir, tenofavir 
or atazanavir]). Patients who are negative for Hepatitis B, or if infected 
with Hepatitis B, receiving anti-Hepatitis B therapy are eligible. All 
subjects will be required to be screened for Hepatitis B and C. Per IDSA 
and AASD guidelines, those subjects that show no immunity, defined by 
the lack of Hepatitis B surface antibody, and show evidence of chronic 
infection (i.e. HBsAg+, HBcore+, HBsAB-) will be required to be on anti-
Hepatitis B therapy, during the study, in order to be eligible. Patients will 
be permitted to enroll in the study provided liver function tests meet 
criteria listed under Section 3.1.7.2 above, and there is no evidence of 
cirrhosis. The exact Hepatitis B therapy will be at the discretion of the 
infection disease specialist or investigator. However all patients who 
present with acute hepatitis B or show normal transaminases and are 
HBsAg+ and IgM+ for Hepatitis core antigen will not be eligible for trial 
enrollment. Subjects who are Hepatitis C antibody positive, with or 
without a positive Hepatitis C RNA level, will be permitted to enroll in 
the study provided liver function tests meet criteria listed under 3.1.7.2 
above, and have no evidence of cirrhosis. Patients diagnosed with 
Hepatitis C less than 6 months from trial enrollment, will be considered 
to have Acute Hepatitis C and will be excluded from study unless Hep C 
viral load is undetectable. 
3.1.7.3 Creatinine ≤ 2.0 mg/dL or creatinine clearance ≥ 60 mL/min unless due 
to renal involvement by lymphoma. 
 
3.1.8 Concurrent radiation, with or without steroids, for emergency conditions secondary 
to lymphoma (CNS tumor, cord compression, etc.) will be permitted. 
 
 
3.1.9 Females with childbearing potential must have a negative serum pregnancy test 
within 7 days prior of entering into the study.  Men and women must agree to use 
adequate birth control if conception is possible during the study.  Women must 
avoid pregnancy and men avoid fathering children while in the study and for 6 
months following the last study drug treatment. 
3.1.10 Able to give consent. 
3.1.11 Patients already receiving erythropoietin or G-CSF are eligible, although G-CSF 
therapy must be discontinued at least 24 hours prior to receiving chemotherapy. 
3.1.12 The maximum cumulative dose of doxorubicin allowed is 450 mg/m2. Patients who 
have previously received doxorubicin with a cumulative dose of 350 mg/m2 or 
greater are eligible but MAY NOT receive doxorubicin under protocol. 
 
 
3.1 Exclusion Criteria 
  
 
 
3.2.1 Concurrent active malignancies, with the exception of in situ carcinoma of the 
cervix, non-metastatic, non-melanomatous skin cancer, or Kaposi sarcoma not 
requiring systemic chemotherapy.  
 3.2.2 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 


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electrocardiograph evidence of acute ischemic or active conduction system 
abnormalities.   
  3.2.3 Left Ventricular Ejection Fraction (LVEF) that is less than the lower institutional 
limits of normal as assessed by Multiple Gated Acquisition (MUGA) scan or 
echocardiogram within 6 weeks prior to registration. 
3.2.4 Subjects with viral hepatitis who do not meet the criteria listed on 3.1.7.2 will be 
not be eligible. All patients who present with acute hepatitis B including those with 
normal transaminases who are HBsAg+ and IgM + for hepatitis core antigen will 
not be eligible. Subjects who are Hepatitis B core antibody positive are eligible 
only if they start or are on prophylactic therapy. A hepatitis B viral load should be 
confirmed negative on all patients who are hepatitis B core antibody positive, but 
hepatitis B antigen negative. Patients refusing to take any anti-hepatitis B therapy 
during study will also be excluded. Patients diagnosed with Hepatitis C are eligible 
if they meet criteria listed on 3.1.7.2. 
 
3.2.5 Psychological, familial, sociological or geographical conditions that do not permit 
treatment and/or medical follow-up required to comply with the study protocol. 
 
 
3.2.6  Patients may not be receiving any other investigational agents. 
 
3.2.7  Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac 
arrhythmia, or psychiatric illness/social situations that would limit compliance with 
study requirements.  Patients with mycobacterium avium will not be excluded. 
 
      3.2.8   Pregnant or breast-feeding women. 
 
3.2 Enrollment Procedures 
 
To enroll a patient, the study team will follow the University of Miami Sylvester 
Comprehensive Cancer Center Subject Enrollment Requirements SOP.   
 
4.0   
TREATMENT PLAN 
 
Treatment will be administered on an inpatient basis.  Treatment cycles will be given every 
21days (+/- 1 week), depending upon recovery from any hematologic or non-hematologic 
toxicity as specified in Section 6.0.  A treatment cycle is defined below. Each day will be 
calculated as 24 hours day +/- 4 hours. 
 
4.1 Agent Administration 
 
4.1.1 Doxorubicin 20 mg/m2 intravenously will be administered on Day 1 in patients with 
systemic (non-primary CNS) lymphoma as per institutional guidelines at a standard 
rate of 2mg per minutes/maximum infusion time 1mg per minute. For bilirubin ≥3.0 
mg/dL due to hepatic involvement, the initial dose will be decreased by 50%. The 
maximum cumulative dose of doxorubicin allowed is 450 mg/m2. Patients who 
have previously received doxorubicin with a cumulative dose of 350 mg/m2 or 
greater are eligible but MAY NOT receive doxorubicin under protocol. 
4.1.2 Rituximab 375 mg/m2 will be administered on Day 1 in subjects who have CD20+ 
lymphoma provided baseline CD4 count is at least 50 cells/mm3 unless investigator 


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feels adding this drug will not be beneficial after prior use and failure. 
4.1.3 Urine alkalinization will begin on Day 1 with normal ½ saline or 5% dextrose, plus 
sodium bicarbonate.  
4.1.4 On Day 2 when urine output is ≥ 150 mL/hr for approximately four consecutive 
hours, urine pH is ≥ 7.0 and after at least 1 liter of fluids, give Methotrexate 5 gm/m2 
IV in 1000 mL 0.9% sodium chloride over approximately 4 hours x 1 dose only. 
NOTE: Methotrexate may be omitted during the first cycle of treatment in patients 
felt to be at risk for severe toxicity due to debilitated condition, renal function, or 
in post-transplant setting, and can be added in subsequent cycles at the discretion 
of the investigator. 
4.1.5 Leucovorin 10 mg/m2 IV over 15 minutes-2 hours every 6 hours for at least 10 
doses (see Section 4.1.8) – start approximately 24 hours after the BEGINNING of 
the methotrexate infusion.  
4.1.6 Methotrexate level will be obtained approximately 48 hours after the END of the 
methotrexate infusion and the Leucovorin dose adjusted accordingly. 
4.1.7 Zidovudine 750 mg/m2 IV over approximately 1 hour twice daily will begin on Day 
2 (after methotrexate) and continue for a total of 10 doses. (see Section 4.1.8) 
4.1.8 Hydroxyurea 1000 mg by mouth twice daily will begin on Day 2 and continue for 
a total of 10 doses. (see Section 4.1.8) 
4.1.9 Once methotrexate level is normal AND the subject has received 5 doses of 
intravenous zidovudine, the remaining doses of leucovorin and zidovudine may be 
given orally and the subject discharged from the hospital at the discretion of the 
investigator. Subject will be provided with a drug diary to record the remaining 
doses to be taken at home (APPENDIX VII). 
 
4.1.8.1 
Leucovorin 25 mg every 6 hours for at least a total of 10 doses.  The 
number of doses beyond 10 will be prescribed at the discretion of 
the investigator. 
4.1.8.2 
Zidovudine 1200 mg orally twice daily for a total of 10 doses.  
 
4.1.8.3 
Hydroxyurea 1,000 mg orally twice daily will be given for a total of 
10 doses. 
 
4.2       Concurrent Medication 
 
4.2.1 Prevention of herpetic reactivation and EBV viremia: Oral Valganciclovir 450 mg 
twice daily x 10 doses along zidovudine. 
4.2.2 Central Nervous System Treatment and Prophylaxis:  Patients without CNS 
involvement may receive intrathecal chemotherapy as prophylaxis at the 
discretion of the investigator or treating physician. If lymphomatous CNS 
involvement is confirmed in cereprospinal fluid (CSF), these subjects must 
receive aggressive IT chemotherapy per institutional standards. Although the 
specific regimen may vary at each center, a suggested regimen is listed below:  
• Cytarabine 50 mg  
• Methotrexate 12 mg  
• Hydrocortisone 50 mg 


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Intrathecally administer twice a week until CSF is negative, then weekly x 1 
month and then monthly x 6 months. 
4.2.3 Prophylaxis against Pneumocystis carinii is required in HIV+ subjects, with the 
specific regimen at the discretion of the Investigator. Recommended options 
include trimethoprim-sulfamethoxazole (160-800 mg Mondays, Wednesdays, 
Fridays), dapsone 100 mg daily, or atovoquone 1500 mg with food once daily).  
4.2.4 Quinolone antibacterial prophylaxis in JHIV+ subjects: Patients with a CD4 count 
of < 100/mm3 at baseline or whose CD4 count decreases below 100/mm3 during 
therapy are required to receive quinolone prophylaxis. Begin quinolone prophylaxis 
during each cycle no later than Day 8 of chemotherapy and continue until 
documented recovery from neutropenia (ANC ≥ 1000/mm3). If subjects are allergic 
or intolerant of quinolones an alternative antibiotic will be used. 
4.2.5 Antiretroviral therapy (HAART): HIV+ subjects on an antiretroviral regimen 
should be receiving treatment that is in accordance with the current International 
AIDS Society guidelines. The specific agents are at the discretion of the 
Investigator and use of agents currently available on an expanded access basis is 
allowed, but the use of experimental antiretroviral agents or those containing 
zidovudine (including Combivir® and Trizivir®) are prohibited. Changes to 
HAART therapy may be made if medically necessary (toxicity, failure of regimen, 
etc.). Antiretroviral naïve subjects: Subjects who are not on HAART at study 
entry must begin therapy AFTER Cycle 1 of chemotherapy has been completed. 
Changes to HAART therapy may be made if medically necessary (toxicity, failure 
of regimen, etc.). 
4.2.6 Prophylaxis against other common opportunistic infection (OI) is encouraged in 
HIV+ subjects, dependent upon the subject’s CD4 cell count at study entry, and at 
the discretion of the Investigator. Topical and/or antifungal agents are permitted. 
Prophylaxis against mycobacterium avium is recommended if CD4 cells are < 
100/mm3. 
4.2.7 Prevention of tumor lysis syndrome (Cycle 1 only):  For patients with evidence of 
high tumor burden (bone marrow involvement, LDH > twice the upper limit of 
normal) it is recommended subjects receive allopurinol 300 mg 24 hours prior to 
the initiation of chemotherapy followed by a minimum of 300 mg daily for at least 
the first seven treatment days. It is also recommended that appropriate IV hydration 
be maintained and serum electrolytes, BUN, phosphorous, creatinine, calcium and 
uric acid be monitored closely.  Allopurinol dosing may be adjusted and electrolytes 
replaced or corrected at the discretion of the treating physician. 
4.2.8 All antibiotics may be administered as clinically indicated. 
4.2.9 Topical and/or antifungal agents are permitted. 
4.2.10 Growth factors may be used as clinically indicated. 
4.2.11 Growth Factor (GF) therapy with G-CSF, GM-CSF, or pegfilgrastim will be used 
in all subjects after each chemotherapy cycle, beginning at least 48 hours after 
completion of methotrexate. 
4.2.12 Nausea and Vomiting: Nausea and vomiting should be managed according to 
standard practice as outlined in the published American Society of Clinical 
Oncology (ASCO) document “Preventing and Treating Nausea and Vomiting 


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Caused by Cancer Treatment.” Briefly, antiemetic agents including, but not limited 
to, 5HT-3 antagonists, aprepitant, lorazepam, diphenhydramine, or phenothiazines 
may be considered. 
 
4.3 Drug Treatment Schedule 
 
4.3.1 Chemotherapy cycles will be repeated every 21days (+/- 1 week) depending upon 
blood counts and recovery from other toxicity.  Chemotherapy cycles will be given 
every 21days (+/- 1 week) as long as the following criteria are met: 
• ANC ≥ 1000/mm3 
• Platelet count ≥ 75,000/mm3 
4.4 Duration of Therapy 
 
4.4.1 Patients will be evaluated for response after the second, fourth and sixth cycles (if 
given) of therapy.  Patients will receive two cycles of therapy beyond initially 
documenting a CR.  A minimum of 4 and a maximum of 6 cycles of therapy will 
be given.  Patients with PR after cycles 2 and 4, who remain on study at the 
investigator’s discretion, will receive a maximum of 6 cycles of therapy. 
4.4.2 Patients with stable disease (SD) after 2 cycles may remain on study or be removed 
from study at the discretion of the investigator. Patients with SD after 4 cycles will 
be removed from the study. 
 
4.4.3 If CR is achieved after cycle 2, the patient will be referred for stem cell transplant 
evaluation to begin search for stem cell donor at the discretion of the investigator 
also receive up to 2 additional cycles of chemotherapy.  Patients who are not 
candidate will be followed as per Section 5.3 once they have completed cycles 3 
and 4 of chemotherapy. 
 
5.0  Clinical and Laboratory Evaluations 
 
5.1 
Baseline/Pretreatment Evaluation (Appendix II) 
 
5.1.1 Complete medical history within 4 weeks prior to enrollment unless otherwise 
indicated.  
 
5.1.1.1 Date of initial and/or relapsed diagnosis of lymphoma.  A copy of the 
pathology report must be available in the medical record. Unstained 
slides must be submitted for pathology correlative studies (see Appendix 
V) 
5.1.1.2 Documentation of the presence or absence of “B” symptoms 
(unexplained fevers, night sweats, involuntary weight loss > 10% of 
normal body weight).  
5.1.1.3 History of other symptoms related to non-Hodgkin’s lymphoma. 
5.1.1.4 History of drug allergies.  
5.1.1.5 Current medication list.  
5.1.1.6 Previous therapy received for this lymphoma, including total cumulative 
dose of previously received Doxorubicin (if applicable). 


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16 
 
 
5.1.2 Complete physical examination includes: performance status score (Appendix 
I), vital signs, weight, height, body surface area, neurologic examination, 
careful measurement of all palpable peripheral lymph nodes and measurement 
of other sites of disease present on physical examination. 
 
5.1.3 Laboratory and other tests within 7 days prior to enrollment unless 
otherwise indicated : 
 
5.1.3.1 Hematology: CBC, differential, and platelet count. 
5.1.3.2 Serum electrolytes, blood urea nitrogen (BUN), creatinine, total 
bilirubin, alkaline phosphatase (ALP), LDH, total protein, albumin, 
calcium, phosphorous, AST, ALT, uric acid. 
5.1.3.3 Assessment for Hepatitis C antibody, Hepatitis B surface antibody, 
Hepatitis B core antibody, Hepatitis B surface antigen (HBsAg). A 
baseline Hepatitis B or C viral load should be obtained on all patients 
who are Hepatitis B core antibody positive, Hepatitis B antigen positive, 
and/or Hepatitis C positive respectively. 
5.1.3.4 T-cell subsets (in HIV + patients only) 
5.1.3.5 HIV viral load (in HIV + patients only) 
5.1.3.6 Serum pregnancy test where indicated within 7 days of treatment 
initiation and at any time during protocol therapy if pregnancy is 
suspected. 
5.1.3.7 EKG (within 14 days) prior to enrollment. 
5.1.3.8 Determination of LVEF by MUGA scan or echocardiogram (within 6 
weeks of enrollment).  Patients will not be enrolled if LVEF is below 
institutional limits. 
5.1.3.9 EBV viral load (Two 7 ml green top tubes) (See Appendix III). 
5.1.3.10  Measurement of EBV reactivation in PBMCs (Two 10 ml yellow top 
tubes) (See Appendix IV). This will be done at baseline (Day 0 or -1) 
prior to starting treatment under protocol. 
5.1.3.11  Measurement of immune activation markers and inflammation 
associated cytokines in peripheral blood (one 10 ml purple top tubes with 
EDTA or equivalent). This will be done at baseline (Day 0 or -1) prior to 
starting treatment under protocol. (See Appendix VIII). 
 
5.1.4 Staging Evaluation:  The following studies will be done for baseline evaluation 
of the extent of disease within 28 days of treatment initiation. 
 
5.1.4.1 CT scans of the brain, neck (if involved by adenopathy), chest, abdomen, 
and pelvis with contrast unless contraindicated, in which case nuclear 
imaging methods for lymphoma staging can be used or non-contrast CTs. 
CT/PET may substitute for CT scans. 
5.1.4.2 Bone marrow biopsy and aspirate are optional, but should still be done 
whenever possible and/or at the discretion of the principal investigator 
within 6 weeks prior to patient registration.  Bone marrow aspirate will 


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be sent for lymphoma markers and flow cytometry. If performance of 
bone marrow biopsy will delay treatment initiation (e.g., falling on a 
weekend or holiday), it may be delayed but must be performed to confirm 
CR whenever that occurs. 
5.1.4.3 Lumbar puncture (LP) with routine studies and cytology, unless L3 
leukemia is present, will be done at the discretion of the physician if 
lymphomatous CNS involvement is suspected. 
 
5.2   
Evaluations During Treatment (Appendix II)  
 
5.2.1 Physical examination including performance status score (Appendix I) will be 
repeated prior to each cycle of chemotherapy.  Disease measurable on physical 
examination should be measured in two dimensions. 
5.2.2 The following must be performed within 48 hours prior to beginning of each cycle 
of chemotherapy: 
5.2.2.1.1 CBC, differential and platelet count 
5.2.2.1.2 Serum electrolytes, blood urea nitrogen (BUN), creatinine, total 
bilirubin, alkaline phosphatase (ALP), LDH, total protein, 
albumin, calcium, phosphorous, AST and ALT, uric acid 
5.2.2.1.3 Baseline evaluation laboratory tests may be used toward cycle 1 
requirements, if done within 48 hours of treatment initiation. 
5.2.3  EBV viral load will be obtained at the beginning of cycle 1 (prior to the 
administration of Doxorubicin) (as in 5.1.3.10), on cycle 1 prior to the 
administration of ZDV 20-24 hours after the administration of doxorubicin, after 
the 5th dose of intravenous ZDV cycle 1 (to determine if ZDV induces the EBV 
lytic cycle) and within the last 7 days of the end of cycle 1. Thereafter, EBV viral 
load will be done within the last 7 days of the end of cycle 2, 4, (minus 1-week 
window) and after cycle 6 (2-6 weeks after last treatment) (See Appendix III). 
5.2.4 Measurement of EBV reactivation in PBMCs will be obtained at the beginning of 
cycle 1, prior to the administration of Doxorubicin  (as in 5.1.3.11), on Day 2 of 
Cycle 1 prior to the administration of ZDV 20-24 hours after the administration of 
Doxorubicin, and after the 5th dose of ZDV (See Appendix IV). 
5.2.5 Measurement of immune activation markers and inflammation associated cytokines 
in peripheral blood (one 10 ml purple top tubes with EDTA or equivalent). This 
will be done at completion of cycles 2, 4 (minus 1-week window for each) and after 
cycle 6 (2-6 weeks after last treatment). 
5.2.6 HIV studies (in positive patients only): HIV-1 viral load and T-cell subsets 
following completion of cycle 2 (minus 1-week window) and cycle 6 (2-6 weeks 
after last treatment) 
5.2.7 Restaging evaluation:  CT scans (and other studies as indicated) will be performed 
following completion of cycles 2, 4 and 6 (minus 1-week window for each), and 2 
to 6 weeks after completion of cycle 6 treatment. 
5.2.8 If the patient had initial bone marrow involvement, then a repeat bone marrow 
biopsy should be performed when the patient has no other evidence of disease in 
order to determine CR status. 
 


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5.3   
Post-Treatment Evaluation for Patients Not Receiving Bone Marrow Transplant 
(Appendix II)  
 
5.3.1 EBV viral load will be obtained after cycle 6 (2-6 weeks after last treatment) as per 
section 5.2.3, and at least every three months for one year (+/- 2 weeks) (See 
Appendix III). EBV viral load will also be obtained upon disease progression or 
relapse. 
5.3.2 Measurement of immune activation markers and inflammation associated cytokines 
in peripheral blood (one 10 ml purple top tubes with EDTA or equivalent) will be 
obtained upon disease progression or relapse 
5.3.3 The following procedures and studies should be repeated post-therapy at least every 
3 months for 2 years (+/- 4 weeks) unless indicated otherwise below, every 6 months 
for the third-fifth years, or as clinically indicated.  These procedures and studies are 
required at these intervals until disease progression or death. No additional studies 
are required after disease progression. (Whichever occurs first, see section 12.0).   
5.3.2.1 
History 
5.3.2.2 
Physical exam/tumor measurement 
5.3.2.3 
Performance status 
5.3.2.4 
The following labs: CBC, differential and platelet count, serum 
electrolytes, blood urea nitrogen (BUN), creatinine, total bilirubin, 
alkaline phosphatase (ALP), LDH, total protein, albumin, calcium, 
AST, ALT 
5.3.2.5 
Adverse events/toxicity notation 
5.3.2.6 
CT scans of the brain, neck (if initially involved), chest, abdomen, 
and pelvis with contrast unless contraindicated, in which case 
nuclear imaging methods for lymphoma staging can be used or non-
contrast CTs will be performed every 6 months for two years, or 
more often if clinically indicated (+/- 4 weeks). 
5.3.2.7 
HIV studies (in positive patients only): HIV-1 viral load and T-cell 
subsets will be performed 2-6 weeks after last treatment (as in 5.2.6), 
and at least every 3 months (per standard practice) for up to one year 
after the completion of chemotherapy (+/- 4 weeks). 
 
 
 
 
5.4  
Final Evaluations for Patients Accepted For Bone Marrow Transplant 
 
Patients referred and accepted for bone marrow transplant will have a complete 
physical examination, blood drawn for the following studies:  CBC, differential and 
platelet count Serum electrolytes, blood urea nitrogen (BUN), creatinine, total 
bilirubin, alkaline phosphatase (ALP), LDH, total protein, albumin, calcium, AST, 
ALT and EBV viral load, and a toxicity evaluation.  No additional studies are required.  
Patients will be followed at least yearly for 5 years for survival only. 
 
6.0  
DOSING DELAYS/DOSE MODIFICATIONS 


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6.1 
Hematologic Toxicity 
 
6.1.1 No dose modifications will be made for anemia. This will be managed by 
transfusion of packed cells and/or administration of growth factors at the discretion 
of the investigator.  We do expect severe pancytopenia and thrombocytopenia. 
6.1.2 If ANC <1,000 cells/mm3 start G-CSF 3-5 mcg/kg (daily) and repeat CBC weekly 
until ANC > 1000 cells/mm3. 
6.1.3 If platelets < 75,000 cells/mm3 repeat weekly until platelets are > 30,000 cells/mm3 
unless thrombocytopenia is due to HIV-related immune thrombocytopenia.  Platelet 
transfusions may be given at the discretion of the physician. 
6.1.4 If on day one of any cycle, ANC < 1000 cells/mm3 and/or platelets < 30,000 
cells/mm3, delay up to 2 weeks until ANC and platelets have increased above these 
levels.  Treatment with G-CSF or pegfilgrastim is encouraged. 
 
6.2 
Non-Hematologic Toxicity 
 
6.2.1 Hepatic toxicity: Dose adjustment for hyperbilirubinemia 
6.2.1.1 
Bilirubin 1.2 to 3.0 mg/dl, reduce doxorubicin dose by 50%. 
6.2.1.2 
Bilirubin 3.1 to 5.0 mg/dl, reduce doxorubicin dose to 25% of full dose. 
6.2.1.3 
Bilirubin >5.0 mg/dl doxorubicin should not be administered. 
6.2.1.4 
If bilirubin> 3.0 mg/dl for more than 30 days and is not associated with the 
presence of hepatic involvement by NHL, the patient will be removed from 
study. 
6.2.1.5 
No dosage adjustment is required for isolated hyperbilirubinemia associated 
with the use of indinavir, tenofovir, or atazanavir. 
 
Note: Persons at high risk of viral hepatitis infection should be screened before 
initiation of rituximab. Subjects with chronic viral hepatitis will be eligible 
provided the meet criteria listed under Section 3.1.7.2. Subjects with chronic 
Hepatitis B, or Hepatitis B core antibody should be closely monitored for clinical 
and laboratory signs of active HBV infection and for signs of hepatitis during and 
for up to several months following rituximab therapy. Any subject who develops 
HBV reactivation or acute Hepatitis B as defined by the presence or reappearance 
of hepatitis B surface antigen, a positive IgM hepatitis B core antibody, and a 
positive viral load will be permanently removed from the study. Any patient with 
Hepatitis B or C who have worsening liver function necessitating drug adjustment 
as defined in Section 6.2.1 will also be removed from study. Rituximab and any 
concomitant chemotherapy should be discontinued and appropriate treatment 
including antiviral therapy initiated. There are insufficient data regarding the safety 
of resuming rituximab therapy in patients who develop hepatitis subsequent to 
HBV reactivation.  
6.2.2 Cardiac toxicity:  If clinical findings suggesting congestive heart failure are present, 
doxorubicin will be discontinued and evaluation by echocardiogram or MUGA will 
be performed.  Some patients will have received doxorubicin prior to this protocol, 
although at total doses far below the threshold for toxicity. 


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6.2.3 Renal toxicity: Methotrexate dose will be decreased by 20% in the case of grade 3 
or 4 renal toxicity on the prior cycle. 
6.2.4 Other viral infections: The following additional serious viral infections, either new, 
reactivated or exacerbated, have been identified in clinical studies or postmarketing 
reports. The majority of patients received rituximab in combination with 
chemotherapy or as part of a hematopoietic stem cell transplant. These viral 
infections included JC virus (progressive multifocal leukoencephalopathy (PML), 
cytomegalovirus, herpes simplex virus, parvovirus B19, varicella zoster virus, West 
Nile virus, and hepatitis C. In some cases, the viral infections occurred up to one 
year following discontinuation of rituximab and have resulted in death. 
 
7.0  
AGENT FORMULATION AND PROCUREMENT 
 
7.1 Zidovudine (Retrovir, AZT) 
 
7.1.1 Classification: Zidovudine, a thymidine analogue, is an inhibitor of the replication 
of some retroviruses including HIV.   
7.1.2 Mechanism of Action: Zidovudine triphosphate interferes with the HIV viral RNA 
dependent DNA polymerase (reverse transcriptase) and thus, inhibits viral 
replication.  In vitro, zidovudine triphosphate has been shown to be incorporated 
into growing chains of DNA by viral reverse transcriptase.  
 
 
7.1.3  Metabolism: The mean half-life of peak serum concentration is approximately 1 
hour. Most of the drug is excreted through the kidneys. 
7.1.4 Human toxicity: The dose-limiting toxicity is anemia. Other toxicities include:   
More common:  fever, chills or sore throat; pale skin; headache, myalgia, back pain, 
rigors; paresthesia; constipation; malaise and weakness; nausea and vomiting; 
difficulty in sleeping; weight loss.  Neutropenia and thrombocytopenia may also 
occur.  
 
Less common:  bluish-brown colored bands on nails; changes in skin color. 
 
Rare:  Abdominal discomfort; confusion; convulsions; diarrhea; general feeling of 
discomfort; loss of appetite; mood or mental changes. 
 
Please refer to the approved package insert for complete prescribing and toxicity 
information. 
 
 
7.1.5  Pharmaceutical Data/Formulation: Zidovudine is supplied in 20ml vials as a sterile 
solution in water for injection with 10 mg of Zidovudine per ml. Zidovudine is also 
available in 100 mg capsules and as syrup (50 mg/5ml). 
 
 
7.1.6  Storage and stability: The capsules are stored at 15-30°C, and should be protected 
from the sun.  The I.V. solution, after dilution, is physically and chemically stable 
for 24 hours at room temperature and 48 hours if refrigerated. 
 
 
7.1.7  Administration: Zidovudine I.V. infusion is administered intravenously at a 
constant rate over one hour.  Zidovudine should be diluted in D5W to achieve a 
concentration of less than or equal to 4 mg/ml prior to administration. 
 
 
7.1.8  Supplier: Commercially available. 


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7.2.  
Doxorubicin (Adriamycin) 
 
7.2.1 Classification:  anthracycline antibiotic. 
7.2.2 Mechanism of action:  Doxorubicin binds tightly with DNA, inhibits nucleic acid 
synthesis and causes DNA strand breaks. Although active throughout the cell cycle, 
cells in S phase are most sensitive. 
7.2.3 Metabolism: Doxorubicin is primarily excreted by the liver, and any liver 
impairment will increase toxicity.  Some of the drug is excreted in the urine.  The 
drug has a very short plasma half-life of < 20 minutes.  Animal studies indicate 
cytotoxic levels persist in tissue for as long as 24 hours. 
7.2.4 Human Toxicity:  Moderate to severe myelosuppression with the nadir for 
leukopenia occurring at 10-14 days.  Other common side effects include alopecia, 
and stomatitis, which is dose-related and may be severe.  Drug- induced 
cardiomyopathy, which may result in congestive heart failure is a cumulative dose-
dependent effect and risk becomes considerable at total doses exceeding 500 
mg/m2.  Doxorubicin is a vesicant causing severe local necrosis at the site of 
injection if extravasation occurs.  Nausea and vomiting are frequent.  Other side 
effects are listed in the table below.   
 
 
 
 
Common (> 30%) 
Uncommon (< 30%) 
Rare (< 5%) 
Esophagitis 
Hair loss 
Infection 
Leukopenia 
Nausea 
Red colored urine 
Stomatitis 
Vomiting 
Congestive heart failure 
Darkening of the soles and 
palms 
Diarrhea 
Hyperpigmentation of the 
fingernails 
Uric acid nephropathy 
 
Allergic dermatitis 
Allergic reaction 
Anaphylaxis 
Bronchospasm 
Drug fever 
Hives 
Shortness of breath 
Skin rash 
Wheezing 
 
 
 
Please refer to the approved package insert for complete prescribing and toxicity 
information. 
 
7.2.5 Pharmaceutical Data/Formulation:  Doxorubicin is available in 10, 20, 50, 100, and 
150 mg vials for intravenous use. It should be diluted with 0.9% sodium chloride 
to yield a final concentration of 2 mg/mL. 
7.2.6 Storage and Stability:  Store under refrigeration 2oC to 8oC (36oF to 46oF). Protect 
from light.  Retain in carton until time of use.  Multi-dose vial contains no 
preservatives.  Doxorubicin Hydrochloride for Injection, USP, is supplied in single 
dose vials as a sterile red orange lyophilized powder. The vials are packed in 
individual cartons.  Store under refrigeration 2oC to 8oC (36oF to 46oF).  After 
reconstitution the solution is stable for 7 days at room temperature and 15 days 
under refrigeration 2oC to 8oC (36oF to 46oF).  Discard unused portion. 
7.2.7   Administration:  Administer slowly over 3 to 5 minutes with a rapid flowing IV.  
Care in the administration of doxorubicin hydrochloride will reduce the chance of 
peri-venous infiltration.  It may also decrease the chance of local reactions such as 
urticarial and erythematous streaking.  On intravenous administration of 


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doxorubicin, 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 injection or 
infusion should be immediately terminated and restarted in another vein.  If it is 
known or suspected that subcutaneous extravasation has occurred, local infiltration 
with an injectable corticosteroid and flooding the site with normal saline has been 
reported to lessen the local reaction.  Because of the progressive nature of 
extravasation reactions, the area of injection should be frequently examined and 
plastic surgery consultation obtained.  If ulceration begins, early wide excision of 
the involved area should be considered. 
7.2.8 Supplier:  Commercially available 
 
 
7.3  
Methotrexate (Methotrexate sodium, MTX, MexateR, Mexate-AQR, FolexR, Folex 
PFSR, AbitrexateR, RheumatrexR, Amethopterin). 
 
7.3.1 Classification:  Antimetabolite. 
7.3.2 Mechanism of action:  Methotrexate inhibits the enzyme dihydrofolate reductase, 
thereby blocking the conversion of folic acid to its active form, tetrahydrofolic acid.  
Inhibition of this enzyme reduces purine synthesis and the conversion of 
deoxyuridylate to thymidylate that inhibits the synthesis of DNA, RNA and 
proteins. 
7.3.3 Metabolism:  Methotrexate given IV reaches an immediate peak with an unknown 
duration.  Methotrexate is excreted unchanged in the urine, except at high doses 
when it is partially metabolized to hydroxy-MTX and excreted. 
7.3.4 Human Toxicity:  Myelopsuppression, with the nadir for anemia at 6-13 days, for 
leukopenia at 4-7 days, and for thrombocytopenia at 5-12 days.  Common:  
anorexia; azotemia; bacterial infection; cutaneous vasculitis; gastroenteritis; gastric 
ulcers; stomatitis; hyperuricemia; nausea and vomiting; nephropathy. 
Uncommon:  renal failure; acne; cirrhosis; demyelination; hair loss; itching; 
pneumonitis; pulmonary fibrosis; skin rash. 
Other side effects:  Dermatologic: photosensitivity; furunculosis; depigmentation 
or hyperpigmentation; telangiectasia; skin desquamation (exfoliative dermatitis) 
and 
bullae 
formation; 
folliculitis. 
Gastrointestinal: 
diarrhea; 
anorexia; 
hematemesis; melena.  Genitourinary: Renal dysfunction: dose-related, more likely 
to occur in patients with already compromised renal function, dehydration, or on 
other nephrotoxic drugs, manifested by increased creatinine, hematuria.  Hepatic: 
Increased SGOT, mild and transient; hepatic fibrosis and cirrhosis, more likely to 
occur in patients receiving long-term continuous or daily methotrexate treatment.  
Neurologic:  tiredness, weakness, confusion, ataxia, tremors, irritability, seizures, 
coma.  Allergic: Fever and chills; rash; urticaria; anaphylaxis.  Ocular: 
Conjunctivitis; excessive lacrimation; cortical blindness has occurred with high 
doses. Pulmonary:  Cough dyspnea.  Other: Malaise; osteoporosis (aseptic necrosis 
of the femoral head); hyperuricemia; reversible oligospermia. 
 
 
Please refer to the approved package insert for complete prescribing and toxicity 
information. 


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7.3.5 Pharmaceutical Data/Formulation:  Lyophilized 20, 50, 100, and 250 mg vials are 
reconstituted with sterile water, normal saline or 5% dextrose to a concentration no 
greater than 25 mg/ml.  The 1000 mg vials are reconstituted with 19.4 ml to provide 
a concentration of 50 mg/ml.  Higher doses (> 100 mg) are often further diluted 
with 100 ml or more of 0.45%-0.9% sodium chloride or 5% dextrose. 
7.3.6 Storage and stability:  Store 
at 
room 
temperature 
protected 
from 
light.  
Reconstituted solutions are stable at room temperature for at least 1 week. Solutions 
(50 mg/100 ml) in PVC bags of 5% dextrose may be frozen at -20 C for at least 30 
days when thawed in 2 minutes by microwave radiation.  There is no loss of potency 
after 5 freeze-thaw cycles.  Doses of > 80 mg/week should be accompanied by 
leucovorin rescue. 
7.3.7 Administration: Usually administered by IV bolus (< 100 mg) or slow IV infusion 
over 30 minutes or longer (> 100 mg). Has also been given intrathecally, intra-
muscularly, orally, intra-arterially, intraperitoneally and intravesicularly.  For 
patients who are to begin methotrexate therapy at a dose of 1 gm/m2 or greater: 
Proper functioning of kidneys must be documented. Proper hydration and 
alkalinization of urine must be maintained. 
7.3.8 Supplier:  Commercially available  
 
 
 
7.4 Hydroxyurea (Other Names:  Hydrea, hydroxycarbamide (rINN), NSC-32065, 
SQ-1089,WR 83799 R) 
 
7.4.1 Classification:  Miscellaneous agent (substituted urea). 
7.4.2 Mechanism of Action:  Inhibits ribonucleotide reductase enzyme system thus 
inhibiting DNA synthesis.  It is S-phase specific. 
7.4.3 Metabolism:  Hydroxyurea reaches its peak 2 hours after oral administration and 
its duration is 24 hours.   
7.4.4 Human Toxicity:  Hematologic: Thrombocytopenia, leukopenia, anemia, 
megaloblastic erythropoiesis.  Gastrointestinal: Nausea, vomiting, diarrhea, 
constipation, mucositis, anorexia.  Dermatologic: Maculopapular rash, facial 
erythema, pruritus, alopecia, radiation recall phenomenon.  Neurologic: Headache, 
drowsiness, dizziness, disorientation, hallucinations, convulsions.  Renal: 
Hyperuricemia, dysuria, increased BUN and serum creatinine, proteinuria.  Liver: 
Transient elevation of hepatocellular enzymes, jaundice.  Other: Pulmonary edema; 
self-limited hepatitis and a flu-like syndrome (case report); acral erythema (case 
report). 
 
Please refer to the approved package insert for complete prescribing and toxicity 
information. 
7.4.5 Pharmaceutical Data/Formulation:  Available in 200, 300, 400, and 500 mg 
capsules. 
7.4.6 Storage and Stability:  Stored in tight containers at room temperature. Avoid 
excessive heat. 
7.4.7 Administration:  Oral.   
7.4.8 Supplier:  Hydroxyurea is commercially available. 


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7.5 
Leucovorin:  (Other Names:  Leucovorin Calcium, Wellcovorin‚ citrovorum 
factor, folinic acid, 5-formyl tetrahydrofolate, LV, LCV) 
 
7.5.1 Classification:  Tetrahydrofolic acid derivative. 
7.5.2 Mechanism of Action:  Leucovorin acts as a biochemical cofactor for 1-carbon 
transfer reactions in the synthesis of purines and pyrimidines. Leucovorin does not 
require the enzyme dihydrofolate reductase (DHFR) for conversion to 
tetrahydrofolic acid.  Leucovorin can potentiate the cytotoxic effects of fluorinated 
pyrimidines (i.e., fluorouracil and floxuridine). After 5-FU is activated within the 
cell, it is accompanied by a folate cofactor, and inhibits the enzyme thymidylate 
synthetase, thus inhibiting pyrimidine synthesis. Leucovorin increases the folate 
pool, thereby increasing the binding of folate cofactor and active 5-FU with 
thymidylate synthetase. 
7.5.3 Metabolism:  Oral leucovorin has its onset of action in 20-30 minutes, reaches its 
peak in 2-3 hours and has duration of 3-6 hours.  Intravenous leucovorin has its 
onset of action in 5 minutes, reaches its peak at 10 minutes and has duration of 3-6 
hours. 
7.5.4 Human Toxicity:  Hematologic: Thrombocytosis.  Dermatologic: Skin rash. 
Gastrointestinal: Nausea, upset stomach, and diarrhea.  Allergic: Skin rash, hives, 
pruritus.  Pulmonary: Wheezing (possibly allergic in origin).  Other: Headache; 
may potentiate the toxic effects of fluoropyrimidine therapy, resulting in increased 
hematologic and gastrointestinal (diarrhea, stomatitis) adverse effects. 
Please refer to the package insert for complete prescribing and toxicity information. 
7.5.5 Pharmaceutical Data/Formulation:  The 50 and 100 mg vials for injection are 
reconstituted with 5 and 10 ml of sterile water, respectively, resulting in a 10 mg/ml 
solution. The 350 mg vial is reconstituted with 17 ml of sterile water resulting in a 
20 mg/ml solution. Due to the increased preservative content with the higher doses 
of bacteriostatic water, only sterile water should be used for reconstitution of 
leucovorin doses greater than 10 mg/m2.  Also available in 5, 10, 15 and 25 mg 
tablets. 
7.5.6 Storage and Stability:  All dosage forms are stored at room temperature. At 
concentrations of 0.5-0.9 mg/ml the drug is chemically stable for at least 24 hours 
at room temperature under normal laboratory light. 
7.5.7 Administration:  Intravenous infusion over 15minutes- 2 hours.  Compatibilities:  
Leucovorin (0.5-0.9 mg/ml) is chemically stable for at least 24 hours in normal 
saline, 5% dextrose, 10% dextrose, Ringer's injection or lactated Ringer's injection. 
Leucovorin is also compatible with fluorouracil. 
 
7.5.7 Availability:  Commercially available. 
 
7.6 
Rituximab 
 
7.6.1 Rituximab is a chimeric mouse/human anti-CD 20 monoclonal antibody that has 
been shown to bind human C1q, mediate complement-dependent cell lysis and lyse 
human target cells through antibody dependent cellular cytotoxicity. It has 


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documented anti-tumor activity in low grade or follicular B-cell non-Hodgkin’s 
lymphoma and was recently FDA-approved for that indication. Rituximab will not 
be supplied by PMB for this protocol. The agent must be commercially obtained. 
 
7.6.2 Adverse Events and Potential Risks List for Rituximab  
The Adverse Event and Potential Risks list provides a single list of reported and/or 
potential adverse events (AE) associated with Rituximab.  
 
Common adverse events (frequency >20%), occurring among patients receiving Rituximab (MoAb 
C2B8 anti CD20, chimeric): 
• Nausea 
• Chills, fever 
• Infusion related reaction  
• Decrease in lymphocyte count  
 
 
 
Occasional and serious adverse events (frequency ≤ 20%), occurring among patients receiving 
Rituximab (MoAb C2B8 anti CD20, chimeric): 
• 
Anemia which may require 
blood transfusions 
• 
Anemia 
• 
Blood and lymphatic 
system disorders - Other 
(Hyperviscosity: 
Waldenstrom’s) 
• 
Febrile neutropenia 
• 
Myocardial infarction 
• 
Sinus tachycardia 
• 
Supraventricular 
tachycardia 
• 
Abdominal pain 
• 
Diarrhea 
• 
Nausea  
• 
Edema limbs  
• 
Fatigue 
• 
Pain 
• 
Allergic reaction, serum 
sickness 
• 
Skin and subcutaneous 
tissue disorders - Other 
(angioedema) 
• Rash maculo-papular 
• Urticaria 
• 
Flushing 
• 
Hypertension 
• 
Hypotension 
• 
Infections and infestations - Other (Activation of Hepatitis B, C, 
CMV, parvovirus B19, JC virus, varicella zoster, herpes simplex, 
West Nile virus) 
• 
Infections and infestations - Other (Infection in HIV Positive 
Patients) 
• 
Neutrophil count decreased 
• 
Platelet count decreased 
• 
White blood cell decreased 
• 
Hyperglycemia 
• 
Hypocalcemia 
• 
Hypokalemia 
• 
Arthralgia 
• 
Back pain 
• 
Myalgia 
• 
Tumor pain 
• 
Dizziness 
• 
Headache 
• 
Lethargy 
• 
Seizure 
• 
Acute kidney injury 
• 
Allergic rhinitis 
• 
Bronchospasm 
• 
Cough 
• 
Dyspnea 
• 
Hypoxia 
• 
Pneumonitis 
• 
Sore throat 
• 
Hyperhidrosis 
• 
Pruritus 
 


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Rare but serious adverse events ( frequency ≤3), among patients receiving Rituximab (MoAb C2B8 anti 
CD20, chimeric): 
• 
Anaphylaxis  
• 
Tumor Lysis Syndrome  
• 
Nervous system disorders - Other (progressive multifocal leukoencephalopathy) 
• 
Adult respiratory distress syndrome 
• 
Erythema multiforme 
• 
Stevens-Johnson syndrome 
• 
Toxic epidermal necrolysis 
Also reported on rituximab trials but with the relationship to rituximab still undetermined: 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Bone marrow hypocellular; Hemolysis 
CARDIAC DISORDERS - Atrial fibrillation; Atrial flutter; Cardiac disorders - Other (cyanosis); 
Left ventricular systolic dysfunction; Sinus bradycardia; Ventricular fibrillation 
EYE DISORDERS - Conjunctivitis; Eye disorders - Other (ocular edema); Uveitis; Watering eyes 
GASTROINTESTINAL DISORDERS - Constipation; Dyspepsia; Dysphagia; Gastrointestinal 
obstruction3; Gastrointestinal perforation4; Mucositis oral 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Flu like 
symptoms; Non-cardiac chest pain 
INFECTIONS AND INFESTATIONS - Infections and infestations - Other (Opportunistic 
infection associated with >=Grade 2 Lymphopenia) 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Fracture 
INVESTIGATIONS - Alkaline phosphatase increased; Aspartate aminotransferase increased; 
Blood bilirubin increased; Cardiac troponin I increased; Cardiac troponin T increased; Creatinine 
increased; Investigations - Other (hyperphosphatemia); Investigations - Other (LDH increased); 
Weight loss 
METABOLISM AND NUTRITION DISORDERS - Anorexia; Hypercalcemia; Hyperkalemia; 
Hypermagnesemia; 
Hypernatremia; 
Hyperuricemia; 
Hypoglycemia; 
Hypomagnesemia; 
Hyponatremia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthritis 
NERVOUS SYSTEM DISORDERS - Nervous system disorders - Other (Cranial Neuropathy 
NOS); Peripheral motor neuropathy; Peripheral sensory neuropathy; Pyramidal tract syndrome; 
Reversible posterior leukoencephalopathy syndrome; Syncope 
PSYCHIATRIC DISORDERS - Agitation; Anxiety; Depression; Insomnia 
RESPIRATORY, 
THORACIC 
AND 
MEDIASTINAL 
DISORDERS 
- 
Epistaxis; 
Pharyngolaryngeal pain; Pleural effusion; Pulmonary edema; Respiratory, thoracic and 
mediastinal disorders - Other (bronchiolitis obliterans) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Skin and subcutaneous 
tissue disorders - Other (paraneoplastic pemphigus) 
VASCULAR DISORDERS - Phlebitis; Thromboembolic event; Vasculitis 
Note: Rituximab in combination with other agents could cause an exacerbation of any adverse 
event currently known to be caused by the other agent, or the combination may result in events 
never previously associated with either agent. 


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7.6.3 Method of Administration 
 
The administration of rituximab will be accomplished by slow IV infusion.  
 
CAUTION: DO NOT ADMINISTER AS AN INTRAVENOUS PUSH OR BOLUS.  
 
Rituximab infusions may be administered to patients in an outpatient clinic setting. Oral 
pre- 
medication (650 mg of acetaminophen and 50 mg diphenhydramine hydrochloride) will be 
 
administered 30 to 60 minutes prior to starting each infusion of rituximab. A central 
intravenous  
line will be established. During the rituximab infusion, the patient’s vital signs 
(blood pressure,  
pulse, respiration, temperature) should be monitored every 15 minutes times 
4 or until stable and  then hourly until the infusion is discontinued. Available at the bedside prior 
to rituximab  administration will be epinephrine for subcutaneous injection, diphenhydramine 
hydrochloride  for intravenous injection, and resuscitation equipment for the emergency 
management of  
anaphylactic reactions. IV pumps such as the IMED 960 may be used with 
the rituximab  infusion. DO  NOT INFUSE CONCOMITANTLY with another IV solution or IV 
medications.  Prime the line with the rituximab solution such that approximately 30 mL are 
delivered. This will  saturate the tubing. If a delay in administration of the infusion occurs after 
the product is  prepared, the properly identified container may be kept refrigerated at 2-8°C (36-
46 degrees F)  for 24 hours and at room temperature for an additional 12 hours. The initial dose 
rate at the time  
of the first rituximab infusion should be 50 mg/hr for the first hour. If no 
toxicity is seen, the  dose rate may be escalated gradually (50 mg/hr increments at 30 minute 
intervals) to a maximum  
of 400 mg/hr. If the first dose of rituximab is well tolerated, the 
starting flow-rate for the  
administration of subsequent doses will be 100 mg/hr then increased 
gradually (100 mg/hr  increments at 30 minute intervals) not to exceed 400 mg/hr. Rituximab may 
be given at a slower  infusion rate if it is consistent with institutional policy.  
 
 
8.0  
CORRELATIVE/SPECIAL STUDIES 
 
Parallel translational studies will be performed, see Appendix II, as part of this protocol.  
An important question is the effect of our regimen on EBV viral load and modulation of 
gene expression profile.  This is particularly relevant in view of the recent finding that 
quantification of EBV DNA is useful for monitoring patients with nasopharyngeal 
carcinoma and lymphoma (25, 26).  It will also be particularly important to determine the 
effect of chemotherapy on viral reactivation (lytic cycle) from tumor and latently infected 
peripheral blood memory B cells, since we hypothesize a higher proportion of these harbor 
latent virus, and the viral load in the presence of high dose ZDV.  See Appendices III and 
IV for collection instructions. 
 
 
 
We will also perform studies on available primary tumors to determine:  (1) pattern of EBV 
latency and (2) expression of EBV kinases (BGLF/vPK and BXLF1/vTK). The antivirals 
used in this protocol (ZDV and ganciclovir) are excellent substrates for the viral kinases. 
These studies are highly relevant and will provide important information as to whether the 
expression patterns of EBV change in tumors from patients with relapsed lymphomas. 
 


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Finally, we will measure the effects of drug therapy used in this protocol on HIV infection 
(in positive subjects), immune activation markers in peripheral blood T-cells, and plasma 
cytokines in order to investigate whether treatment results in immune re-constitution or 
exhaustion, and the effect of treatment and disease status with inflammation. These studies 
have not been done previously within the context of a HIV or EBV lymphoma trials. 
 
9.0  
MEASUREMENT OF EFFECT 
 
All patients will be evaluated for clinical response by physical examination following each 
chemotherapy cycle and by imaging studies at the conclusion of cycles 2, 4 and at the 
conclusion of cycle 6.   
 
9.1 
Response Assessment 
 
Response is assessed on the basis of clinical, radiologic, and pathologic (i.e. bone marrow) 
criteria. 
 
1. CT scans remain the standard for evaluation of nodal disease. Brain, thoracic, 
abdominal, and pelvic CT scans will be performed for staging even if those areas were 
not initially involved because of the unpredictable pattern of recurrence in NHL. Neck 
CT scans will be required if disease involving this area was present at baseline. 
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. 
 
9.2 
Definition of Response 
 
9.2.1 Complete Response (CR) 
 
9.2.1.1 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. lactate dehydrogenase (LDH) or calcium] definitely 
assignable to NHL. 
9.2.1.2 All lymph nodes and tumor masses must have disappeared or regressed to 
normal size (less than or equal to 1.5 cm in their greatest transverse 
diameters for nodes >1.5 cm before therapy).  
9.2.1.3 Previously involved nodes that were 1.1 to 1.5 cm in their greatest 
transverse diameter before treatment must have decreased to less than or 
equal to 1 cm in their greatest transverse diameter after treatment, or by 
more than 75% bin the sum of the products of the greatest diameters 
(SPD). 
9.2.1.4 The spleen, if considered enlarged before therapy on the basis of a CT 
scan, must have decreased in size and must not be palpable on physical 
examination. Similarly, other organs considered to be enlarged before 
therapy due to involvement by NHL, such as liver and kidneys, must have 


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decreased in size. 
9.2.1.5 If the bone marrow was involved by NHL before treatment, the infiltrate 
must be cleared on repeat bone marrow aspirate and biopsy of the same 
site. 
9.2.1.6 No new sites of disease. 
9.2.1.7 Typically FDG-avid lymphoma:  in subjects with no pre-treatment PET 
scan or when the PET scan was positive before therapy, a post-treatment 
residual mass of any size in permitted as long as it is PET negative. 
9.2.1.8 Variably FDG-avid lymphomas/FDG activity unknown:  in subjects 
without a pre-treatment PET scan, or if a pre-treatment PET scan was 
negative, all lymph nodes and nodal masses must have regressed on CT 
to normal size (1.5 cm in their greatest transverse diameter for nodes > 
1.5 cm before therapy).  Previously involved nodes that were 1.1 to 1.5 
cm in their long axis and more than 1.0 cm in their short axis before 
treatment must have decreased to 1.0 cm in their short axis after treatment. 
 
9.2.2 Clinical Complete Response (CCR):   
 
 
Clinical complete responders will be grouped with complete responders if they 
qualify for inclusion by meeting all of the following criteria: 
 
9.2.2.1 No abnormal palpable lymph nodes.  In the event there is a suspicious or 
equivocal palpable lymph node, a negative biopsy is required. 
9.2.2.2 No “B” symptoms (unexplained fevers, night sweats, involuntary weight 
loss greater than 10% normal body weight). 
Chest radiograph and/or CT chest scan must be normal or, if mediastinal 
widening persists, the abnormal extra width must be diminished by at least 
50% compared with pretreatment radiographs and there must have been 
no progression for eight weeks or more after the completion of therapy. 
9.2.2.3 Residual opacified lymph nodes must return to normal as demonstrated 
by appearance on plain film of the abdomen or repeat lymphangiogram. 
If abnormal, there must have been at least a 50% reduction in the abnormal 
enlargement of the lymph nodes and there must have been no change in 
size for at least eight weeks after the completion of therapy.  Architecture 
should be ignored for this type of evaluation. 
9.2.2.4 CT abdomen/pelvic scan should be normal, or if abnormal, at least an 80% 
reduction from the initial abnormal enlargement of the measurable lesions 
should be seen and maintained for at least eight weeks after the 
completion of therapy. 
 
9.2.3 Partial Response (PR) requires the following: 
 
9.2.3.1 At least ≥ 50% decrease in sum of the product diameter (SPD) of the six 
largest dominant nodes or 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 


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from disparate regions of the body as possible, and (c) they should include 
mediastinal and retroperitoneal areas of disease whenever these sites are 
involved. 
9.2.3.2 No increase in the size of the other nodes, liver, or spleen. 
9.2.3.3 Splenic and hepatic nodules must regress by at least 50% in the SPD or, 
for single nodules, in the greatest transverse diameter. 
9.2.3.4 With the exception of splenic and hepatic nodules, involvement of other 
organs is usually assessable and not measurable disease should be present. 
9.2.3.5 Bone marrow assessment is irrelevant for determination of a PR if positive 
before treatment.  However, if positive, the cell type should be specified 
in the report, (e.g., large cell lymphoma or small neoplastic B cells).  
Subjects who achieve CR by the above criteria, but who have persistent 
morphologic bone marrow involvement will be considered partial 
responders.  When the bone marrow was involved before therapy and a 
clinical CR was achieved, but with no bone marrow assessment after 
treatment, subjects should be considered partial responders.  
9.2.3.6 No new sites of disease. 
9.2.3.7 Typically FDG-avid lymphoma:  in subjects with no pre-treatment PET 
scan or when the PET scan was positive before therapy, the post-treatment 
PET should be positive in at least one previously involved site. 
9.2.3.8 Variably FDG-avid lymphomas/FDG activity unknown:  in subjects 
without a pre-treatment PET scan, or if a pre-treatment PET scan was 
negative CT criteria should be used. 
 
9.2.4 Stable disease is defined as less than a PR (see above) but is not progressive disease 
(see below). 
 
9.2.4.1 Typically FDG-avid lymphomas:  the PET should be positive at prior sites 
of disease with no new areas of involvement on the post-treatment CT or 
PET. 
9.2.4.2 Variably FDG-avid lymphomas/FDG –avidity unknown:  subjects 
without a pre-treatment PET scan or if the pre-treatment PET was 
negative, there must be no change in the size of the previous lesions on 
the post-treatment CT scan.  
 
9.2.5 Relapsed Disease (after CR)/Progressive Disease (after PR, SD) 
9.2.5.1 Lymph nodes should be considered abnormal if the long axis is more than 
1.5 cm regardless of the short axis.  If a lymph node has a long axis of 1.1 
to 1.5 cm, it should only be considered abnormal if its short axis is more 
than 1.0 cm.  Lymph nodes 1.0 x 1.0 cm will not be considered as 
abnormal for relapse or progressive disease. 
9.2.5.2 Appearance of any new lesion more than 1.5 cm in any axis during or at 
the end of therapy, even if other lesions are decreasing in size.  Increased 
FDG uptake in a previously unaffected site should only be considered 
relapsed or progressive disease after confirmation with other modalities.  
In subjects with no prior history of pulmonary lymphoma, new lung 


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nodules identified by CT are mostly benign.  Thus, a therapeutic decision 
should not be made solely on the basis of the PET without histologic 
confirmation. 
9.2.5.3 At least a 50% increase from nadir in the SPD of any previously involved 
nodes, or in a single involved node, or the size of other lesions (e.g., 
splenic or hepatic nodules).  To be considered progressive disease, a 
lymph node with a diameter of the short axis of less than 1.0 cm must 
increase by 50% and to a size of 1.5 x 1.5 cm or more than 1.5 cm in the 
long axis. 
9.2.5.4 At least a 50% increase in the longest diameter of any single previously 
identified node more than 1 cm in its short axis. 
9.2.5.5 Lesions should be PET positive if observed in a typical FDG-avid 
lymphoma or the lesion was PET positive before therapy unless the lesion 
is too small to be detected with current PET systems (< 1.5 cm in its long 
axis by CT. 
9.2.5.6 Measurable extra nodal disease should be assessed in a manner similar to 
that for nodal disease.  For these recommendations, the spleen is 
considered nodal disease.  Disease that is only assessable (e.g., pleural 
effusions, bone lesions) will be recorded as present or absent only, unless, 
while an abnormality is still noted by imaging studies or physical 
examination, it is found to be histologically negative. 
9.2.6 Recurrent disease is defined as the appearance of tumor following documentation 
of a complete remission.  
9.2.7 Time to response is defined as time from the first dose of chemotherapy until 
documentation of first response.  
9.2.8 Time to progression is defined as time from initiation of chemotherapy to 
documentation of first progression. 
9.2.9 Response duration is defined as the time from first documentation of response to 
documentation of first progression. 
9.2.10 Failure–free survival (FFS) will be measured from the date of treatment initiation 
until date of documented disease progression, relapse after response, or death from 
any cause.  For patients alive and free of relapse or progression, follow-up time will 
be censored at the last documented date of failure-free status. 
9.2.11 Overall survival (OS) will be measured from the date of initiation of study treatment 
until date of death from any cause.  In the absence of death, the follow-up will be 
censored at date of last contact (censored observation). 
 
10.0 
ADVERSE EVENT REPORTING  
 
 
 
The descriptions and grading scales found in the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for adverse event 
reporting.  A copy of the CTCAE version 4.0 can be downloaded from the CTEP web site 
(http://ctep.cancer.gov/reporting/ctc.html).   
 
10.1 
Definitions 
 


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10.1.1 Adverse Event (AEs) – Any unfavorable and unintended sign (including 
any clinical significant 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).  Each AE is a unique representation of a specific event used for 
medical documentation and scientific analysis. 
 
10.1.2 Serious Adverse Event (SAE) – Any adverse event (except those listed in 
section 10.2.5) occurring at any dose that results in any of the following 
outcomes: death, a life-threatening adverse event, inpatient hospitalization 
or prolongation of existing hospitalization, a persistent or significant 
disability/incapacity, or a congenital anomaly/birth defect. 
 
SAEs are defined by the FDA and therefore seriousness (not severity) serves 
as a guide for defining regulatory reporting obligations for patient/subject 
safety.  Serious is based on patient/event outcome or action criteria usually 
associated with events that pose a threat to a patient’s life or functioning. 
 
10.1.3 Expected events are those that have been previously identified as resulting 
from administration of the agent(s). 
 
10.1.4 An adverse event is considered unexpected when either the type of event 
or the severity of the event is not listed in the:  current NCI Agent-Specific 
Adverse Event List; investigator’s brochure; drug package insert; or the 
drug information section of this protocol. 
 
10.1.5 The definition of related is that there is a reasonable possibility that the drug 
caused the adverse experience. 
Attribution categories: 
 
Definite – The adverse event is clearly related to the investigational 
agent(s). 
Probable – The adverse event is likely related to the investigational agent(s). 
Possible – The adverse event may be related to the investigational agent(s). 
Unlikely – The adverse event is doubtfully related to the investigational 
agent(s). 
Unrelated – The adverse event is clearly NOT related to the investigational 
agent(s). 
 
10.2 Adverse Events with Commercial Agents 
 
The following adverse reactions must be reported to the Principal Investigator and the 
Institutional Review Board in the manner described below.   
 


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Commercial Agents: 
Zidovudine, 
Hydroxyurea, 
Doxorubicin, 
Methotrexate, 
Leucovorin 
 
10.2.1 Investigators are required to report adverse events which fit the following 
criteria within 10 working days of the time the investigator becomes aware of 
them: 
 
10.2.1.1 
Event is UNANTICIPATED (An unanticipated event is any adverse 
experience where the nature, severity or frequency is not identified in 
the drug package insert or described in the protocol.  Events which are 
already cited in the drug package insert or protocol are not 
unanticipated and do not have to be reported),  
 
AND  
 
Event is RELATED to the study design, procedures, or 
drug/device (possibly, probably, definitely related, or 
unknown).  If the adverse event is clearly not related to the 
study drug, device, procedures, or washout process, it would 
not represent a risk to other subjects in the research and, 
therefore, does not have to be reported. 
10.2.2 Do not report adverse events that are clearly not related to the study drug, 
device, procedures, or washout process.   
10.2.3 Any death, regardless of causality or relationship to the protocol, must be 
reported within 24 hours of the knowledge of the event.  Attribution to treatment 
or other cause must be provided. 
10.2.4  Clinical laboratory results that are outside of the normal ranges are adverse 
events if they meet criteria as per 10.2.1.1 
10.2.5 In this protocol the following clinical laboratory abnormalities are 
 
expected and will not be reported as SAEs except those ≥ Grade 3 
• Anemia 
• Leucopenia (including neutropenia and lymphopenia) 
• Thrombocytopenia 
• HIV viral load (if applicable) 
• T Cell subsets (if applicable) 
 
11.0 
DATA REPORTING 
 
 
 
11.1 
Records to be kept 
 
 
 
Paper Case Report forms (CRFs) will be provided for each subject.  Subjects will be 
identified by a Patient Identification Number assigned by coordinating site study team 
upon registration. Any requested information that is not obtained as specified in the 
protocol should have an explanation noted on the paper CRF as to why the required 


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information was not obtained. SAEs and AEs will be entered in Velos eResearch 
program for each subject. 
 
11.2 Role of Data Management 
 
11.2.1 Instructions concerning the recording of study data on CRFs will be provided 
by the project coordinator. 
11.2.2 The timeline for forms submission can be found in Appendix V. 
11.2.3 Record Retention 
11.2.3.1 
Federal regulations require that records of drug disposition, source 
documentation, CRFs, and all reports of this investigation shall be 
retained by the principal investigator for a minimum of 2 years following 
notification by the PI that the IRB has been notified of the study’s 
discontinuation.  
 
12.0 
CRITERIA FOR DISCONTINUATION OF THERAPY 
 
12.1 
Permanent Withdrawal  
 
After enrollment, the patient will be permanently withdrawn from study           
treatment for any of the following reasons: 
 
12.1.1 Development of an intercurrent illness that prevents further administration 
of treatment.  
12.1.2 Unacceptable adverse events. Progressive disease at any time while on 
study.   
12.1.3 Voluntary withdrawal.  
12.1.4 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. 
 
12.2 Permanent Withdrawal Evaluations 
 
 
 
 
Subjects going off treatment prior to completion of therapy or for progressive 
disease will have a complete physical examination, a toxicity evaluation and blood 
drawn for the following studies: CBC, differential and platelet count Serum 
electrolytes, blood urea nitrogen (BUN), creatinine, total bilirubin, alkaline 
phosphatase (ALP), LDH, total protein, albumin, calcium, , AST, ALT and EBV 
viral load. No additional studies are required.  Subjects that achieve CR will be 
followed at least yearly for survival only, as well as those who voluntarily withdraw 
consent, are removed by the principal investigator from the study for clinical 
reasons, received or not bone marrow transplant. 
 
13.0 
STATISTICAL CONSIDERATIONS 
 
13.1 Overview 
 


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The primary objective of this phase II study is to determine the clinical response of 
patients with relapsed EBV+ associated non-Hodgkin’s or Hodgkin’s lymphoma or 
post-transplant lymphoproliferative disease treated with high dose parenteral 
zidovudine and oral hydroxyurea and combination chemotherapy with Doxorubin, 
Methotrexate, and Leucovorin.  Secondary objectives include evaluate 1-year overall 
survival and failure-free survival, toxicity, and correlative studies endpoints, such as, 
EBV reactivation, circulating EBV viral load, and immune response parameters. 
 
13.2 Definitions  
 
13.2.1 
At the time signed informed consent is given, a patient is considered to be on 
study. 
 
13.2.2 
 Evaluable patients will be study-eligible patients who initiate the study 
treatment, regardless of the number of treatment cycles completed.  All 
evaluable patients will be assessed for treatment response, toxicity, disease 
progression, and survival.   
 
13.2.3 
Patients are considered to be on treatment as long as they continue to receive 
study treatment.  Patients who are off treatment will remain on study and will 
be followed for toxicity, response, progression, and survival. 
 
13.2.4 
Exclusions from study (not evaluable patients): 
 
13.2.4.1 Patients who are enrolled on study but not treated (do not receive 
any dose of study treatment) will be excluded from all analyses, 
including analyses of failure-free and overall survival, and safety.  
Reasons for such withdrawals, such as eligibility not confirmed or 
consent withdrawn, will be characterized. 
13.2.4.2 Any patient who is treated but later found to be ineligible for study 
(a “protocol violation”) will be withdrawn from study but followed 
for survival and toxicity.  Such patient experience will be 
characterized separately from that of evaluable patients, whose 
experience will represent the main basis for evaluating the 
therapeutic regimen of this phase II trial. 
 
13.2.5 
Failure–free survival (FFS) will be measured from the date of treatment 
initiation until date of documented disease progression, relapse after response, 
or death from any cause.  For patients alive and free of relapse or progression, 
follow-up time will be censored at the last documented date of failure-free 
status. 
 


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13.2.6 
Overall survival (OS) will be measured from the date of initiation of study 
treatment until date of death from any cause.  In the absence of death, the 
follow-up will be censored at date of last contact (censored observation). 
 
13.3 
Statistical Plan:  
 
Study Size: We plan to enroll a total of 26 evaluable patients over a period of 4 years 
(5-6 patients per year) and follow them for a minimum of 1 year. The resulting study 
falls within our capacity for enrollment and provides sufficient precision for our main 
objective. 
 
Efficacy: Assessment of treatment efficacy will be made with regard to the rate of 
overall response (complete, complete/unconfirmed, or partial responses), failure-free 
survival, and overall survival.  The overall response rate (CR+PR) and rates of the 
individual categories of best clinical response (CR, PR, SD, and PD) will be estimated 
by the percentage of patients achieving each specific response type. The precision of 
these estimates will be characterized by the corresponding 90% confidence intervals 
using the exact binomial method (28).  The time to onset and duration of response will 
be summarized (median and range) for each response type.  
 
Analysis of primary and secondary endpoints will be based on all evaluable patients, 
i.e., patients who are study eligible and initiate the study treatment, regardless of 
whether they receive the complete first cycle of treatment.  Secondary analyses will 
consider evaluable patients receiving 3 or more cycles of treatment.   
 
Demographic (age at diagnosis, gender, and race/ethnicity), and other baseline 
characteristics (performance status, previous therapies, molecular and viral 
characteristics of EBV lymphoma: EBV viral load, protein expression) will be 
summarized using plots and descriptive statistics (28) counts and percentages, range, 
median, mean, and standard deviation, as appropriate.  
 
Toxicity: Adverse events and toxicities will be tabulated by severity, attribution to 
treatment, and treatment cycle according to the most recent NCI CTCAE criteria.  A 
patient-level summary by worse grade adverse event will be included.  
 
Treatment feasibility: The feasibility of administering the per-protocol treatment will 
be characterized by the percentage of evaluable patients who initiate and complete each 
treatment cycle.  Number of cycles of therapy required to achieve best response, total 
number of cycles completed, reasons for study withdrawal, laboratory data, and 
concomitant medications, will be summarized descriptively. 
 
Efficacy: Assessment of treatment efficacy will be made with regard to the rate of 
overall response (complete, complete/unconfirmed, or partial responses), failure-free 
survival, and overall survival for all subjects and separate disease entities. 


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The overall response rate (CR+PR) and rates of the individual categories of best clinical 
response (CR, PR, SD, and PD) will be estimated by the percentage of patients 
achieving each specific response type. The precision of these estimates will be 
characterized by the corresponding 90% confidence intervals using the exact binomial 
method (28).  The time to onset and duration of response will be summarized (median 
and range) for each response type. Failure-free survival (FFS) and overall survival (OS) 
will be estimated by the Kaplan-Meier method. Estimates of FFS and OS rates at 3, 6, 
9, and 12 months will be reported along with corresponding 90% confidence intervals 
(29).  Median failure-free time and survival, if achieved, will be estimated along with 
corresponding 90% confidence intervals. The amount of patient follow-up will be 
characterized descriptively by the range and median for patients who experience the 
event (progression or death) and for those who do not (censored observations). To the 
extent possible with 26 patients, Cox proportional hazards regression (29) will be used 
to assess whether FFS and OS are affected by demographic and baseline disease 
characteristics, or any correlative laboratory or clinical parameters.  Given the small 
number of patients, all analyses are essential exploratory in nature and no adjustments 
for multiple comparisons will be made. 
Survival. We plan to enroll a total of 26 evaluable patients over a period of 4 years (5-
6 patients per year) and follow them for a minimum of 1 year.  The resulting study falls 
within our capacity for enrollment at multiple clinical sites and provides sufficient 
precision for our main objective. It is expected that the study treatment will result in a 
median overall survival of 6 months or better, that is a 6-month survival rate of 50% or 
higher.  
Study precision can be expressed in terms of the 90% confidence interval (90% CI) for 
the 6-month survival rate.  Assuming 50% of the 26 evaluable patients remain alive for 
6 months, and no losses to follow-up, Peto's approximation (27) for the standard error 
of the 6-month survival rate is 9.8%, and the corresponding 90% CI is 33.9% to 66.1%.  
Such a finding would establish with high confidence (95%) that the true 6-month 
survival rate for this treatment regimen is not less than 33.9%.  We note further that the 
estimated study precision based on 26 patients is only slightly less than that for a much 
larger investigation attaining a similar result.  Specifically, a study of 36 patients (38% 
more patients) in which 50% are alive at 6 months would yield a 90% CI of 36.3% to 
63.7%, which is only slightly narrower than the interval based on 26 patients (width 
27.4% v. 32.2%). 
Table 13.1 below illustrates possible study findings on survival based on 26 patients, 
assuming no patient is lost to follow up within 6 months of treatment initiation.  The 
first row shows the expected 6-month survival rate of 50%, which “rules out" 6-month 
survival rates smaller than 33.9%.  The second row shows that a less favorable study 
outcome of 38.5% alive at 6 months would only "rule out" 6-month survival rates 
smaller than 22.8%.  A more favorable finding shown in the third row, namely 6-month 
survival rate of 61.5%, would indicate with high confidence (95%) that the true 6-
month survival rate is at least 45.8%.  The far right column of this table presents the 
median time to progression, derived under the assumption of exponential survival, 
corresponding to the 6-month rates in the second column.  


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38 
 
Table 13.1 Possible outcomes for survival with 26 patients 
# 
of 
pts 
alive/26  
with min 6-month follow-up 
6-month  
survival rate 
90% 
confidence 
interval* 
Median 
survival 
time** 
Expected study finding 
 
 
 
13/26 
50% 
33.9% - 66.1% 
6 months 
Less favorable finding 
 
 
 
10/26 
38.5% 
22.8% - 54.2% 
4.4 months 
More favorable finding 
 
 
 
16/26 
61.5% 
45.8% - 77.2% 
8.6 months 
  * Based on Peto's formula for the standard error and assuming no censoring within the first 6 
months of follow-up. 
 ** Based on the 6-month OS rates and under the assumption of exponential survival. 
 
 
13.4 
Correlative Studies 
 
13.5.1  
Determining EBV gene or viral protein (kinase) and latency/lytic gene 
expression patterns on available tissue in patients with relapsed Epstein Barr 
Virus associated lymphomas and any association with treatment response 
and survival. Tissue will be stored for future studies, which may include 
immunohistochemistry or in situ hybridization for BGLF4/vPK, 
BXLF1/vTK, LMP-1, BZLF-1, and EBV gene expression array studies, 
genome wide gene expression arrays, next generation sequencing, and the 
use of new genomic or proteomic technologies that become available in the 
future 
 
 
13.5.2 Measurements of plasma circulating EBV viral loads (by quantitative EBV PCR) 
 
obtained at baseline, at various times during treatment, and post treatment will be 
 
summarized using plots and descriptive statistics, in order to study the effects of 
 
chemotherapy/AZT on blood circulating memory B cells which harbor latent virus, 
 
peripheral blood mononuclear cells will be evaluated for EBV reactivation using our 
 
specialized EBV gene expression array (Dr. Dittmer laboratory). Measurements of the 
 
effects  of drug therapy on HIV infection (in positive subjects) and immune activation 
 
markers in peripheral blood T-cells will investigate immune re-constitution or 
 
exhaustion. 
 
14.0 DATA AND SAFETY MONITORING 
 
14.1 
Role of Research Team and Data and Safety Monitoring Committee (DSMC) 
The Research Team will continuously monitor study accruals, toxicities, and response to 
treatment, as measured by overall survival. The UM/Sylvester Comprehensive Cancer 
Center’s Data and Safety Monitoring Committee (DSMC) will monitor this protocol 
according to the Cancer Center’s DSM plan.  In its oversight capacity, the DSMC bears 
responsibility for suspending or terminating this study. 


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39 
 
DSMC oversight of the conduct of this trial includes ongoing review of adverse event data 
and periodic review of response to treatment, as measured by overall survival.  The DSMC 
also reviews reports from internal audits of protocol compliance and data integrity 
conducted by the University of Miami, Office of Research Compliance Assessment.  The 
guidelines in this section are offered for DSMC consideration in assessing adverse events 
and response to study treatment. 
14.2  
Early stopping guidelines  
We propose the following guidelines for the DSMC in its review of accumulating data 
on toxicity and response to treatment, as measured by overall survival.  These 
guidelines were developed using Bayesian methods, which can be applied at any stage 
of enrollment without pre-specification of the number of interim analyses to be 
performed, or the number of patients evaluable for toxicity or survival at the time such 
assessments are made (30,31).  Under the Bayesian method, we assign a prior 
probability (level of belief at the start of the trial) to a range of possible values for the 
true rate.  As data on treated patients become available, this probability distribution is 
revised and the resulting posterior probability becomes the basis for recommending 
either early termination or continuation of the study.  In the sections that follow, we 
provide specific stopping guidelines based on posterior probabilities for interim 
monitoring of toxicity and efficacy over the course of this trial.  Underlying 
assumptions for the prior distribution are also presented. 
  
 
Safety:  Early stopping due to toxicity 
 
If a treatment-related (possible, probable, or definite) death occurs, enrollment will be 
suspended and continuation of the study will be reassessed by the DSMC. We do not 
plan to stop this study early due to toxicity because we expect 80% of study patients 
will experience grade 3-4 toxicity related to treatment such as neutropenia, 
thrombocytopenia, anemia, neutropenia fever, mucositis, etc.  Such toxicities are 
manageable by medications and or delays in treatment.  Due to the poor prognosis of 
these patients criteria for stopping the study will be based on survival and not toxicity.  
 
  
Early stopping due to lack of efficacy:  monitoring the survival 
 
Although we expect that study treatment will lead to increased median survival to about 
6 months (that is, 6-months survival rate of 50%), to ensure patient safety the DSMB 
will monitor the accumulating study data for the possibility of a reduced survival time 
on study. Such interim monitoring will be done by computing the Bayesian posterior 
probability (PPr) that the median survival is less than or equal to 3 months based on 
interim data and a prior distribution. As a guideline for early stopping, if the posterior 
probability is 80% or greater, that is,  
 
PPr (median survival ≤ 3 months | current data and prior) ≥ 0.80, 
 
 
then the DSMB will consider stopping the study early.  If the study is stopped early 


           CLINICAL RESEARCH SERVICES                                  
40 
 
under this circumstance, then enrollment of new patients would be terminated and study 
treatment would be stopped for the currently enrolled patients. 
 
The posterior probability will be computed based on interim study data and a prior 
distribution representing a proponent’s degree of belief in the target survival 
improvement, since such an individual needs to be convinced of potential harm. Under 
assumption of exponential distribution for overall survival time, the proponent’s belief 
can be represented by a normal distribution for the log hazard rate centered around a 
mean value corresponding to the expected 6 months median survival (mean = log 
hazard rate= log [(-log 0.5)/ 6] = loge (0.1155)= -2.1583). The variance (σ2= 0.6783) is 
derived by assigning a 20% probability (weak prior belief) to the possibility that the 
median overall survival is ≤3 months (log hazard rate= log [(-log 0.5)/ 3] = loge 
(0.2310) =-1.4651).  
 
 
Table 14.2 provides hypothetical illustration of the posterior probability calculation 
described above based on patient enrollment, observed number of deaths, and total 
follow-up (in months) considering all patients enrolled in the study by the time of 
interim analysis. (Total follow-up, which is the person-time at risk, and observed 
number of deaths, are used for calculating the data-driven estimates of hazard rate and 
median survival).  
 
Table 14.2. Hypothetical Example of Interim Results Regarding Survival 
Patients 
Total follow-
up1 (months) 
Observed 
number of 
deaths 
Expected2 number of deaths 
if median is 
Posterior 
probability 
that median survival is  ≤ 
3 months 
3 mos. 
6 mos. 
5 
5 
2 
1.16 
0.59 
0.516 
5 
7 
4 
1.62 
0.81 
0.867 
8 
15 
4 
3.47 
2.60 
0.424 
1  Sum of follow-up time from start of treatment to date of death, or to last date of documented alive at the 
time of interim analysis. 
2  Expected = Total follow-up x [(-log 0.5)/Md], Md = median = 3, 6. 
 
Taking the second row of table 14.2 as an example, if 4 out of 5 patients have died and 
the total follow-up time is 7 months, the posterior probability that the median survival 
time is smaller than or equal to 3 months is 0.867. Thus, an interim analysis finding 
such as this would suggest that early termination of the study should be considered 
since there is a high chance (86.7%) that the median time to progression is ≤ 3 months. 
An example of a more favorable potential outcome is given in row 3. Specific 
calculations will be provided to the DSMC for interim review of actual trial data. 
 
14.3    Interim Review of Safety Data 
 
The protocol management team, consisting of two of the investigators for this study 
AND the statistician, will continuously monitor study accruals, toxicities, and response 
to treatment.   


           CLINICAL RESEARCH SERVICES                                  
41 
 
The protocol management team may convene at their discretion to review the 
accumulated safety data.  Accrual will continue as long as the protocol management 
team has no clinical concerns regarding the incidence of Grade 3 or 4 adverse events 
and the relationship of the events to treatment with the study drugs.   
The protocol management team will have access to all available safety data and will 
carefully review the data for safety issues.  The protocol management team may close 
the trial if there are major safety problems, especially Grade 4 adverse events.  
 
Suspension of Study:  
If safety concerns arise during the study, the DSMC may suspend, amend or terminate 
the study.  The study may be suspended by the DSMC until the situation or safety 
concern has been resolved. 
 
14.4  
Study Termination  
The DSMC retains the right to terminate the study for any other cause, suspending 
patient enrollment and related study materials from the study site at any time.  Specific 
instances, which may precipitate such termination at a site, are as follows: 
• Deviation from protocol requirements  
• Inaccurate and/or incomplete data recording on a recurrent basis 
• Unauthorized use of investigational products or administration to any subject 
not enrolled as part of the protocol 
• Delinquent fulfillment of obligation on the part of the Investigator with regard 
to adverse reaction reporting, unacceptable patient enrollment or other 
responsibilities as outlined in this protocol. 
 
 
 
The DSMC will Review the Following: 
1.DSMC will review: 
2.Number of patients enrolled to date  
3.Summary of all adverse events regardless of grade and 
 attribution.  
4.Dose modifications 
5.Deviations 
6.Data collection/entry  
 
 


           CLINICAL RESEARCH SERVICES                                  
42 
 
15.0 
REFERENCES 
 
1.Fisher SG, Fisher RI.  The epidemiology of non-Hodgkin’s lymphoma.  Oncogene. 2004.  
23:6524-6534. 
2.Spreafico F et al.  Intensive, very short-term chemotherapy for advanced Burkitt’s 
lymphoma in children.  J Clin Oncol.  2002.  20: 2783-2788. 
3.Young LS, Murray PG.  Epstein-Barr virus and oncogenesis:  from latent genes to 
tumors.  Oncogene.  2003.  22: 5108-5121. 
4.Jacobs P.  The malignant lymphomas in Africa.  Hematology Oncology Clinic North Am.  
1991.  5: 953-982. 
5.Knowles DM.  Etiology and pathogenesis of AIDS-related non-Hodgkin’s lymphoma.  
Hematology Oncology Clinic North Am.  2003.  17: 785-820. 
6.Bellan C et al.  Burkitt’s lymphoma:  new insights into molecular pathogenesis.  J Clin 
Pathol.  2003.  56: 188-192. 
7.Leight ER, Sugden B.  EBNA-1:  a protein pivotal to latent infection by Epstein-Barr 
virus.  Rev Med Virol.  2000.  10: 83-100. 
8.Touitou R et al.  Heterogeneous Epstein-Barr virus latent gene expression in AIDS-
associated lymphomas and in type I Burkitt’s lymphoma cell lines.  J Gen virol.  2003.  
84: 949-957. 
9.Advani SH, Doval DC, Gopal R, Nair CN, Kutty PM.  Therapy-related leukemia.  A 
report of five patients and a review of the literature.  Oncology.  1983.  40: 268-272. 
10. Xue SA et al.  Promiscuous expression of Epstein-Barr virus genes in Burkitt's 
lymphoma from the central African country Malawi.  Int J Cancer.  2002.  99: 635-643. 
11. Feng WH, Cohen JI, Fischer S, Li L, Sneller M, Goldbach-Mansky R, Raab-Traub N, 
Delecluse HJ, Kenney SC.  Reactivation of latent Epstein-Barr virus by methotrexate: a 
potential contributor to methotrexate-associated lymphomas.  J Natl Cancer Inst.  2004.  
96:1691-1702. 
12. Kurokawa M, Ghosh SK, Ramos JC, Mian AM, Toomey NL, Cabral L, Whitby D, 
Barber GN, Dittmer DP, Harrington WJ Jr.  Azidothymidine inhibits NF-kappaB and 
induces Epstein - Barr virus gene expression in Burkitt lymphoma.  Blood.  2005.  
106:235-240. 
13. Araujo I et al.  Expression of Epstein-Barr virus-gene products in Burkitt’s lymphoma 
in Northeast Brazil.  Blood.  1996.  87: 5279-5286. 
14. Sandlund JT et al.  Predominance and characteristics of Burkitt lymphoma among 
children with non-Hodgkin lymphoma in northeastern Brazil.  Leukemia.  1997.  11: 
743-746. 
15. Klumb CE et al.  Geographic variation in Epstein-Barr virus-associated Burkitt’s 
lymphoma in children from Brazil.  Int J Cancer.  2004.  108: 66-70. 
16. Davis RE, Brown KD, Siebenlist U, Staudt LM.  Constitutive nuclear factor kappaB 
activity is required for survival of activated B cell-like diffuse large B cell lymphoma 
cells.  J Exp Med.  2001.  194: 1861-1874.15. 
17. Cahir-McFarland ED, Davidson DM, Schauer SL, Duong J, Kieff E.  NF-kappa B 
inhibition causes spontaneous apoptosis in Epstein-Barr virus-transformed 
lymphoblastoid cells.  Proc Natl Acad Sci USA.  2000.  97: 6055-6060. 
18. Brown HJ, Song MJ, Deng H, Wu TT, Cheng G, Sun R.  NF-kappaB inhibits 
gammaherpesvirus lytic replication.  J Virol.  2003, 77: 8532-8540. 


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19. Moore SM, Cannon JS, Tanheheo YC, Hamzeh FM, Ambinder RF.  Induction of 
Epstein-Barr virus kinases to sensitize tumor cells to nucleoside analogues.  Antimicrob 
Agents Cehmother.  2000, 45:2082-2091. 
20. Feng WH, Israel B, Raab-Traub N, Busson P, Kenney SC.  Chemotherapy induces lytic 
EBV replication and confers ganciclovir susceptibility to EBV-positive epithelial cell 
tumors. Cancer Res.  2002.  62:1920-6. 
21. Gill PS, Harrington W Jr, Kaplan MH, Ribeiro RC, Bennett JM, Leibman HA, 
Bernstein-Singer M, Espina BM, Cabral L, Allen S, et al.  Treatment of adult T-cell 
leukemia-lymphoma with a combination of interferon alfa and zidovudine.  N Engl J 
Med.  1995.  332:1744-1748. 
22. Gustafson EA, Schinazi RF, Fingeroth JD.  Human herpesvirus 8 open reading frame 
21 is a thymidine and thymidylate kinase of narrow substrate specificity that efficiently 
phosphorylates zidovudine but not ganciclovir.  J Virol.  2000.  74:684-692. 
23. Hoggard PG, et al.  Time-dependent changes in HIV nucleoside analogue 
phosphorylation and the effect of hydroxyurea.  AIDS.  2002.  16: 2439-2446. 
24. Bayraktar UD, et al. Zidovudine-based lytic-inducing chemotherapy for Epstein-Barr 
virus-related lymphomas. Leuk Lymphoma. 2014 Apr; 55(4):786-94. 
25. Lin J-C, et al.  Quantification of plasma Epstein-Barr virus DNA in patients with 
advanced nasopharyngeal carcinoma.  NEJM.  2004.  350:2461-2470. 
26. Au WY, Pang A, Choy C, Chim CS, Kwong YL.  Quantification of circulating Epstein-
Barr virus (EBV) in the diagnosis and monitoring of natural killer cell and EBV-
positive lymphomas in immunocompetent patients.  Blood.  2004. 104:243-249. 
27. Cantor AB.  Projecting the standard error of the Kaplan-Meier estimator.  Stat Med.  
2001.  20:2091-8. 
28. Armitage P, Berry G, Matthews JNS.  Statistical Methods in Medical Research, 4th ed.  
Oxford:  Blackwell Scientific, 2002. 
29. Collett D.  Modeling Survival Data in Medical Research, 2nd ed.  New York: CRC 
Press, 2003. 
30. Spiegelhalter DJ, Freedman LS, Parmar MK, Bayesian approaches to randomized trials 
(with discussion). J Royal stat soc Ser A 1994; 157: 357-416 
31. Fayers, PM, Ashby D., Parmer MKB, Tutorial in biostatistics: Bayesian data 
monitoring in clinical trials. Stat Med 1997; 16: 1413-30 
 
 
 




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APPENDIX II – STUDY CALENDAR 
 
X1 EBV viral load will be obtained at the beginning of cycle 1 prior to the administration of Doxorubicin.  On cycle 
1 also prior to ZDV administration, after the 5th dose of intravenous ZDV, and within the last 7 days of the end of 
 
Baseline/ 
Pre-treatment 
See Sec 5.1 for 
timeframes 
Chemo 
Therapy 
Day 1 each 
cycle 
Cycle 1 
Only1 
After 
Cycles 2, 4 
and 6 
Post 
Therapy 
Each Visit 
Early 
Discontinuati
on/BM 
Transplant 
Complete History 
X 
 
 
 
 
 
Physical Exam/ 
X 
X 
 
 
X3 
X 
Tumor Measurement 
X 
X 
 
 
X3 
 
Performance Status 
X 
X 
 
 
X3 
 
CBC, Diff, Platelets 
X8 
X 
 
 
X3 
X 
Blood urea nitrogen, 
creatinine, total 
bilirubin, alkaline 
phosphatase, LDH, 
total protein, 
albumin, calcium, 
phosphorous, AST, 
ALT, uric acid  
X8 
X 
X 
 
X3 
X 
Serum 
Pregnancy 
Test within 7 days 
(Females) 
X 
 
 
 
 
 
HIV viral load 
X 
 
 
X4 
X4 
 
T-cell subsets 
X 
 
 
X4 
X4 
 
Hepatitis B Core Ab, 
Surface Ab & Surface 
Ag,,and hepatitis C Ab. 
A baseline Hep B and 
Hep C viral load should 
be obtained in Hep B 
Core 
Ab 
(+) 
and 
Surface 
antigen 
(+) 
cases, and Hepatitis C 
Ab 
(+) 
cases 
respectively. 
X 
 
 
X9 
 
 
EBV Viral Load 
X1 
 
X1 
X4 
X4 
X4 
EBV reactivation 
X1 
 
X1 
 
 
 
Immune 
activation 
and 
inflammation 
markers 
X 
 
 
X5 
 
X5 
EKG 
X 
 
 
 
 
MUGA or Echo 
X 
 
 
 
 
 
CT scans 
X 
 
 
X 
X6 
 
Bone Marrow 
X 
 
 
X2 
 
 
Lumbar Puncture 
X 
 
 
 
 
 
Concurrent 
Medications 
X 
 
 
 
 
Toxicity Notation 
X 
X 
 
 
 
X 


           CLINICAL RESEARCH SERVICES                                  
46 
 
cycle 1 (Appendix III).  Blood for measurement of EBV reactivation will be obtained prior to the initiation of 
treatment, on Day 2 prior to ZDV administration, and after the 5th dose of intravenous ZDV of cycle 1 (Appendix 
IV). 
X2 If the patient had initial bone marrow involvement, then a repeat bone marrow biopsy should be performed when 
the patient has no other evidence of disease in order to determine CR status. 
X3 Post therapy visits will occur (unless otherwise noted) every 3 months for 2 years, every 6 months for the third-
fifth years and yearly thereafter. See Section 5.3 for more details.  (+/- 4 weeks) 
X4 EBV viral load, HIV-1 viral load, and T-cell subsets will be obtained after completion of cycle 2 (minus 1-week 
window), post cycle 6 (2-6 weeks after last treatment), and every 3 months (+/- 4 weeks) for one year. 
X5 Immune activation and inflammation markers will be obtained after completion of cycle 2 and 4 (minus 1-week 
window), post cycle 6 (2-6 weeks after last treatment), and/or anytime upon disease progression, or disease relapse 
during follow-up period 
X6 CT or CT/PET will be performed every 6 months (+/- 4 weeks) for two years or more often if clinically indicated. 
X7 Uric acid and Phosphorus are only required at baseline (+/- 2 weeks) 
X8 Baseline evaluation laboratory tests may be used toward cycle 1 requirements, if done within 48 hours of treatment 
initiation.  
X9 HBV and/or HCV viral load in subjects who were HBV antigen or core antibody positive, or HCV antibody 
positive with undetectable viral particles or viral load at baseline, at the end of cycles 2, 4, and 2-6 weeks post Day 1 
of cycle 6.








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50 
 
APPENDIX VI:  FORMS SUBMISSION TABLE 
 
Form 
Baseline 
Cycle 1 
Cycle 2, 4, 6 
Post-
therapy 
PRN 
Registration 
X 
 
 
 
 
Eligibility 
X 
 
 
 
 
History 
X 
 
 
 
 
Prior Medications 
X 
 
 
 
 
Vital Signs & 
Physical Exam 
X 
X 
X 
X 
 
Hematology 
X 
X 
X 
X 
 
Chemistries and 
LFTs 
X 
X 
X 
X 
 
Study Drug 
Treatment 
 
X 
X 
 
 
Concomitant 
Medications 
 
X 
X 
X 
 
Adverse Events 
 
X 
X 
X 
 
Lymphoma 
Evaluation  
X 
 
X 
X 
 
Comments  
 
 
 
 
X 
Missed Visits 
 
 
 
 
X 
Off Study  
 
 
 
 
X 
Death 
 
 
 
 
X 
 
 
 


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APPENDIX VII:  DRUG DIARY 
YOU MUST KEEP THIS DIARY AND BRING IT TO EVERY APPOINTMENT. 
 
Study ID #:  _______________ 
Cycle ____ 
 
Please record in the chart below the date and time that your dose was taken.  Be sure to record the doses when 
you take them, and avoid writing entries for several days at once.  When you are finished, bring this diary with 
you when you next see the Doctor or Study Staff.  In the “Comments” section write any problems you are 
having with the medicines or if you missed a dose and why or if you only took part of the medicine.  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Leucovorin 
25 mg             
Every 6 
hours 
(Times) 
Zidovudine 
1200 mg     
twice daily    
(Times) 
Hydroxyurea   
500 mg       
twice daily     
(Times) 
Comments 
Date: 
 
 
 
 
 
 
Date: 
 
 
 
 
 
 
Date: 
 
 
 
 
 
 
Date: 
 
 
 
 
Date: 
 
 
 
 
Date: