Clinical trial NCT00006436
Conditions: Lymphoma, AIDS-related Lymphoma, Large B-Cell, Diffuse
Keywords: AIDS Malignancy Antiretroviral Chemotherapy Monoclonal
Sponsor: National Cancer Institute (NCI)
Start date: 2001-01-29; Completion date: 2024-01-18
Enrollment: 68 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Background:

* Human immunodeficiency virus (HIV)-infected patients have a weakened immune system, and chemotherapy, which is used to treat lymphoma, probably causes further damage to the immune system.
* Limiting the amount of immune damage due to chemotherapy might decrease the number of infections and the risk of developing cancer in the future in HIV-infected patients with non-Hodgkin's lymphoma.

Objectives:

* To determine whether reducing the total amount of chemotherapy using a specific combination of drugs called EPOCH-R (etoposide, doxorubicin, vincristine, cyclophosphamide and rituximab) will rid the body of lymphoma quickly while decreasing the risk of infections and future cancers.
* To determine whether the lymphoma will remain undetectable for at least one year if treatment is stopped one cycle after the patient enters remission.

Eligibility:

-Patients with non-Hodgkin's lymphoma and HIV infection 4 years of age and older who have not been treated previously with rituximab or cytotoxic chemotherapy.

Design:

* Patients receive EPOCH-R in 3-week treatment cycles for at least three and no more than six cycles.
* The lymphoma is evaluated using computed tomography (CT) and positron emission tomography (PET) scans at the end of treatment cycles 2 and 3. A bone marrow biopsy is repeated after cycle 2 if a biopsy was initially positive on screening for participation in the study.
* Anti-HIV therapy is stopped before chemotherapy begins and is restarted when EPOCH-R treatment ends.
* Patients are monitored for treatment response with blood tests and imaging scans at baseline, when treatment ends, 2 months after treatment ends and then every 3 to 6 months for a total of 24 months following chemotherapy.

Detailed description:
Background:

This is a study to investigate in a preliminary fashion the feasibility of short course chemotherapy to participants with HIV-associated non-Hodgkin's lymphoma (HIV-NHL).

This study will investigate if the paradigm for treatment can be successfully changed from a standard of 6 cycles to one cycle beyond complete remission with 6 total allowable cycles.

Objective:

To assess with 90 percent probability that at least 50 percent of participants treated with short-course EPOCH-R (etoposide, doxorubicin, vincristine, cyclophosphamide and rituximab) will be progression free at one year.

Eligibility:

Aggressive B-lymphocyte antigen CD20 (CD20) positive Diffuse large B cell lymphoma (DLBCL).

HIV+ serology.

All stages (I-IV) of disease.

Eastern Cooperative Oncology Group (ECOG) Performance status 0-4.

Non-Hodgkin's Lymphoma (NHL) previously untreated with cytotoxic chemotherapy.

Age greater than or equal to 18 years.

May not be pregnant or nursing.

May not have received previous rituximab.

Design:

Participants will be treated every three weeks with a combination of EPOCH and rituximab for one cycle beyond complete remission (CR)/complete response unconfirmed (CRu) by computed tomography (CT) scan of all detectable tumors for a minimum of three and maximum of six cycles. Following cycle 2, CT, positron emission tomography scans (PET), and bone marrow biopsies (if initially positive) will be performed.

At the conclusion of the study, we will estimate whether the number of cycles can be reduced using the paradigm. If the cumulative number of participants to relapse exceeds 25 percent by 6 months, the study will be closed.

Following the completion of chemotherapy, restaging will be performed 2 months following the end of treatment, then every 3 months for one year, every 6 months for one year, then every 12 months until relapse, death, or loss to follow up.

Antiretroviral therapy (ART) will be given concurrently with treatment regimen.

To study the effects of treatment approach on parameters of HIV disease, measurements of cluster of differentiation 4 (CD4) cells and viral loads will be made at baseline and at the completion of therapy, and then 2 months following the end of treatment, and then every 3-6 months for a total of 24 months following chemotherapy.

Arms: arm 1: Combination chemo and biological therapy
Interventions: intervention 1: Rituximab intervention 2: Filgrastim intervention 3: EPOCH
Intervention descriptions: intervention 1: 2 doses of rituximab every cycle: first dose on Day 1 and 2nd dose on Day 5 intervention 2: Filgrastim day 6 until absolute neutrophil count (ANC) reaches 5000 after the nadir, every cycle intervention 3: combination chemotheray: EPOCH every 3 weeks for minimum of 3 cycles and max of 6 cycles

Protocol documents:
ICF_001.pdf: 
PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 03/17/2021
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CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
PRINCIPAL INVESTIGATOR: Mark Roschewski, M.D
STUDY TITLE:
Short-Course EPOCH-Rituximab for Untreated CD-20+ 
HIV-Associated Lymphomas
STUDY SITE:
NIH Clinical Center
Cohort: 
Standard 
Consent Version:  
03/17/2021 
WHO DO YOU CONTACT ABOUT THIS STUDY? 
Dr. Mark Roschewski
Email: Mark.Roschewski@nih.gov
Telephone: 240-760-6183 
This consent form describes a research study and is designed to help you decide if you would like 
to be a part of the research study.  
The remaining document will now describe the research study in more detail.  This information 
should be considered before you make your choice. Members of the study team will talk with you 
about the information in this document. Some people have personal, religious, or ethical beliefs 
that may limit the kinds of medical or research interventions in which they would want to 
participate. Take the time you need to ask any questions and discuss this study with NIH staff, and 
with your family, friends, and personal health care providers.
 If the individual being asked to participate in this research study is not able to give consent for 
themselves, you, as the Legally Authorized Representative, will be their decision-maker and you 
are being asked to give permission for this person to be in this study. For the remainder of this 
document, the term “you” refers to you as the decision-maker and/or the individual being asked to 
participate in this research.  
IT IS YOUR CHOICE TO TAKE PART IN THE STUDY
You may choose not to take part in this study for any reason. If you join this study, you may change 
your mind and stop participating in the study at any time and for any reason. In either case, you 
will not lose any benefits to which you are otherwise entitled. However, to be seen at the NIH, you 
must be taking part in a study or are being considered for a study. If you do choose to leave the 
study, please inform your study team to ensure a safe withdrawal from the research.  
WHY IS THIS STUDY BEING DONE?
The major purpose of this research study is to determine if the experimental combination of 
chemotherapy drugs given to you through your veins can lead to disappearance of lymphoma (by 
our best ability to test for it) within as few cycles as possible, and to see if the lymphoma will 
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continue to stay undetectable for at least one year if the treatment is stopped one cycle after you 
enter remission.
WHY ARE YOU BEING ASKED TO TAKE PART IN THIS STUDY?
You have a cancer called non-Hodgkin’s lymphoma (NHL) and you are also infected with the 
human immunodeficiency virus (HIV).  In patients like yourself, the lymphoma often grows and 
spreads rapidly so chemotherapy is usually used for treatment.  Chemotherapy will be discussed 
in more detail later in this document.  
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY? 
About 80 people will take part in this study.
DESCRIPTION OF RESEARCH STUDY
The HIV infection has damaged your immune system, and chemotherapy probably causes further 
damage to your immune system.  If it were possible to limit the amount of immune damage due to 
chemotherapy, this might decrease the number of infections and decrease the risk of developing 
cancer in the future.  This research protocol is designed to help answer whether it may be possible 
to limit the amount of damage chemotherapy causes to the immune system by reducing the total 
amount of chemotherapy given.  However, if too little chemotherapy is given, then the cancer will 
not be cured.  In this research protocol, we will administer a combination of drugs for lymphoma 
and perform sensitive tests to see if all evidence of your cancer goes away very early in the course 
of your treatment.  If the cancer goes away quickly, then the treatment will be stopped after 9 
weeks of therapy.  If your cancer continues to be evident, you will receive up to 18 weeks of 
treatment.  The standard treatment for your type of cancer is usually given for 18 to 24 weeks.  We 
will also monitor your immune system to see how much immune damage occurs with the 
treatment.  After you finish treatment, we will monitor your immune system to see if it improves 
or not, and we will look for evidence of the cancer coming back.
WHAT WILL HAPPEN IF YOU TAKE PART IN THIS RESEARCH STUDY?  
None of the drugs in this treatment are experimental.  The United States Food and Drug 
Administration has approved all of the drugs for use in lymphoma.  However, as explained below, 
the way the drugs in this research protocol are given in combination together is experimental.
In addition to receiving chemotherapy into your veins, you will also receive chemotherapy directly 
into your spinal fluid using a procedure called lumbar puncture (explained in the next paragraph).  
This part of the therapy is not experimental.  The spinal fluid bathes the brain and spinal cord and 
is separated from the rest of your body fluids by tissue that prevents the chemotherapy drugs given 
by vein from getting into the spinal fluid.  It is important to get the chemotherapy into the spinal 
fluid because in AIDS-lymphoma, the spinal fluid and brain frequently get lymphoma in them.  
The chemotherapy must therefore be given by lumbar puncture or some other method to get it 
directly into the spinal fluid.  We will test to see whether there is any evidence of lymphoma in 
your brain or spinal fluid before deciding how to treat the spinal fluid.  If there is no evidence that 
the lymphoma has gotten into your brain or spinal fluid, you will receive the chemotherapy into 
the spinal fluid twice weekly every third week for 6 doses.  If there is evidence of brain or spinal 
fluid lymphoma, then you will receive up to 3 drugs simultaneously into the spinal fluid.  These 
treatments will be given twice weekly for at least 4 weeks, and will continue for once weekly for 
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at least 4 more weeks, and then once monthly for at least 6 more treatments. Sometimes it is 
necessary to have the neurosurgeons perform an operation to place a device called an Ommaya 
into your head that the chemotherapy is given through if the lumbar punctures are not feasible.  If 
you need an Ommaya, you will be consented separately for that.  Additionally, you may require 
radiation therapy to your head and spine.  As stated above, this part of the therapy is not 
experimental, and will be determined on the basis of your individual medical needs.  Even though 
this part of the therapy is not experimental, it is required as part of the research protocol.
BEFORE YOU BEGIN THE STUDY
Prior to getting any treatment, there are a number of tests that must be completed.  As reviewed in 
the paragraph above, you will undergo a lumbar puncture to remove a small amount of spinal fluid 
(about 1-2 teaspoons) that will be tested for the presence of lymphoma cells.  A lumbar puncture 
is done by inserting a small sterile needle through the skin and muscle, going between the bones 
of the spine in the lower back until the needle punctures the spinal canal covering.  The spinal fluid 
will then drain out through the needle on its own.  
Other tests that you will have done include either a computed tomogram (CAT Scan) of the head, 
or an MRI of the head.  These tests help to see if there are any tumors growing in the brain tissue.  
CAT scans will also be done of your chest, abdomen, and pelvis.  This will help to see if there are 
any tumors in these parts of your body.  Another test to help determine whether lymphoma is 
present is a positron emission tomography scan (PET scan).  This scan is accomplished by injecting 
a kind of glucose into your blood, and the scanning machine can measure how different cells in 
the body use it.  This can help determine where the lymphoma is, because the lymphoma cells use 
the glucose differently from other types of cells.  Another procedure required is called a bone 
marrow biopsy.  This procedure is done by inserting a small hollow needle through the bone, 
usually in the back of the pelvis bone, to get some of the bone marrow.  The bone marrow is then 
inspected for evidence of lymphoma. You will also have an Electrocardiogram (ECG) which is a 
test that is performed while you lie still for about 5 minutes.  It involves placing electrodes (small 
stickers that are attached to wires that go to the machine) on your chest and arms/legs and recording 
the electrical activity of your heart.  
During the study
EPOCH-R Chemotherapy
The chemotherapy you will receive on this experimental protocol is called EPOCH-R.  Each letter 
in this name stands for the name of a drug that is part of the chemotherapy regimen.  The individual 
drugs will be discussed below.  EPOCH-R is different from standard chemotherapy because some 
drugs are administered over a 4-day period (96-hours) instead of over several hours.  Experimental 
studies in patients with AIDS-lymphoma and in lymphoma without HIV infection suggest that 
administering some drugs over a 4-day (96 hours) period may increase their effectiveness and 
reduce toxicity.   Although EPOCH-R is a combination of 6 non-experimental drugs, the way the 
drugs are used is experimental in AIDS-related lymphoma.  Rituximab is a monoclonal antibody 
(a protein that specifically binds to proteins that occur on the surface of lymphoma cells). When 
rituximab attaches to these cell surface proteins, it may cause the lymphoma cells to die, or make 
them more sensitive to EPOCH.  The Food and Drug Administration has approved rituximab for 
use in a type of lymphoma that is not HIV-associated.  Rituximab is not an experimental drug.  
The use of rituximab with EPOCH in AIDS is experimental.  There is a theoretical possibility that 
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EPOCH with rituximab can worsen your immune function, because rituximab decreases the 
number of B-lymphocytes in your body.  B-lymphocytes are important in that they produce 
antibodies that are important in certain kinds of infections.  Therefore, rituximab could make you 
more prone to bacterial and other infections.  The rationale for using the rituximab with EPOCH 
is to see if there is evidence that combining these therapies is tolerated or not, and to see if it 
appears to improve the effect of the EPOCH against the lymphoma so that fewer than the standard 
number of cycles of standard therapy can be administered.  The rituximab will be administered 
twice during each treatment cycle: first immediately before the other drugs are given, and second, 
at the end of the 96 hours right before the cyclophosphamide is given.  It may take several hours 
to give the rituximab because if it is infused too quickly it can make you feel ill (headache, 
shortness of breath, rash).
You will receive three of the drugs, etoposide, doxorubicin and vincristine, over 4 days (days 1 to 
5) through a catheter placed in a large vein.  A portable pump that you will carry around with you 
will infuse the drugs.  You do not need to be hospitalized for this therapy but you will have to 
come to the clinic every day to have the chemotherapy replaced in the pumps. You will also take 
prednisone by mouth on days 1 through 5, and on day 5, you will receive cyclophosphamide by 
intravenous injection (the drug will be injected directly into the vein with a needle or catheter) 
over approximately 30 minutes.  The doses of chemotherapy will be adjusted, based on how well 
you tolerate the therapy.  Because chemotherapy damages your bone marrow, you will receive a 
non-experimental drug called filgrastim (also called granulocyte-colony stimulating factor or G-
CSF), which helps stimulate bone marrow function.  You will receive this for approximately two 
weeks, beginning on the sixth day of therapy.  The nurses will teach you to administer the 
filgrastim as a daily injection just under the skin (like an insulin shot).
You will receive as few as three cycles and a maximum of six cycles of EPOCH-R chemotherapy.  
Each cycle is repeated every 3 weeks, although a cycle may be delayed for medical reasons.  The 
size of your tumors will be evaluated with computerized tomography (CT) scans, and PET scans 
before you start treatment.  These scans will be repeated after you have completed the 2nd through 
6th cycles of EPOCH-R.  You will receive one additional cycle of treatment past when it appears 
that your tumor has completely responded to treatment: therefore, you may receive as few as 3 
cycles of chemotherapy.
Treatment will be stopped if the tumor is growing or if you are unable to safely tolerate the therapy. 
Supportive Therapy
Because chemotherapy can lower your resistance to infection, you will receive preventative 
therapy for a kind of pneumonia called Pneumocystis carinii with a drug called 
trimethoprim/sulfamethoxazole (Bactrim®).  This is administered three times a week during the 
time you receive EPOCH and rituximab.  If you are allergic to Bactrim or cannot tolerate it, you 
may receive an alternative therapy.  If you need prophylaxis or treatment for other AIDS-related 
infections such as fungal infections (like thrush), mycobacterium avium complex (MAC), 
tuberculosis (TB), toxoplasmosis, cryptosporidium, or cytomegalovirus, those medications may 
have to be stopped during the EPOCH infusions to avoid potentially harmful drug interactions.
While you are being treated with EPOCH, the intent is that your anti-HIV drugs will be continued.  
These drugs may inhibit your bone marrow function or interact with the chemotherapy to cause 
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other or increased side effects. However, it has been shown that continuing anti-retroviral drugs 
may be important for your overall treatment. 
Samples for Research
Blood samples will be collected for research studies to look at the response of HIV and the cancer 
to the treatment.  These will be collected prior to and after each cycle of treatment (up to 4 
tablespoons each time), and after treatment at about 2 months, every 3 months for 1 year, and every 
6 months for an additional year (up to 4 tablespoons each time).    In addition, portions of tissue 
collected as part of other, routine procedures that you may have had in the past or in the future for 
your disease will also be collected for research studies.  
Optional Blood Collection for Research
You may be asked to donate a small amount of blood for research. If you agree to this, you will 
have up to 7 tablespoons of blood collected up to 4 times after you complete treatment. 
The blood collected is exclusively for research purposes and will not benefit you.  It might help 
other people in the future.  The decision to participate in this part of the research is optional, and 
no matter what you decide to do, it will not affect your care. 
If you agree to the optional blood samples, your agreement will be documented in the records.
What tests will be done on my samples?
Your blood and tissue that is collected will be used to look for specific changes in the DNA in 
tumors that could be used to develop new ways of diagnosing and treating cancer, and to 
understand more about HIV.   DNA (also called deoxyribonucleic acid) are the molecules inside 
cells that carry genetic information and pass it from one generation of cells to the next – like an 
instruction manual. Normal tissue contains the DNA (instructions) that you were born with, DNA 
in tumor cells has changed – or mutated – and we think that change in the DNA is what causes 
tumors to form and to grow, forming the cancer genome or DNA.  In order to determine which 
parts of the DNA have mutated, we will compare the DNA in your tumor cells to DNA from your 
normal cells.  When we are examining these pieces of your DNA, it is possible that we could 
identify possible changes in other parts of your DNA that are not related to this research.  These 
are known as “incidental medical findings”. 
These include: 

Changes in genes that are related to diseases other than cancer 

Changes in genes that are not known to cause any disease. These are known as normal 
variations. 

Changes in genes that are new and of uncertain clinical importance. This means that we do 
not know if they could cause or contribute to a disease or if they are normal variations. 
However, the analyses that we perform in our laboratory are for research purposes only; they are 
not nearly as sensitive as the tests that are performed in a laboratory that is certified to perform 
genetic testing. Changes that we observe unrelated to our research may or may not be valid.  
Therefore, we do not plan to inform you of the results of testing on your tissue and blood that is 
performed in our research lab.  However, in the unlikely event that we discover a finding believed 
to be clinically important based on medical standards at the time we first analyze your results, we 
will contact you. This could be many years in the future.   We will ask you to have an additional 
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tube of blood drawn to verify the findings we have seen in our lab. If the results are verified, you 
will be re-contacted and offered the opportunity to come to NIH to have genetic education and 
counseling to explain this result; at the time of any such event(s), these activities will be paid for 
by the NCI. If you do not want to come to NIH a referral to a genetic healthcare provider will be 
provided to discuss the results (at your expense).  
Who else besides the investigators on this study will know the results of my sample testing?
Once we obtain any of the samples listed above, the investigators take all your personal 
information off those samples and label them with a study code number.  Only the investigators 
on this study know who the sample came from.  The key linking your personal information with 
the code number is kept in a secure computer data base, with access only to key research staff who 
will be discussing this study with you.  Once the sample has been labeled with a code, it is sent to 
a variety of NIH laboratories for storage and testing.  No one testing your samples will be able to 
link the results to you personally.  Specimens obtained during your participation in this study may 
be sent for testing to investigators outside of NCI or the NIH.  All samples will be coded to protect 
your privacy and no personal information will be included.  Other investigators on this study will 
have access to limited clinical and biologic data such as age, gender and disease status.
How long will your samples be stored?
The samples collected during this study will be stored for as long as the study is open.  When this 
study is closed, we will keep the samples for future research.
When you are finished taking the drugs (treatment)
If your disease does not enter remission or it recurs, you may need further therapy.  If no protocols 
are available for the treatment of your disease, you will be returned to the care of your local 
physician.  It is important to stress that participation in this protocol does not constitute a promise 
of long-term medical care at the Clinical Center.   
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BIRTH CONTROL
Because it is possible that drugs in EPOCH-R can affect a developing fetus, and because you can 
transmit HIV to your sexual partner, you will be asked to practice an effective method of barrier 
birth control and safe sex while you are participating in this study. 
Effective forms of birth control include:
•
abstinence 

intrauterine device (IUD)
•
hormonal [birth control pills, injections, or implants]
•
tubal ligation
•
vasectomy
Because of the danger of HIV infection with the exchange of body fluids, all participants in this 
study must agree to safe sex practices and to use condoms while engaging in sexual intercourse.
RISKS OR DISCOMFORTS OF PARTICIPATION
What side effects or risks can I expect from being in this study? 
Your physicians will watch you closely for these side effects and will stop treatment if any side 
effects become a serious threat to your life or wellbeing. Your physicians will also stop the 
treatments if it becomes clear that the treatment is not successfully controlling your disease. 
There are unforeseeable risks whenever investigational treatment programs are undertaken, 
including death.  Chemotherapy has the potential of causing a rapid acceleration of HIV disease 
and increasing the chances of developing opportunistic infections with viruses, parasites or fungi.  
Your doctors will monitor you carefully for these complications.  If they should become a threat 
to your health and it is considered dangerous to proceed with the investigational treatment 
protocol, you will be removed from the study.  If you have complications of therapy, you will be 
evaluated and appropriately treated for any acute effects of treatment.  In the event of emergency 
medical needs, referral to the closest facility is mandatory, and NIH cannot reimburse for those 
costs.
Risks and side effects related to the treatment and the procedures on this study are identified below:
EPOCH-R
The drugs used in EPOCH-R are not experimental.  This chemotherapy regimen can cause severe 
fatigue. It can also cause you to have abnormal lab values, most of which cause no symptoms and 
do not require treatment. Side effects that have been observed with the drugs in this program when 
they are used individually include the following:
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Doxorubicin:
COMMON, SOME MAY BE SERIOUS
In 100 people receiving Doxorubicin, more than 20 and up to 100 may have:
Hair loss
Vomiting
Red colored urine, saliva, or sweat 
OCCASIONAL, SOME MAY BE SERIOUS
In 100 people receiving Doxorubicin, from 4 to 20 may have:
Heart failure or heart attack which may cause shortness of breath, swelling of ankles, 
cough or tiredness which may occur years after the dose
Abnormal heartbeat
Cancer of the bone marrow (leukemia) caused by chemotherapy
Damage to the lungs which may cause shortness of breath when combined with radiation
Infection, especially when white blood cell count is low
Bruising, bleeding
Anemia which may cause tiredness, or may require transfusion
Hepatitis or damage to the liver which may cause yellowing of eyes and skin, swelling
Kidney damage which may require dialysis
Sores in the mouth or throat
Belly pain
Nausea, diarrhea
Allergic reaction which may cause rash, low blood pressure, wheezing, shortness of 
breath, swelling of the face or throat
Damage to the skin which may cause pain
Swelling and redness at the site of the medication injection or area of previous radiation
Loss of nails
Darkening of the nail beds or skin or hands and feet
RARE, AND SERIOUS
In 100 people receiving Doxorubicin, 3 or fewer may have:
Severe blood infection
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Cyclophosphamide:
COMMON, SOME MAY BE SERIOUS
In 100 people receiving Cyclophosphamide, more than 20 and up to 100 may have:
Hair loss, skin changes, rash, change in nails
Nausea, vomiting, diarrhea, loss of appetite, pain in belly
Sores in mouth
Infection, especially when white blood cell count is low
Absence of menstrual period which may decrease the ability to have children
Blood in urine
OCCASIONAL, SOME MAY BE SERIOUS
In 100 people receiving Cyclophosphamide, from 4 to 20 may have:
Damage to the bone marrow (irreversible) which may cause infection, bleeding, may 
require transfusions
Allergic reaction which may cause rash, low blood pressure, wheezing, shortness of 
breath, swelling of the face or throat
Loss or absence of sperm which may lead to an inability to father children
Stuffy nose
Scarring of the lungs which may cause shortness of breath
Fluid around the heart
RARE, AND SERIOUS
In 100 people receiving Cyclophosphamide, 3 or fewer may have:
Severe skin rash with blisters and peeling which can involve mouth and other parts of the 
body
Damage to the heart or heart failure which may cause shortness of breath, swelling of 
ankles, cough or tiredness
A new cancer including cancer of bone marrow (leukemia) caused by chemotherapy
Swelling of the body including the brain which may cause dizziness, confusion
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Prednisone:
COMMON, SOME MAY BE SERIOUS
In 100 people receiving Prednisone, more than 20 and up to 100 may have:
High blood pressure which may cause headaches, dizziness, blurred vision
Pain in belly
Loss of bone tissue
Mood swings
In children and adolescents: decreased height
Swelling of the body, tiredness, bruising
Increased appetite and weight gain in the belly, face, back and shoulders
Difficulty sleeping
Skin changes, acne
OCCASIONAL, SOME MAY BE SERIOUS
In 100 people receiving Prednisone, from 4 to 20 may have:
Blood clot which may cause swelling, pain, shortness of breath
Infection
Kidney stones
Diabetes
Glaucoma
Cloudiness of the eye, visual disturbances, blurred vision
A tear or a hole in the bowels which may cause belly pain or that may require surgery
Heartburn
Damage to the bone which may cause joint pain and loss of motion
Numbness and tingling of the arms, legs and upper body
Muscle weakness 
Non-healing wound
RARE, AND SERIOUS
In 100 people receiving Prednisone, 3 or fewer may have:
Bleeding from sores in the stomach
Broken bones
IRB NUMBER: 01C0030
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Hydrocortisone:
COMMON, SOME MAY BE SERIOUS
In 100 people receiving Hydrocortisone, more than 20 and up to 100 may have:
High blood pressure 
Damage to the bone which may cause joint pain or loss of motion
State of mind that involves a "loss of contact with reality"
OCCASIONAL, SOME MAY BE SERIOUS
In 100 people receiving Hydrocortisone, from 4 to 20 may have:
Diabetes 
Swelling of the body and weight gain, tiredness, bruising
Glaucoma
Cloudiness of the eye, visual disturbances
Abnormal menstrual period
Facial hair growth in women
RARE, AND SERIOUS
In 100 people receiving Hydrocortisone, 3 or fewer may have:
None
Dexamethasone:
COMMON, SOME MAY BE SERIOUS
In 100 people receiving Dexamethasone, more than 20 and up to 100 may have:
High blood pressure which may cause headaches, dizziness
Pain in belly 
Infection
Diabetes
Loss of bone tissue
Damage to the bone which may cause joint pain or loss of motion
Mood swings
In children and adolescents: decreased height
Swelling of the body, tiredness, bruising
Increased appetite and weight gain in belly, face, back and shoulders
Difficulty sleeping
Skin changes, rash, acne
IRB NUMBER: 01C0030
IRB APPROVAL DATE: 03/31/2021


PATIENT IDENTIFICATION
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NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
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OCCASIONAL, SOME MAY BE SERIOUS
In 100 people receiving Dexamethasone, from 4 to 20 may have:
Blood clot which may cause swelling, pain, shortness of breath
Kidney stones
Glaucoma
Cloudiness of the eye, visual disturbances, blurred vision
A tear or a hole in the bowels which may cause pain or that may require surgery
Heartburn
Numbness and tingling of the arms, legs and upper body
Muscle weakness
Non-healing wound
RARE, AND SERIOUS
In 100 people receiving Dexamethasone, 3 or fewer may have:
Bleeding from sores in stomach
Broken bones
Vincristine:
COMMON, SOME MAY BE SERIOUS
In 100 people receiving Vincristine, more than 20 and up to 100 may have:
Constipation, nausea, vomiting
Hair loss
Pain or redness at the site of injection
Numbness and tingling of fingers or toes
Headache, jaw pain and/or muscle pain
Weakness and difficulty walking
Swelling of lower legs
OCCASIONAL, SOME MAY BE SERIOUS
In 100 people receiving Vincristine, from 4 to 20 may have:
Swelling that may be accompanied by confusion, and dizziness
Paralysis, weakness, headache, confusion
Hoarseness
Drooping eyelids
Visual loss
Difficulty with balance and hearing
IRB NUMBER: 01C0030
IRB APPROVAL DATE: 03/31/2021


PATIENT IDENTIFICATION
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NIH-2977 (4-17)
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RARE, AND SERIOUS
In 100 people receiving Vincristine, 3 or fewer may have:
Seizure
Etoposide:
COMMON, SOME MAY BE SERIOUS
In 100 people receiving Etoposide, more than 20 and up to 100 may have:
Infection, especially when white blood cell count is low
Anemia which may require transfusion
Bruising, bleeding
Sores in mouth which may cause difficulty swallowing
Diarrhea, loss of appetite, nausea, vomiting
Tiredness
Fever
Chills
Hair loss
OCCASIONAL, SOME MAY BE SERIOUS
In 100 people receiving Etoposide, from 4 to 20 may have:
Heart failure or heart attack which may cause chest pain, shortness of breath, swelling of 
ankles, and tiredness
Liver damage which may cause yellowing of eyes and skin, swelling
Severe skin rash with blisters and peeling which can involve inside of mouth and other 
parts of the body
RARE, AND SERIOUS
In 100 people receiving Etoposide, 3 or fewer may have:
Cancer of bone marrow caused by chemotherapy
Allergic reaction which may cause rash, low blood pressure, wheezing, shortness of 
breath, swelling of the face or throat
IRB NUMBER: 01C0030
IRB APPROVAL DATE: 03/31/2021


PATIENT IDENTIFICATION
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NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
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Rituximab (Rituxan):
COMMON, SOME MAY BE SERIOUS
In 100 people receiving Rituximab, more than 20 and up to 100 may have:
Nausea
Chills, fever
Reaction during or following infusion of the drug
Infection, especially when white blood cell count is low
Anemia which may require blood transfusions
Numbness and tingling of the arms and legs
Tiredness
OCCASIONAL, SOME MAY BE SERIOUS
In 100 people receiving Rituximab, from 4 to 20 may have:
Bruising, bleeding
Abnormal heartbeat
Heart attack or heart failure which may cause shortness of breath, swelling of ankles, and 
tiredness
Sores in eye
A tear or a hole in the bowels that may require surgery
Diarrhea, vomiting
Pain
Swelling of the body
Hepatitis, or liver damage which may cause yellow eyes and skin
Dizziness, headache
Kidney damage which may require dialysis
Cough
Scarring of the lungs
Stuffy nose
Blockage of internal organs which may cause shortness of breath, wheezing, vomiting
Increased sweating
Itching, rash, blisters on the skin
Severe skin rash with blisters and peeling which can involve mouth and other parts of the 
body
Low blood pressure which may cause feeling faint
IRB NUMBER: 01C0030
IRB APPROVAL DATE: 03/31/2021


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
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RARE, AND SERIOUS
In 100 people receiving Rituximab, 3 or fewer may have:
Damage to the brain caused by a virus which may result in tiredness, weakness, changes 
in thinking, and disability.  This is called progressive multifocal leukoencephalopathy 
(PML).
Heart stops beating
Filgrastim:
COMMON, SOME MAY BE SERIOUS
In 100 people receiving Filgrastim, more than 20 and up to 100 may have:
Nose bleed
Anemia which may require transfusion
Pain
Diarrhea
Fever
Tiredness
Hair loss
OCCASIONAL, SOME MAY BE SERIOUS
In 100 people receiving Filgrastim, from 4 to 20 may have:
Fluid in the organs which may cause low blood pressure, shortness of breath, swelling of 
ankles
Damage to the lungs which may cause shortness of breath
Internal bleeding which may cause coughing up blood
Cough
Swelling or tenderness of vessels
Headache
RARE, AND SERIOUS
In 100 people receiving Filgrastim, 3 or fewer may have:
Rupture of the spleen causing sudden or severe pain in the left side of abdomen spreading 
up to your shoulder
IRB NUMBER: 01C0030
IRB APPROVAL DATE: 03/31/2021


PATIENT IDENTIFICATION
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NIH-2977 (4-17)
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Other risks 

There is also the possible side effect of significant nerve damage, that may result in 
weakness in the extremities, including in one or both legs (also called “peripheral motor 
neuropathy”).  This is a rare, but possible risk of intrathecal therapy, including with 
cytarabine and methotrexate, and has been seen on this study. 

It is important to emphasize that when you have a decreased white blood cell count 
following chemotherapy, you are at high risk of developing an infection. Such infections 
may be very serious and cause death if not quickly and properly treated. Therefore, if you 
have a temperature greater than 38.3°C (101°F), you must call your doctor immediately. 

Chemotherapy may also cause your platelets to fall; since platelets are the blood elements 
that permit blood to clot, this may place you at increased risk of serious bleeding. It may 
be necessary to give you transfusions of platelets if your platelet counts reach very low 
levels.  

There is a small chance that damage to the normal bone marrow may eventually result in 
bone marrow failure, leading to a serious shortage of one or more kinds of cells in the 
blood, leukemia and death.

Many of the drugs used in this treatment program are toxic to the egg cells in the ovary 
and sperm cells in the testicle and may produce sterility. Recovery of normal fertility, 
although theoretically possible, is very uncertain.
Risks associated with the study procedures:
To determine if this research study is suitable for you, a number of tests need to be done. This 
period of evaluation may take up to two weeks and if possible will be done on an outpatient basis.  
These may include blood and urine tests, Computerized tomography (CT) or magnetic resonance 
imaging (MRI) scans, radioisotope scans, glucose uptake scans, ECG and biopsies of tumor tissue 
and bone marrow, and a spinal tap (removal of a small amount spinal fluid from the spinal canal 
by inserting a needle into the lower back).  Over the course of this study, approximately one pint 
of blood will be taken.  

The risks associated with bone marrow biopsies include local pain, bleeding, and infection.  

The risks associated with a spinal tap also include pain, bleeding, and local infection.  
Under very rare circumstances, brain damage can occur, causing death.  This only occurs 
if there is a large brain mass or tumor causing pressure, and for this reason, we will obtain 
a brain scan if there is any suspicion that you have a brain tumor.

The risks of radiation related to FDG and CT scans are described below.  In addition to 
those radiation risks, CT scans that employ contrast may cause allergic reactions, injection 
site reactions abdominal discomfort and fainting.  MRIs carry no radiation risks but are 
contraindicated in participants with metal in their bodies. In patients that receive 
gadolinium contrast with MRIs, allergic reactions, injection site reactions and kidney 
damage may occur. 
IRB NUMBER: 01C0030
IRB APPROVAL DATE: 03/31/2021


PATIENT IDENTIFICATION
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NIH-2977 (4-17)
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
The risk related to blood sampling include pain and bruising, lightheadedness, and rarely, 
fainting.   
It is important to obtain fresh biopsies of tumor tissue, even if you already had a biopsy before 
coming to the NIH.  This is done to both confirm the diagnosis and for research purposes. If you 
have a biopsy done, we will collect portions of it for the research study as it will help us understand 
why AIDS-related lymphomas are difficult to treat.   Biopsies requiring major surgery (e.g. in the 
chest or the abdomen) will not be performed for research purposes alone but only if necessary for 
your medical care.  Risks of biopsies include pain, bleeding, infection, and the risks to the 
particular area undergoing surgery. General anesthesia itself is generally safe but has a very small 
risk of major complications such as heart attack or stroke.  The risks of general anesthesia will be 
explained to you in more detail at the time of surgery if it is needed.   Blood samples, other body 
fluids and tissues that are obtained during testing, operative procedures, or other standard medical 
practices will also be used for research purposes.
In order to receive EPOCH-R, you will need to have a catheter placed in a large vein.  This catheter 
can be placed in the arm, neck, chest or groin areas.  In general, the chest, neck or arm is preferred.  
For most people, the safest catheters are placed temporarily and removed after each chemotherapy 
treatment.  For some patients, semi-permanent catheters are preferable.  These catheters stay in 
place until all cycles of therapy are completed.  While they may seem more convenient, they are 
associated with a more frequent occurrence of complications.  The risks associated with insertion 
of catheters include pain, bleeding, infection, and puncture of the lung.  A lung puncture can result 
in lung collapse, which might require insertion of a tube into the chest cavity (usually for a day or 
two) to help the lung reinflate.  The long-term risks of catheters include infection and clotting of 
the vein, and this is more common with semi-permanent catheters.  If side effects occur, it may be 
necessary to remove the catheter, and to treat the infection and/or clot with medication.  These 
risks will be explained to you in more detail at the time of the catheter insertion.  You will be 
advised witch catheter type is likely to be best for you.  The catheter type that is best for you may 
change over the course of therapy.
What are the risks of radiation from being in this study? 
During your participation in this research study, you may be exposed to radiation from CTs of the 
Chest, Abdomen and Pelvis and PET scans each year.  The amount of radiation exposure from 
these procedures is equal to approximately 17.1 rem. A rem is a unit of absorbed radiation. 
Every day, people are exposed to low levels of radiation that come from the sun and the 
environment around them.  The average person in the United States receives a radiation exposure 
of 0.3 rem per year from these sources.  This type of radiation is called “background radiation.”  
This study will expose you to more radiation than you get from everyday background radiation. 
No one knows for sure whether exposure to these low amounts of radiation is harmful to your 
body. 
The CT and PET scans that you get in this study will expose you to roughly the same amount of 
radiation as 57 years’ worth of background radiation. Being exposed to too much radiation can 
cause harmful side effects such as an increase in the risk of cancer.  The risk depends on how much 
radiation you are exposed to. Please be aware that about 40 out of 100 people (40%) will get cancer 
during their lifetime, and 20 out of 100 (20%) will die from cancer. The risk of getting cancer from 
IRB NUMBER: 01C0030
IRB APPROVAL DATE: 03/31/2021


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the radiation exposure in this study is 1.7 out of 100 (1.7%) and of getting a fatal cancer is 0.9 out 
of 100 (0.9%) 
You may not participate in this study if you are pregnant. If you are able to become pregnant, we 
will perform a pregnancy test before exposing you to radiation. You must tell us if you may have 
become pregnant within the previous 14 days because the pregnancy test is unreliable during that 
time.
Drugs used in the spinal fluid for lymphoma:

Methotrexate, when administered into the spinal fluid, may cause low blood counts and 
ulcerations in the mouth, stomach, and intestines.  It can cause acute headache, back pain, 
stiff neck, and /or fever; it can also cause weakness or paralysis of certain muscles.  It can 
cause seizures and coma.  Other side effects it can cause are usually associated with 
intravenous administration rather than intrathecal (lumbar puncture administration), but 
these include liver function abnormalities, inflammation and scarring of the lungs, 
inflammation of the tissue covering the heart, and severe skin reactions.  This drug can 
rarely cause damage to the lungs.

Leucovorin is related to the vitamin folic acid.  For the most part, it is nontoxic in 
therapeutic doses.  However, severe allergic reactions have been reported, but these are 
rare.  It is used to decrease the side effects of the methotrexate.

Cytosine Arabinoside given my lumber puncture can cause nausea, vomiting, fever, and 
headaches.  Rarely, it can cause weakness and seizures.  When given into the spinal fluid, 
it does not usually cause systemic toxicity, but we will monitor you for low blood counts, 
and liver function abnormalities, which can occur with cytosine arabinoside when given 
by vein.  
Other risks:
As a patient-volunteer, you may experience considerable psychological stress.  This study 
requires a substantial time commitment over a 2-year period with requirements for blood tests, 
x-ray’s, drug administration, and physician appointments. There is also uncertainty regarding the 
ultimate outcome of your treatment.  Some patients will feel worse, for at least some period 
during the investigational treatment period, than they did before treatment.   Patient-volunteers 
are encouraged to discuss their feelings with staff members.  Your treating physicians, in concert 
with other members of the treatment team, wish to identify any problems that are affecting your 
emotional wellbeing, and to help you deal with them.  Should you experience sad or disturbing 
feelings, we have counselors available, and you should notify a member of the treatment team 
so that arrangements can be made for counseling if you wish it.
Psychological or Social Risks Associated with Loss of Privacy 
The following general points are indirectly related to your participation in the research study:
1.
Unanticipated medical information: During the course of this investigation, it is possible 
(although not likely) that we will obtain unanticipated information about your health or 
genetic background.  
IRB NUMBER: 01C0030
IRB APPROVAL DATE: 03/31/2021


PATIENT IDENTIFICATION
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2.
Release of genetic information:  

Your privacy is very important to us and we will use many safety measures to protect 
your privacy. However, in spite of all of the safety measures that we will use, we cannot 
guarantee that your identity will never become known. Although your genetic 
information is unique to you, you do share some genetic information with your children, 
parents, brothers, sisters, and other blood relatives. Consequently, it may be possible that 
genetic information from them could be used to help identify you. Similarly, it may be 
possible that genetic information from you could be used to help identify them. 

While the controlled-access databases developed for this project will not contain 
information that is traditionally used to identify you, such as your name, address, 
telephone number, or social security number, people may develop ways in the future that 
would allow someone to link your genetic or medical information in our databases back 
to you. For example, someone could compare information in our databases with 
information from you (or a blood relative) in another database and be able to identify you 
(or your blood relative). It also is possible that there could be violations to the security of 
the computer systems used to store the codes linking your genetic and medical 
information to you.

Since some genetic variations can help to predict the future health problems of you and 
your relatives, this information might be of interest to health providers, life insurance 
companies, and others. Patterns of genetic variation also can be used by law enforcement 
agencies to identify a person or his/her blood relatives. Therefore, your genetic 
information potentially could be used in ways that could cause you or your family 
distress, such as by revealing that you (or a blood relative) carry a genetic disease.

There also may be other privacy risks that we have not foreseen.
Protections against misuse of genetic information 
This study involves genetic testing on samples.  Some genetic information can help predict future 
health problems of you and your family and this information might be of interest to your employers 
or insurers. The Genetic Information Nondiscrimination Act (GINA) is a federal law that prohibits 
plans and health insurers from requesting genetic information or using genetic information. It also 
prohibits employment discrimination based on your health information. However, GINA does not 
address discrimination by companies that sell life insurance, disability insurance, or long-term care 
insurance. GINA also does not protect you against discrimination based on an already-diagnosed 
condition or disease that has a genetic component.
POTENTIAL BENEFITS OF PARTICIPATION
Are there benefits to taking part in this study? 
As a result of participating in this investigational treatment program, you will receive evaluation 
and treatment of your lymphoma and AIDS.  All of the medications, tests, hospitalizations and 
physician services at the NIH will be free of charge to you.  As information is gathered from this 
trial, results will be shared with you (of course information regarding other patients will never 
IRB NUMBER: 01C0030
IRB APPROVAL DATE: 03/31/2021


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include the patients name or any other identifying information, to insure patient confidentiality).  
Although the EPOCH-R chemotherapy is experimental, all of the drugs in EPOCH-R except the 
rituximab are contained in standard treatment regimens for HIV-related lymphomas.    Moreover, 
we have tested EPOCH alone in AIDS-lymphoma, and it appears to be safe and effective.  
However, we cannot be certain if you will be cured of your lymphoma and it is possible your tumor 
may be resistant to chemotherapy, and if this occurs, you may not receive any benefit from this 
treatment.  
ALTERNATIVE APPROACHES OR TREATMENTS
Alternative treatments for AIDS-lymphoma include:

Standard combination chemotherapy regimens. These are sometimes given in lower than 
standard doses along with antiretroviral therapy.

Treatment with single chemotherapy drugs.  Therapy with single drugs is better tolerated 
than combination therapy, and often produce shrinkage of tumor.  However, they rarely 
cure lymphomas. 

Radiation (X-ray) treatments.  Tumor growth can be stopped in the areas that receive 
radiation, but it cannot control disease that has spread to multiple areas because the whole 
body cannot be irradiated without extreme toxicity.

Surgery can successfully remove tumors.  However, removal of a tumor by surgery rarely 
if ever cures lymphoma because the tumors have spread to multiple areas.  

Occasionally, patients do not want therapy unless the tumor is causing problems.  
However, AIDS-related lymphomas are almost always aggressive and will quickly cause 
symptoms unless treated.  Some patients may feel that chemotherapy is not the best 
approach for them and may wish to have comfort care only. These are issues that should 
be discussed with your physicians.
STOPPING THERAPY
Your doctor may decide to take you off this study for the following reasons:
•
if he/she believes that it is in your best interest
•
if your disease comes back during treatment
•
if you have side effects from the treatment that are your doctor thinks are too severe
•
if new information shows that another treatment would be better for you
•
if you do not follow the study requirements (for instance, if you are not coming for 
your study visits when scheduled).
In this case, you will be informed of the reason therapy is being stopped.
You can stop taking part in the study at any time. However, if you decide to stop taking part in the 
study, we would like you to talk to the study doctor and your regular doctor first.
If you decide at any time to withdraw your consent to participate in the trial, we will not collect 
any additional medical information about you. However, according to FDA guidelines, 
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information collected on you up until that point may still be provided to designated representatives. 
If you withdraw your consent and leave the trial, any samples of yours that have been obtained for 
the study and stored at the NCI can be destroyed upon request. However, any samples and data 
generated from the samples that have already been distributed to other researchers or placed in the 
research databases cannot be recalled and destroyed. 
CONFLICT OF INTEREST
The National Institutes of Health (NIH) reviews NIH staff researchers at least yearly for conflicts 
of interest.   This process is detailed in a Protocol Review Guide.  You may ask your research 
team for a copy of the Protocol Review Guide or for more information.  Members of the research 
team who do not work for NIH are expected to follow these guidelines but they do not need to 
report their personal finances to the NIH.
Members of the research team working on this study may have up to $15,000 of stock in the 
companies that make products used in this study.  This is allowed under federal rules and is not a 
conflict of interest. 
USE OF SPECIMENS AND DATA FOR FUTURE RESEARCH
To advance science, it is helpful for researchers to share information they get from studying human 
samples.  They do this by putting it into one or more scientific databases, where it is stored along 
with information from other studies. A researcher who wants to study the information must apply 
to the database and be approved.  Researchers use specimens and data stored in scientific databases 
to advance science and learn about health and disease.  
We plan to keep some of your specimens and data that we collect, use them for future research and 
share them with other researchers. We will not contact you to ask about each of these future uses. 
These specimens and data will be stripped of identifiers such as name, address or account number, 
so that they may be used for future research on any topic and shared broadly for research purposes. 
Your specimens and data will be used for research purposes only and will not benefit you. It is 
also possible that the stored specimens and data may never be used.  
Results of research done on your specimens and data will not be available to you or your doctor.  
It might help people who have cancer and other diseases in the future.  If you do not want your 
stored specimens and data used for future research, please contact us in writing and let us know 
that you do not want us to use your specimens and data. Then any specimens that have not already 
been used or shared will be destroyed and your data will not be used for future research. However, 
it may not be possible to withdraw or delete materials or data once they have been shared with 
other researchers.
Genomic Data Sharing
As part of this research study, we will put your genomic data in a large database for broad sharing 
with the research community. These databases are commonly called data repositories. The 
information in this database will include but is not limited to genetic information, race and 
ethnicity, and sex.  If your individual data are placed in one of these repositories, they will be 
labeled with a code and not with your name or other information that could be used to easily 
identify you, and only qualified researchers will be able to access them. These researchers must 
IRB NUMBER: 01C0030
IRB APPROVAL DATE: 03/31/2021


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receive prior approval from individuals or committees with authority to determine whether these 
researchers can access the data.
NIH policies require that genomic data be placed in a repository for sharing. Therefore, we cannot 
offer you a choice of whether your data will be shared.  If you do not wish to have your data placed 
in a repository, you should not enroll in this study. 
PAYMENT
Will you receive any type of payment for taking part in this study?
You will not receive any payment for taking part in this study. 
REIMBURSEMENT
Will you receive reimbursement or direct payment by NIH as part of your participation?
On this study, the NCI will reimburse the cost for some of your expenses such as those for hotel, 
travel, meals.  Some of these costs may be paid directly by the NIH and some may be reimbursed 
after you have paid. The amount and form of these payments are determined by the NCI Travel 
and Lodging Reimbursement Policy.  You will be given a summary of the policy which provides 
more information.
If your travel to the NIH Clinical Center (e.g. flight, hotel) is arranged and paid for by the NIH, 
the agency making the reservations and their representatives will have access to your identifiable 
information.
COSTS
Will taking part in this research study cost you anything? 
NIH does not bill health insurance companies or participants for any research or related clinical 
care that you receive at the NIH Clinical Center. 
If you choose to take part in the study, the following will apply, in keeping with the NIH policy:

You will receive study treatment at no charge to you. This may include surgery, 
medicines, laboratory testing, x-rays or scans done at the Clinical Center, National 
Institutes of Health (NIH), or arranged for you by the research team to be done outside 
the Clinical Center, NIH if the study related treatment is not available at the NIH. 

There are limited funds available to cover the cost of some tests and procedures 
performed outside the Clinical Center, NIH.  You may have to pay for these costs if they 
are not covered by your insurance company.

Medicines that are not part of the study treatment will not be provided or paid for by the 
Clinical Center, NIH.

Once you have completed taking part in the study, medical care will no longer be 
provided by the Clinical Center, NIH.
IRB NUMBER: 01C0030
IRB APPROVAL DATE: 03/31/2021


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CLINICAL TRIAL REGISTRATION AND RESULTS REPORTING 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law. This Web site will not include information that can identify you. At most, the Web 
site will include a summary of the results. You can search this Web site at any time.
CONFIDENTIALITY PROTECTIONS PROVIDED IN THIS STUDY  
Will your medical information be kept private? 
We will do our best to make sure that the personal information in your medical record will be 
kept private.  However, we cannot guarantee total privacy.  Organizations that may look at 
and/or copy your medical records for research, quality assurance, and data analysis include: 

The NIH and other government agencies, like the Food and Drug Administration (FDA), 
which are involved in keeping research safe for people.

National Institutes of Health Intramural Institutional Review Board

Some of the specimens and/or data obtained may be sent to researchers outside of the 
National Cancer Institute to perform additional research studies designed to help us better 
understand lymphoma.
The researchers conducting this study and the NIH follow applicable laws and policies to keep 
your identifying information private to the extent possible.  However, there is always a chance 
that, despite our best efforts, your identity and/or information about your participation in this 
research may be inadvertently released or improperly accessed by unauthorized persons.
In most cases, the NIH will not release any identifiable information collected about you without 
your written permission.  However, your information may be shared as described in the section of 
this document on sharing of specimens and data, and as further outlined in the following sections.    
Further, the information collected for this study is protected by NIH under a Certificate of 
Confidentiality and the Privacy Act. 
Certificate of Confidentiality
To help us protect your privacy, the NIH Intramural Program has received a Certificate of 
Confidentiality (Certificate). With this certificate, researchers may not release or use data or 
information about you except in certain circumstances.  
NIH researchers must not share information that may identify you in any federal, state, or local 
civil, criminal, administrative, legislative, or other proceedings, for example, if requested by a 
court.  
The Certificate does not protect your information when it:  
1. is disclosed to people connected with the research, for example, information may be used 
for auditing or program evaluation internally by the NIH; or 
2. is required to be disclosed by Federal, State, or local laws, for example, when information 
must be disclosed to meet the legal requirements of the federal Food and Drug 
Administration (FDA); 
3. is for other research;
IRB NUMBER: 01C0030
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4. is disclosed with your consent. 
The Certificate does not prevent you from voluntarily releasing information about yourself or your 
involvement in this research. 
The Certificate will not be used to prevent disclosure to state or local authorities of harm to self or 
others including, for example, child abuse and neglect, and by signing below you consent to those 
disclosures. Other permissions for release may be made by signing NIH forms, such as the Notice 
and Acknowledgement of Information Practices consent.
Privacy Act
The Federal Privacy Act generally protects the confidentiality of your NIH medical records we 
collect under the authority of the Public Health Service Act.  In some cases, the Privacy Act 
protections differ from the Certificate of Confidentiality.  For example, sometimes the Privacy Act 
allows release of information from your medical record without your permission, for example, if 
it is requested by Congress. Information may also be released for certain research purposes with 
due consideration and protection, to those engaged by the agency for research purposes, to certain 
federal and state agencies, for HIV partner notification, for infectious disease or abuse or neglect 
reporting, to tumor registries, for quality assessment and medical audits, or when the NIH is 
involved in a lawsuit.  However, NIH will only release information from your medical record if it 
is permitted by both the Certificate of Confidentiality and the Privacy Act.
POLICY REGARDING RESEARCH-RELATED INJURIES  
The NIH Clinical Center will provide short-term medical care for any injury resulting from your 
participation in research here. In general, no long-term medical care or financial compensation for 
research-related injuries will be provided by the NIH, the NIH Clinical Center, or the Federal 
Government. However, you have the right to pursue legal remedy if you believe that your injury 
justifies such action.
PROBLEMS OR QUESTIONS
If you have any problems or questions about this study, or about your rights as a research 
participant, or about any research-related injury, contact the Principal Investigator, Dr. Mark 
Roschewski, Email: Mark.Roschewski@nih.gov, Telephone number: 240-760-6183. You may 
also call the NIH Clinical Center Patient Representative at 301-496-2626, or the NIH Office of 
IRB Operations at 301-402-3713, if you have a research-related complaint or concern.
CONSENT DOCUMENT 
Please keep a copy of this document in case you want to read it again.
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Adult Research Participant: I have read the explanation about this study and have been given the opportunity 
to discuss it and to ask questions. I consent to participate in this study.
Signature of Research Participant
Print Name of Research Participant
Date
Legally Authorized Representative (LAR) for an Adult Unable to Consent: I have read the explanation 
about this study and have been given the opportunity to discuss it and to ask questions. I am legally authorized 
to make research decisions on behalf of the adult participant unable to consent and have the authority to provide 
consent to this study. As applicable, the information in the above consent was described to the adult participant 
unable to consent who agrees to participate in the study.
Signature of LAR
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Investigator:
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Witness to the oral short-form consent process only: 
Signature of Witness*
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Date
*NIH ADMINISTRATIVE SECTION TO BE COMPLETED REGARDING THE USE OF AN 
INTERPRETER:
An interpreter, or other individual, who speaks English and the participant’s preferred language facilitated
the administration of informed consent and served as a witness. The investigator obtaining consent may not 
also serve as the witness.
An interpreter, or other individual, who speaks English and the participant’s preferred language facilitated
the administration of informed consent but did not serve as a witness. The name or ID code of the person 
providing interpretive support is:
.
IRB NUMBER: 01C0030
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Prot_SAP_002.pdf: 
Abbreviated Title: Short-Course Therapy AIDS-NHL
Version Date:  07/01/2022
1
Abbreviated Title: Short-Course Therapy AIDS-NHL
NIH Protocol #:  01C0030 
CTEP Protocol #:  2890 – not CTEP sponsored since Amendment L
Version Date: 07/01/2022
NCT Number:  NCT00006436
SHORT-COURSE EPOCH-RITUXIMAB FOR UNTREATED 
CD-20+ HIV-ASSOCIATED LYMPHOMAS
NCI Principal Investigator: Mark Roschewski, M.D. 
Lymphoid Malignancies Branch (LYMB)
Center for Cancer Research (CCR) 
National Cancer Institute (NCI)
National Institutes of Health (NIH)
Building 10, Room 4N115
9000 Rockville Pike
Bethesda, MD 20892
Phone:  240-760-6183
Email:  roschewskimj@mail.nih.gov 
Commercial Agents:  EPOCH-R = etoposide, prednisone, vincristine, cyclophosphamide, 
doxorubicin, rituximab


Abbreviated Title: Short-Course Therapy AIDS-NHL
Version Date:  07/01/2022
2
PRÉCIS
Background:  

This is a study to investigate in a preliminary fashion the feasibility of short course 
chemotherapy to participants with HIV-associated non-Hodgkin’s lymphoma (HIV-NHL).  

This study will investigate if the paradigm for treatment can be successfully changed from a 
standard of 6 cycles to one cycle beyond complete remission with 6 total allowable cycles.  
Objective:

To assess with 90% probability that at least 50% of participants treated with short-course 
EPOCH-R will be progression free at one year.
Eligibility:

Aggressive CD20 positive DLBCL.

HIV+ serology.

All stages (I-IV) of disease.

ECOG Performance status 0-4

NHL previously untreated with cytotoxic chemotherapy.  

Age  18 years 

May not be pregnant or nursing

May not have received previous rituximab
Design:

Participants will be treated every three weeks with a combination of EPOCH and rituximab 
for one cycle beyond CR/CRu by CT scan of all detectable tumors for a minimum of three 
and maximum of six cycles. Following cycle 2, CT, positron emission tomography scans 
(PET), and bone marrow biopsies (if initially positive) will be performed.  

At the conclusion of the study, we will estimate whether the number of cycles can be reduced 
using the paradigm.  If the cumulative number of participants to relapse exceeds 25% by 6 
months, the study will be closed.  

Following the completion of chemotherapy, restaging will be performed 2 months following 
the end of treatment, then every 3 months for one year, every 6 months for one year, then 
every 12 months until relapse, death, or loss to follow up.

Antiretroviral therapy (ART) will be given concurrently with treatment regimen.   

To study the effects of treatment approach on parameters of HIV disease, measurements of 
CD4 cells and viral loads will be made at baseline and at the completion of therapy, and then 
2 months following the end of treatment, and then every 3-6 months for a total of 24 months 
following chemotherapy.


Abbreviated Title: Short-Course Therapy AIDS-NHL
Version Date:  07/01/2022
3
TABLE OF CONTENTS
PRÉCIS...........................................................................................................................................2
TABLE OF CONTENTS ................................................................................................................3
STATEMENT OF COMPLIANCE ................................................................................................6
1
INTRODUCTION ...................................................................................................................7
1.1
Study Objectives..............................................................................................................7
1.2
Background and Rationale...............................................................................................7
2
ELIGIBILITY ASSESSMENT AND ENROLLMENT .......................................................12
2.1
Eligibility Criteria..........................................................................................................12
2.2
Screening Evaluation.....................................................................................................13
2.3
Participant Registration and Status Update Procedures.................................................14
2.4
Baseline Evaluation .......................................................................................................15
3
STUDY IMPLEMENTATION .............................................................................................15
3.1
Study Design..................................................................................................................15
3.2
Drug Administration......................................................................................................16
3.3
Treatment Modifications ...............................................................................................18
3.4
On Study Evaluations ....................................................................................................19
3.5
Concurrent Therapies.....................................................................................................19
3.6
Radiation Therapy Guidelines .......................................................................................21
3.7
Post-Therapy Evaluation ...............................................................................................21
3.8
Cost and Compensation .................................................................................................21
3.9
Criteria for Removal from Protocol Therapy and Off-Study Criteria ...........................21
4
SUPPORTIVE CARE ...........................................................................................................22
4.1
Cytomegalovirus (CMV)...............................................................................................22
4.2
Fungal Infections ...........................................................................................................23
4.3
Mycobacterium disease .................................................................................................23
4.4
Febrile neutropenia ........................................................................................................23
4.5
Anemia...........................................................................................................................23
4.6
Thrombocytopenia.........................................................................................................23
4.7
Central venous access....................................................................................................23
4.8
Ommaya Reservoirs.......................................................................................................24
4.9
Nutritional Assessment and Psychological Support......................................................24
5
CORRELATIVE STUDIES FOR RESEARCH ...................................................................25


Abbreviated Title: Short-Course Therapy AIDS-NHL
Version Date:  07/01/2022
4
5.1
Biospecimen Collection.................................................................................................25
5.2
Sample Storage, Tracking and Disposition ...................................................................30
5.3
Genetic/Genomic Analysis ............................................................................................32
6
DATA COLLECTION AND EVALUATION .....................................................................33
6.1
Data Collection ..............................................................................................................33
6.2
Data Sharing Plans.........................................................................................................34
6.3
Response Criteria...........................................................................................................35
6.4
Toxicity Criteria.............................................................................................................35
7
NIH REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING PLAN.....36
7.1
Definitions .....................................................................................................................36
7.2
OHSRP Office of Compliance and Training/IRB Reporting ........................................36
7.3
NCI Clinical Director (CD) Reporting ..........................................................................36
7.4
IND Sponsor Reporting Criteria....................................................................................36
7.5
NIH Required Data and Safety Monitoring Plan...........................................................36
8
STATISTICAL CONSIDERATIONS ..................................................................................37
9
COLLABORATIVE AGREEMENTS..................................................................................39
10
HUMAN SUBJECTS PROTECTIONS................................................................................39
10.1
Rationale for Subject Selection .....................................................................................39
10.2
Participation of Children................................................................................................39
10.3
Participation of Subjects Unable to Give Consent ........................................................39
10.4
Evaluation of Benefits and Risks/Discomforts..............................................................40
10.5
Risks/Benefits Analysis.................................................................................................40
10.6
Consent Processes and Documentation .........................................................................41
11
REGULATORY AND OPERATIONAL CONSIDERATIONS..........................................42
11.1
Study Discontinuation and Closure ...............................................................................42
11.2
Quality Assurance and Quality Control.........................................................................43
11.3
Conflict of Interest Policy..............................................................................................43
11.4
Confidentiality and Privacy ...........................................................................................43
12
PHARMACEUTICAL INFORMATION .............................................................................44
12.1
Rituximab ......................................................................................................................44
12.2
Doxorubicin ...................................................................................................................48
12.3
Vincristine......................................................................................................................48
12.4
Etoposide .......................................................................................................................49


Abbreviated Title: Short-Course Therapy AIDS-NHL
Version Date:  07/01/2022
5
12.5
Etoposide/ Doxorubicin/Vincristine Administration.....................................................49
12.6
Cyclophosphamide ........................................................................................................49
12.7
Prednisone......................................................................................................................50
12.8
Filgrastim (G-CSF)........................................................................................................51
12.9
Hydrocortisone, dexamethasone....................................................................................51
12.10 Methotrexate..................................................................................................................51
12.11 Cytarabine......................................................................................................................52
12.12 Leucovorin.....................................................................................................................52
13
REFERENCES ......................................................................................................................53
14
APPENDICES .......................................................................................................................57
14.1
APPENDIX A:  Evaluations Roadmap .........................................................................57
14.2
APPENDIX B:  EPOCH Admixtures: Preparation and Administration .......................58


Abbreviated Title: Short-Course Therapy AIDS-NHL
Version Date:  07/01/2022
6
STATEMENT OF COMPLIANCE
The trial will be carried out in accordance with International Conference on Harmonisation Good 
Clinical Practice (ICH GCP) and the following: 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 
CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812) 
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are 
responsible for the conduct, management, or oversight of NIH-funded clinical trials have 
completed Human Subjects Protection and ICH GCP Training.
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the Institutional Review Board (IRB) for review and approval.  Approval of both 
the protocol and the consent form must be obtained before any participant is enrolled.  Any 
amendment to the protocol will require review and approval by the IRB before the changes are 
implemented to the study.  In addition, all changes to the consent form will be IRB-approved; an 
IRB determination will be made regarding whether a new consent needs to be obtained from 
participants who provided consent, using a previously approved consent form.


Abbreviated Title: Short-Course Therapy AIDS-NHL
Version Date:  07/01/2022
7
1
INTRODUCTION 
1.1
STUDY OBJECTIVES
1.1.1
Primary Objective

To assess with 90% probability that at least 50% of participants treated with short-course 
EPOCH-R will be progression free at one year
1.1.2
Secondary Objectives

Assess toxicity of SC-EPOCH-R

Assess response rate and duration of SC-EPOCH-R

Assess the utility of PET scans to predict freedom from relapse with SC-EPOCH-R

Assess effects of SC-EPOCH-R on CD4 cell depletion and recovery

Assess response to antiretroviral therapy either following or concurrently with SC-
EPOCH-R (effective with Amendment S, antiretroviral therapy will be given 
concurrently) 

Assess 5- year Overall Survival (OS)
1.1.3
Exploratory Objectives

Explore molecular and genomic studies in tissue that may predict response and outcomes
1.2
BACKGROUND AND RATIONALE
HIV-associated lymphomas present unique treatment challenges compared with HIV negative 
lymphomas.  Patients are often profoundly immunosuppressed and generally intolerant of 
aggressive chemotherapy, and have a median survival of 4 to 11 months with standard therapy1, 
2.  Additionally, HIV-associated lymphomas more frequently present with adverse prognostic 
features including multiple extranodal disease sites, elevated LDH, poor performance status and 
advanced stage3.  Despite significant efforts to improve the outcome of HIV-NHL, it continues 
to limit the life expectancy of affected individuals more significantly than any single AIDS-
defining condition except for multifocal leukoencephalopathy 4.  Median survivals for HIV-NHL 
are less than 18 months in most series, even for patients with good prognosis characteristics 1, 5-7.  
To a large extent, efforts to improve treatment outcomes have had modest success at best.  
Treatment strategies primarily include low-dose chemotherapy regimens and given with multi-
agent antiretroviral therapy in an effort to balance the antitumor and immunosuppressive effects 
of treatment.  
Based on first principles, the strategy of low-dose chemotherapy given with antiretroviral 
therapy is appealing.  Lower doses of chemotherapy may be less immunosuppressive relative to 
standard doses, and suppression of HIV may protect patients undergoing anti-lymphoma therapy 
from progressive HIV disease.  However, there are a number of issues that raise concerns as to 
the likely effectiveness of such an approach.  In non-HIV-associated lymphomas, some studies 
have suggested that chemotherapy dose-intensity (the amount of chemotherapy administered 
over time) is associated with curative potential 8.  Indeed, large studies of low- versus standard 
dose chemotherapy in HIV-NHL suggest that more patients in the low-dose groups die with 
active lymphoma than in the standard dose groups 1.  Also, attempts at preservation of CD4 cell 


Abbreviated Title: Short-Course Therapy AIDS-NHL
Version Date:  07/01/2022
8
counts by utilizing concurrent anti-HIV therapy may not be very useful when lymphocytotoxic 
chemotherapy is administered to treat the lymphoma.  In HIV-negative patients undergoing such 
therapy, CD4 cell depletion in excess of 80% of baseline can often occur9, and recovery to 
baseline may not occur for greater than 12 months10.   Thus, lymphocyte depletion occurs 
independently of HIV infection.  Additionally, because of overlapping pharmacokinetic 
interactions and can adversely affect the therapeutic index of the various drugs, optimal 
treatment for both the lymphoma and the HIV infection may be compromised.  Also, if 
chemotherapy-associated toxicity compromises compliance with the antiretroviral drugs, 
development of resistant HIV may be more likely to occur when this strategy is utilized.
However, studies have not shown improved survival, even though the complete response rates 
are generally somewhat higher in patients receiving standard dose chemotherapy 1, 5-7.  To a large 
extent, this is due to the inability of HIV-infected patients to tolerate the more intensive 
chemotherapy regimens, and death due to progressive complications of AIDS counterbalances 
the beneficial effects of such therapy on the lymphoma.  Thus, strategies to successfully 
eradicate the lymphoma but with less immune damage may be one way of balancing these 
effects.  The administration of short-course (2-3 cycles) chemotherapy as we propose would 
represent a significant change in the standard treatment paradigm, which typically employs 6 to 8 
cycles.  Such a strategy may result in significantly less chemotherapy related immune damage 
with better preservation of lymphocytes and potentially reduce the risk for AIDS-related 
mortality.  
The concept of shorter course chemotherapy extends from our initial clinical research in HIV-
associated lymphoma utilizing dose-adjusted EPOCH.   This regimen appears to be effective and 
relatively well-tolerated when administered over 6 cycles11.  Among 30 evaluable patients, 23 
(77%) achieved a complete response, 100% of whom remain disease free with a median follow-
up over 2 years.  Of note, patients who achieved a complete response with EPOCH did so by 
cycle 4, and many had rapid resolution of all palpable tumor masses within 1 to 2 cycles.   
Indeed, the 100% disease free survival rate following 6 cycles of EPOCH alone suggests that 6 
cycles of EPOCH may not be necessary in all patients.  A unique aspect of this trial prior to 
Amendment S, was the suspension of all anti-retroviral treatment during EPOCH to reduce 
potential adverse pharmacokinetic interactions, and the emergence of resistant viral quasi-species 
due to sub-therapeutic antiretroviral drug concentrations6, 12, 13.  Detailed assessment of immune 
status has demonstrated a loss of CD4 cells and increased viral loads, albeit transient, with return 
to baseline within 12 months after treatment11.  However, it is likely that there is still a 
substantial risk of AIDS progression and opportunistic infections with this approach.
Beginning with Amendment S, antiretroviral therapy will be given concurrently with EPOCH. 
Concurrent therapy is felt to be in the best interests of the participants on study at this time. ART 
has been shown to be safe when administered concurrently with EPOCH and is no longer 
routinely stopped during the treatment of HIV-associated malignancies similar to those under 
study 40, 41.
Rituximab is a chimeric antibody, containing the human IgG1 and  constant and murine 
variable regions, which targets the CD20 B cell antigen 14.  CD20 is expressed on the surface of 
normal and neoplastic B cells and is present from the pre-B cell stage through terminal 
differentiation to plasma cells 15, 16. To date, the biological functions of CD20 remain uncertain, 
although incubation of B-cells with anti-CD20 antibody has variable effects on cell cycle 
progression, depending on the monoclonal antibody (MoAb) type.  Ligation of CD20 by B1 


Abbreviated Title: Short-Course Therapy AIDS-NHL
Version Date:  07/01/2022
9
MoAb inhibits B-cell progression from G1 to the S/G2+M phases of the cell cycle following 
mitogen stimulation, whereas IF5 MoAb, which binds to a different CD20 epitope, can deliver 
an activation signal and drive resting Go B cells into G1, but not into S phase 17-19.  
Mechanistically, binding of MoAb to CD20 generates transmembrane signals that produce a 
number of events including autophosphorylation and activation of serine/tyrosine protein 
kinases, and induction of c-myc oncogene expression and major histocompatibility complex 
(MHC) class II molecules 18, 20.  Studies have shown that CD20 is also associated with 
transmembrane Ca2+ conductance, through its possible function as a Ca2+ channel, and may 
explain some of the differential effects of IF5 and B1 MoAb’s on B-cells.  The IF5 MoAb may 
activate resting B cells by facilitating rapid Ca2+ entry, while B1 MoAb does not have acute 
effects on Ca2+ currents.  Both MoAb’s, however, may lead to sustained intracellular Ca2+ levels 
over time with subsequent inhibition of cell cycle progression from G1 into S phase 18, 20.  These 
studies demonstrate the importance of CD20 in B-cell regulation, but do not in themselves 
indicate how ligation of the receptor by MoAb produces cell death independent of ADCC or 
complement mediated pathways.  
The clinically important mechanisms of rituximab cytotoxicity remain unclear.  Although ADCC 
and complement mediated cytotoxicity can be demonstrated in vitro, accumulating evidence 
suggests that disruption of normal signal transduction by CD20 MoAb can directly induce 
apoptosis 21, 22.  Shan et al showed that proliferation of a B-cell line could be directly inhibited by 
the IF5 MoAb in heat-inactivated serum (i.e. inactivated complement) and that complement-
replete serum further contributed to inhibition of proliferation 21.  Of note, in the absence of 
complement, the antiproliferative effect of IF5 MoAb was more dependent on CD20 saturation 
and cell density.  The investigators further determined whether anti-CD20 MoAb’s induced B-
cell apoptosis following inhibition of cell growth through the use of three complementary assays.  
When used alone, neither IF5 nor B1 MoAb’s induced significant apoptosis, but when cross-
linked with a goat anti-mouse antibody (GAM), apoptosis occurred in 22% and 28% of cells at 
24 hours, compared to 5% in the controls; similar results were also produced in tonsil B cells.  
These results suggest that similar cross-linking must occur in vivo for anti-CD20 MoAb to 
directly induce apoptosis.  The investigators postulated that functional cross-linking may occur 
in patients through the binding of the MoAb’s Fc domain to the FcR of adjacent cells and 
showed, using a mouse fibroblast transfected with the human Fc receptor, a similar degree of 
apoptosis as observed with GAM cross-linking.  
Accumulating evidence suggests there is an interplay of both pro and anti-apoptotic events in 
response to a cellular stress such as ligation of the CD20 receptor, which would result in either 
cell survival or death 23.   Although studies in other experimental have identified a number of 
cellular events associated with apoptosis, these pathways are poorly understood with anti-CD20 
MoAb’s.  In a preliminary study, Mathas et al investigated the regulation of apoptosis in a human 
Burkitt-lymphoma cell line following exposure to the IDEC-C2B8 anti-CD20 MoAb 22.   Growth 
inhibition of cells occurred 4 hours after exposure to immobilized MoAb, followed by a 
significant rise in apoptotic cells as early as 6 hours later with 70% apoptotic cells after 20 hours.  
Study of major regulators of apoptosis failed to show a change in bcl-2, bax, bcl-x and bad 
protein levels after 20 hours of incubation.  Of note, caspase-3 activation occurred following 
CD20 ligation, and the caspase-3 target proteins D4-GDI and PARP were shown to be cleaved; 
events that are similar to those observed with surface IgM-mediated (sIgM) apoptosis in human 
Burkitt lymphoma cell lines.  Furthermore, these events could be abrogated by z-DEVD-fmk, an 
inhibitor of caspase-3.  These observations suggest that both sIgM and ligation of CD20 by 


Abbreviated Title: Short-Course Therapy AIDS-NHL
Version Date:  07/01/2022
10
MoAb share a similar apoptotic pathway and maybe clinically relevant mechanisms for 
rituximab-induced cell death.  
It is well established that combinations of biologic and/or cytotoxic agents can potentiate tumor 
cell sensitivity through synergistic interactions or possibly reversal of drug resistance 24, 25.  In 
this regard, it is of great interest to explore such interactions with rituximab because of its unique 
mechanisms of action and targeted approach.  Demidem et al undertook such a study to examine 
the sensitizing effect of C2B8 (rituximab MoAb) to cytotoxic agents on a human B-cell line 26.  
For these studies, the DHL-4 tumor cell line was used because of its relative resistance to 
multiple agents under study including cisplatin, etoposide, doxorubicin, ricin and tumor necrosis 
factor (TNF-), compared to a control T-cell line (CEM).  Incubation of the DHL-4 cells with 4 
g/ml C2B8 for 72 hours sensitized the cells to all agents tested except etoposide.  Using a MTT 
cell kill end-point, pre-treatment with C2B8 produce an approximate 1-log increase in cell kill 
with ricin, TNF-, and cisplatin compared to each agent alone.  There was only a modest 
doubling of doxorubicin cytotoxicity.  Of note, the kinetics of C2B8 preincubation revealed that 
the maximum sensitization was achieved between 2 and 5 days, depending on the agents tested, 
with ricin only requiring 2 days and doxorubicin and cisplatin requiring 4 days of C2B8 
exposure.  The investigators studied several possible mechanisms of sensitization but found no 
effect of C2B8 on expression of the multidrug resistance (MDR-1) protein (gp-170) or bcl-2.  In 
contrast, C2B8 did significantly inhibit TNF- secretion whose expression has been associated 
with resistance to cisplatin and doxorubicin.
The clinical study of rituximab and chemotherapy is at the phenomenological stage with results 
available from a few single armed phase II trials.  Nevertheless, these early trials in indolent and 
aggressive lymphomas suggest the presence of potentially important positive interactions 27-29.  
The interpretation of the results, however, is confounded by the activity of rituximab alone and 
the absence of a control group.  As a single agent in relapsed lymphomas, rituximab has an 
overall response rate of 48% with a median time to progression of 13 months in indolent 
histologies and a response rate of 31% with a median time to progression of over 8 months in 
aggressive histologies 30, 31.  In both studies, fewer than 10% of patients achieved complete 
responses.  
When rituximab was combined with CHOP (bolus cyclophosphamide, doxorubicin, vincristine 
and prednisone) chemotherapy, there appeared to be a significant increase in overall response 
rate and duration, compared to CHOP alone.  In one study of 35 patients with either relapsed or 
untreated indolent lymphomas, 100% of patients responded with 63% complete and 37% partial 
responses 27.  Of significance, a recent update reported that the median for duration of response 
and time to progression had not been reached with a median follow-up of 46 months32.  By 
comparison, the median response duration for doxorubicin-containing regimens alone in indolent 
lymphomas is approximately 18 months (39).   There was also no difference in either response 
rate or duration of response among naïve and previously treated patients.  Furthermore, among 8 
patients who were bcl-2 positive at baseline, 7 converted to negative in both bone marrow and 
peripheral blood, and 5 remain negative at between 36 and 51 months.    
The combination of CHOP and rituximab has also been tested in previously untreated patients 
with aggressive B-cell lymphomas (36).  In a preliminary report of 33 patients, 97% responded 
with 61% complete and 36% partial responses.  Because of the frequent difficulty in interpreting 
the significance of residual masses, the progression-free survival provides an indication of the 


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potential rate of cure for a regimen.  In the present study, 82% of participants have remained 
progression-free at a median follow-up of 24 months. By comparison, approximately 48% of 
patients treated with CHOP alone remain progression-free at 2 years 33.  Although these results 
suggest that rituximab may significantly improve the treatment of aggressive lymphomas, they 
should be tempered by the knowledge that 72% of patients had low (0-2) risk International 
Prognostic Indices (IPI).  
In a third phase II trial, rituximab has been combined with dose-adjusted EPOCH (infusional 
etoposide, vincristine and doxorubicin with bolus cyclophosphamide and prednisone) (EPOCH-
R) chemotherapy in patients with previous untreated aggressive lymphomas 29.  Although the 
results of the trial are early, among the 10 patients enrolled, none had progressed.  Furthermore, 
of 8 evaluable patients, 6 achieved complete responses within 2 cycles, suggesting the 
combination has a high fractional cell kill.  The majority of these patients (70%) also had high 
IPI scores.  These investigators also treated 11 patients with relapsed aggressive lymphomas, 
including 6 with refractory disease, and achieved complete and partial remissions in 6 and 2 
patients respectively, suggesting EPOCH-R has a high response rate in poor prognostic patients.  
Two additional cases with refractory lymphomas demonstrated significant responses to the 
addition of rituximab to EPOCH after progressing on EPOCH alone, suggesting that rituximab 
may have sensitized the patients to the effects of chemotherapy34.  
Hepatitis B virus (HBV) reactivation with fulminant hepatitis, hepatic failure, and death has been 
reported in some patients with hematologic malignancies treated with rituximab.  The majority of 
patients received rituximab in combination with chemotherapy.  The median time to the 
diagnosis of hepatitis was approximately 4 months after the initiation of rituximab and 
approximately one month after the last dose. 
Positron emission Tomography (PET) using F-18 fluorodeoxyglucose (FDG) has been studied as 
a predictive tool for treatment outcome in NHL35.  Pre-chemotherapy FDG-PET standardized 
uptake values (SUV) were compared with those determined 7 and 42 days post initiation of 
chemotherapy in a study of 11 patients.  FDG uptake parameters at day 7 and day 42 were 
correlated with long-term treatment outcome.  The group of patients with long-term remission 
had significantly lower mean values at these time points as compared to those with disease 
relapse.  Thus, early in the chemotherapy of lymphoma, FDG-PET uptake decreases but does not 
necessarily resolve.  
Beginning with Amendment O, there will be no further enrollments for children younger than 18 
years old. 


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2
ELIGIBILITY ASSESSMENT AND ENROLLMENT 
2.1
ELIGIBILITY CRITERIA
2.1.1
Inclusion Criteria
2.1.1.1
Aggressive CD20 positive Diffuse Large B-cell lymphoma confirmed by Laboratory of 
Pathology, NCI.  NOTE:  Participants with aggressive B-cell lymphoma of the 
plasmablastic lymphoma sub-type who do not have surface CD20 expression, are also 
eligible.  
2.1.1.2
HIV+ serology
2.1.1.3
All stages (I-IV) of disease
2.1.1.4
ECOG Performance status 0-4
2.1.1.5
NHL previously untreated with cytotoxic chemotherapy; however, participants may be 
entered if they have had prior cyclophosphamide for an urgent problem at diagnosis 
(e.g. epidural cord compression, superior vena cava syndrome) and/or a single dose of 
intrathecal methotrexate (MTX) at the time of the pre-treatment diagnostic lumbar 
puncture 
2.1.1.6
Age  18 years 
2.1.1.7
Laboratory tests (unless impairment due to respective organ involvement by tumor): 

Creatinine 1.5 mg/dl or creatinine clearance  50 ml/min

Bilirubin < 2.0 mg/dl, or total bilirubin  4.5 mg/dl with direct fraction  0.3 mg/dl in 
participants for whom these abnormalities are felt to be due to protease inhibitor therapy

AST and ALT  3x ULN (AST and ALT  6x ULN for participants on hyperalimentation 
for whom these abnormalities are felt to be due to the hyperalimentation)

ANC  1000/mm3

Platelet  75,000/mm3 (unless impairment due to ITP) 
2.1.1.8
Ability of participant to provide informed consent
2.1.2
Exclusion Criteria
2.1.2.1
Previous rituximab
2.1.2.2
Pregnancy or nursing

Doxorubicin, etoposide, vincristine and cyclophosphamide are teratogenic and may be 
excreted in milk
2.1.2.3
Current clinical heart failure or symptomatic ischemic heart disease
2.1.2.4
Serious underlying medical condition or infection other than HIV that would 
contraindicate SC-EPOCH-R
Examples include, but are not limited to:

Severe AIDS-related wasting

Sever intractable diarrhea

Active inadequately treated opportunistic infection of the CNS


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
Primary CNS lymphoma
2.1.2.5
Primary CNS lymphoma
2.2
SCREENING EVALUATION 
2.2.1
Screening activities performed prior to obtaining informed consent
Minimal risk activities that may be performed before the subject has signed a consent include the 
following: 

Email, written, in person or telephone communications with prospective subjects 

Review of existing medical records to include H&P, laboratory studies, etc.  

Review of existing MRI, x-ray, or CT images

Review of existing photographs or videos

Review of existing pathology specimens/reports from a specimen obtained for diagnostic 
purposes
A waiver of consent for these activities has been requested in section 10.6.2.
2.2.2
Screening activities performed after a consent for screening has been signed
The following activities will be performed only after the subject has signed the study consent OR 
the consent for study 01-C-0129 (provided the procedure is permitted on that study) on which 
screening activities may also be performed. Assessments performed at outside facilities or on 
another NIH protocol within the timeframes below may also be used to determine eligibility once 
a participant has signed the consent.
To be completed within 2 weeks prior to initiation of therapy, except imaging studies, which 
must be completed within 4 weeks of initiation of therapy.  Note: no time limit on previous HIV 
serology.
2.2.2.1
Complete history and physical examination with documentation of abnormalities, 
measurable disease, and assessment of performance status
2.2.2.2
Laboratory tests

CBC/differential 

Prothrombin time, partial thromboplastin time

Hepatic Panel (Alkaline phosphatase, AST, ALT, Total and direct bilirubin)

LDH

Mineral Panel (Albumin, Calcium, Magnesium, Phosphate)

Uric acid

Acute Care Panel (Sodium, Potassium, Chloride, Total CO2, Creatinine, Glucose, Urea 
Nitrogen) 

Creatinine clearance if serum creatinine > 1.5 mg/dl

Urinalysis

Urine pregnancy test in women of childbearing potential


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2.2.2.3
Serology 

HIV (documented from outside lab or obtained at the NIH through standard procedure 
viral serology testing consent.)

Hepatitis B surface and core antigen

Hepatitis C

Toxoplasma antibodies
2.2.2.4
Imaging Studies

CT chest, abdomen, and pelvis

CT or MRI of head

Positron Emission Tomography -may be obtained after initiation of EPOCH-R if 
medically inadvisable treatment delay is required
2.2.2.5
Bone marrow aspiration and biopsy
2.2.2.6
Lumbar puncture for culture, chemistry, cytology, and HIV viral load following head 
CT or MRI scan
2.2.2.7
Electrocardiogram
2.3
PARTICIPANT REGISTRATION AND STATUS UPDATE PROCEDURES
Registration and status updates (e.g., when a participant is taken off protocol therapy and when a 
participant is taken off-study) will take place per CCR SOP ADCR-2, CCR Participant 
Registration & Status Updates found at 
https://ccrod.cancer.gov/confluence/pages/viewpage.action?pageId=73203825.
Please Note: As indicated in Section 10.3, all subjects will be offered the opportunity to 
complete an NIH advanced directives form.  This should be done preferably at baseline 
but can be done at any time during the study as long as the capacity to do so is retained.  
The completion of the form is strongly recommended, but is not required.
2.3.1
Treatment Assignment Procedures
Cohorts 
Number
Name
Description
1
Cohort 1
Up to 80 subjects with HIV-associated non-Hodgkin’s lymphoma 
Arms
Number
Name
Description
1
Arm 1
EPOCH-Rituxan+ filgrastim in 3-week treatment cycles for a minimum 
of 3 cycles and a maximum of 6 cycles
2.3.2
Arm Assignment 
Subjects in Cohort 1 directly assigned to Arm 1.  


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2.4
BASELINE EVALUATION
Studies performed during Screening Evaluation will be used for Baseline Evaluation if they were 
completed in the time frame noted in Section 2.2.2. Exception: Pregnancy test must be 
completed within 3 days prior to initiation of therapy. 
3
STUDY IMPLEMENTATION 
Please note that this protocol was on Administrative Hold from October 17, 2016 through 
December 27, 2016. Amendment Q served as the formal notification to the IRB of the 
Administrative Hold. During the time the protocol was on Administrative Hold, no new 
participants were enrolled; however, participants who were on-study were followed per protocol.
3.1
STUDY DESIGN
Participants undergo pretreatment evaluation with bone marrow biopsy, CT and FDG-PET 
scanning. Participants are treated every 3 weeks with SC-EPOCH-R. Treatment is for one cycle 
beyond complete remission (CR/Cru) - with a minimum of 3 and maximum of 6 cycles. CT and 
FDG-PET are repeated after cycles 2 and 3– bone marrow biopsy is repeated after cycle 2 if 
initially positive (and further repeated on subsequent cycles until negative). 
Systemic therapy is stopped once there has been a decrease of < 25% in CT dimensions and/or a 
total PET SUV decrease of > 50% in areas involved by lymphoma.  These CT and PET 
parameters determine when a participant stops systemic treatment. NOTE:  Prior to Amendment 
S, ART therapy was started 3 weeks after systemic chemotherapy had completed; ART therapy 
will now be given concurrently with systemic chemotherapy.  
Intrathecal prophylaxis will begin on cycle 3 day 1 (refer to Section 3.2.2).  Restaging is repeated 
after every further cycle. If disease dimensions increase by > 25% or new disease sites appear on 
therapy (excluding CNS disease), the participant is taken off study. Note that FDG-PET findings 
require clinical and radiological correlation before treatment decisions are made.  


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3.2
DRUG ADMINISTRATION
3.2.1
EPOCH-R Chemotherapy

Rituximab 375 mg/m2 IV days 1 and 5: (Day 1 dose immediately prior to infused agents 
and day 5 dose prior to administration of cyclophosphamide) – must be in separate port 
or IV line if any other cytotoxic agent is being infused.

Etoposide 50 mg/m2 /day CIVI* over approximately 24 hours x 4 days (days 1 to 4)

Doxorubicin 10 mg/m2 /day CIVI over approximately 24 hours x 4 days (days 1 to 4)

Vincristine 0.4 mg/m2 /day CIVI over approximately 24 hours x 4 days (days 1 to 4)

Prednisone 60 mg/m2/day PO x 5 days (days 1 to 5)

Cyclophosphamide 750 mg/m2 IV (Day 5) 

Filgrastim 300 ug/day if participant weighs < 75kg or 480 ug/day if participant weighs 
≥75kg SQ beginning day 6 until absolute neutrophil count recovery  5000 cells/mm3
3.2.1.1
Rituximab administration

See Section 12.1 for detailed information about rituximab. 

No other drugs should be added to or administered in the same IV line as rituximab. 

Consider administration of acetaminophen 500 mg PO prior to dose. Consider 
administration of diphenhydramine 25 – 50 mg IV prior to dose. 
EPOCH-R Cycle 2 Day 21
Restage CT, PET scans; bone marrow biopsy if initially positive
 < 25% in nodal dimensions 
between cycles 2 and 3 and 
PET SUV   50%
between Cycles 1 and 3, stop 
systemic treatment
Pretreatment Staging (CT and PET Scans)
If lymph nodes increase 
25% or new disease sites 
other than CNS, 
patient is off study
NOTE:  PET scan findings without clinical or 
radiological correlates may not be considered positive.  
Prior to Amendment S, stop systemic treatment and begin 
ART. Beginning with Amendment S, give ART and 
EPOCH concurrently.  
Continue EPOCH-R with restaging after each 
cycle until  < 25% in nodal dimensions 
from last cycle and total PET SUV   50% 
compared with cycle 1 (Max. 6 cycles)
EPOCH-R Cycle 3 Day 21:
Restage CT and PET
 > 25% in nodal dimensions 
between cycles 2 and 3 and 
PET SUV  < 50%
between Cycles 1 and 3
EPOCH-R Cycle 3 Day 1: 
Begin IT prophylaxis (refer to Section 3.2.2)


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
Consider holding antihypertensive medication during the approximately 12-hour period 
prior to dosing 
3.2.2
CNS Prophylaxis  
3.2.2.1
Adult Guidelines:

All participants will receive CNS prophylaxis beginning approximately day 1 cycle 3.

Administer methotrexate (MTX) 12 mg IT days 1 and 5 every 21 days for a total of 6 
doses.  

Administer leucovorin 25 mg PO (or IV) approximately 24 hours after each methotrexate 
dose. 

If signs or symptoms of chemical arachnoiditis occur, administer 10 mg of 
hydrocortisone (HDC) with the methotrexate.  

Cytarabine (Ara-C) 50 mg IT days 1 and 5 every 21 days for a total of 6 doses may be 
used in place of methotrexate after discussion with the principal investigator or protocol 
chair if methotrexate is contraindicated.  
NOTE:  The days of treatment and associated supportive care may be adjusted 3 days to 
accommodate scheduling (e.g., holidays, vacations, etc.)
3.2.3
Antiretroviral therapy (ART)

Prior to Amendment S:  
o
Begin after final cycle of EPOCH-R.  Recommend combination therapy based on 
Department of Health and Human Services Guidelines.  However, participants 
may have extenuating circumstances requiring deviation from these guidelines.  
Additionally, referring physicians may manage this component of participant 
care.

Beginning with Amendment S: 
o
Generally, ART will be prescribed for HIV infected subjects. 
o
Participants requiring modification of ART regimen due to contraindicated agents 
(e.g., cobicistat or ritonavir) or HIV resistance should generally have their ART 
regimen modified during the screening and baseline assessment period.
o
Integrase inhibitor-based regimens are preferred for co-administration with 
EPOCH.
o
Referring physicians may manage this component of participant care while 
liaising with study physician investigators, at the discretion of the Principal 
Investigator
o
Recommend combination therapy will be based on Department of Health and 
Human Services Guidelines for treatment of HIV infection: 
http://aidsinfo.nih.gov/guidelines/html/1/adult-and-adolescent-arv-guidelines/0.  
However, participants may have extenuating circumstances requiring deviation 
from these guidelines. Certain antiretroviral agents with CPY3A4 inhibition are 
contraindicated. 


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3.3
TREATMENT MODIFICATIONS
3.3.1
Rituximab 
For infusion related events or hypersensitivity reactions, the infusion rate should be slowed (e.g. 
for moderate flu-like symptoms of fever, chills, rigors; other infusion related reactions such as 
nausea, urticaria, pruritus, rash, fatigue, headache) or infusion of the drug should be interrupted 
or discontinued as clinically indicated (e.g. for reactions such as angioedema, hypotension, 
bronchospasm); following appropriate treatment and/or resolution of the reaction(s), 
administration of rituximab may be reinitiated at a slower infusion rate (one-half the previous 
infusion rate), and the rate of infusion may be incrementally increased as tolerated.
3.3.2
EPOCH
3.3.2.1
Hematological Toxicity

Nadir Counts:
If ANC<500/mm3 for 2 to 4 days or platelets < 25,000/mm3 for 2 to 4 days reduce 
cyclophosphamide by 187 mg/m2 (i.e. 25% of full dose).  If ANC < 500/mm3  5 days or 
platelets < 25,000/mm3 5 days, reduce cyclophosphamide by 375 mg/m2 (i.e. 50% of full 
dose). In the event that the cyclophosphamide dose had been reduced on the previous cycle, 
it may be increased on the next cycle if the following criteria are met:  if ANC >500/mm3 and 
platelets > 25,000/mm3, then increase cyclophosphamide by 187 mg/m2 each cycle, up to full 
dose (i.e. 750 mg/m2). 

Day One Counts (takes precedent over nadir counts):
If ANC < 1000/mm3 delay up to 2 weeks until ANC has increased (may use filgrastim 300 - 
480 mcg SQ daily). If by day 14, ANC 750 – 999/mm3, reduce cyclophosphamide by 187 
mg/m2. If ANC remains < 750/mm3 on day 14, PI or protocol chair may adjust chemotherapy 
doses as clinically indicated.  

Bone Marrow Lymphoma and ITP:
These dose reductions do not necessarily apply to participants with bone marrow lymphoma.  
Reductions in these participants must be individually discussed with the PI. Platelet based 
dose reductions do not apply to participants with ITP: for participants with ITP, it is difficult 
to differentiate thrombocytopenia due to ITP from that caused by chemotherapy. 
Cyclophosphamide dose adjustments for thrombocytopenia in participants with ITP should 
be individually determined by the PI.
3.3.2.2
Non-Hematological Toxicity
Neurological toxicities:
Vincristine Dose

Constipation > Grade 3
0.3 mg/m2/day

Neuropathy-sensory > Grade 3 
0.3 mg/m2/day

Neuropathy-motor Grade 2
0.3 mg/m2/day

Neuropathy-motor  Grade 3
none

Grade IV toxicity: Treatment may be delayed up to 6 weeks or dose modified according 
to principles of best medical practice


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
Carriers of hepatitis B should be closely monitored for clinical and laboratory signs of 
active HBV infection and for signs of hepatitis throughout their study participation.
3.4
ON STUDY EVALUATIONS
NOTE:  See Sections 3.1 for the schema and 5 for the research blood sample collection details.  
3.4.1
Research bloods and FACS analysis: 

Baseline/Cycle 1 Day 1 (up to 3 days prior to C1D1)

Day 21 after each cycle of therapy (+7 days window)

2 months following treatment (±1 week window), then q 3 months x 1 year (±2 weeks 
window), then q 6 months x 1 year (±4 weeks window) 
3.4.2
Day 1 (-3 days window) all cycles and day 21 (+7 days window) last cycle administered:

CBC/differential; acute care panel; mineral panel; hepatic panel, LDH. 
3.4.3
During cycles: 

CBC/differential BIW
3.4.4
Restaging:

Complete by Day 21, cycles 2 through 6.  Initially negative PET and/or bone marrow 
biopsy will not be repeated unless clinically indicated.  
3.4.5
Optional blood draws

Up to 100 ml of blood may optionally be drawn for immunological testing, establishment 
of cell lines, evaluation of hematologic parameters, or other studies that become clinically 
important during conduct of the trial. Subject consent to agreement of these optional 
samples will be documented in the records.  
o
Blood and tissue specimens collected in the course of this research project may be 
banked and used in the future to investigate new scientific questions related to this 
study. However, this research may only be done if the risks of the new questions 
were covered in the consent document or are of minimal risk.  If new and 
significant risks are associated with the research (e.g. analysis of germ line 
genetic mutations) the principal investigator must obtain IRB approval.  NOTE:  
Effective with Amendment R, the option for exploratory genetic testing was 
added and this protocol amended accordingly, including revised informed 
consent/procedures.  See Section 5 for more information.   

Tests during Intrathecal Chemotherapy administration
o
On day one of each cycle of prophylactic intrathecal chemotherapy 
administration, send CSF for cell count, protein, glucose, and HIV viral load.  If 
participant is receiving active treatment in the CNS, obtain these tests every 3-4 
weeks.
3.5
CONCURRENT THERAPIES
3.5.1
Anti-retroviral therapy
Prior to Amendment S, suspend prior to SC-EPOCH-R commences.  With Amendment S, anti-
retroviral therapy will be given concurrently.  See Section 3.2.3. 


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3.5.2
Pneumocystis jiroveci prophylaxis
3.5.2.1
Bactrim DS PO 3x/week. Monday, Wednesday, Friday is the preferred schedule. 
3.5.2.2
Alternatives include (other options may be considered at PI/designee discretion):

Dapsone 50 – 100 mg PO qd or 100 mg PO 2x/week

Aerosolized pentamidine 300 mg by inhalation.
3.5.3
MAC prophylaxis

Consider for all participants with a historic CD4 nadir less than 100 cells/mm3, for 
participants starting SC-EPOCH-R with CD4 cells 100/mm3 or lower, or for participants 
whose CD4 cells fall below this level while on study. Recommend azithromycin 1200 mg 
once weekly, but other agents are acceptable.  
3.5.4
Hepatitis B antigenemia

For participants with serologic evidence of chronic persistent/active HBV infection, 
consideration will be given toward treating with lamivudine 150 mg PO daily, or other 
agents with demonstrated anti-HBV activity during protocol therapy

Treatment with EPOCH-R will be modified or discontinued in any participant who 
develops active HBV infection or hepatitis as directed by the principle investigator to 
balance the risks of hepatitis reactivation with death from suboptimal treatment of 
lymphoma.
3.5.5
Leptomeningeal lymphoma

If the CSF is positive for malignant cells by cytology or FACS, the participant should 
receive triple therapy with methotrexate, cytarabine and hydrocortisone.    
o
Adult doses for IT administration: methotrexate (MTX) 12 mg, cytarabine (Ara-C) 50 
mg, hydrocortisone (HDC) 50 mg. Doses for intraventricular per Ommaya 
administration: methotrexate 5 mg, cytarabine 50 mg, hydrocortisone 50 mg.  
o
Administer leucovorin 25 mg PO (or IV) 24 hours after each dose of triple therapy 
(methotrexate, cytarabine and hydrocortisone).  
o
In participants who cannot tolerate triple therapy, monotherapy with methotrexate 
and/or cytarabine may be used.  Due to unforeseeable events, the above therapy may 
be modified as clinically indicated.  All decisions should be discussed with the PI.  
o
Administer leucovorin 25 mg PO (or IV) 24 hours after each dose of intrathecal 
single therapy with methotrexate or cytarabine) or triple therapy with methotrexate, 
cytarabine and hydrocortisone.

Treatment Schedule:
o
Induction: Twice weekly for 2 weeks beyond negative cytology or FACS, for a 
minimum of 4 weeks (obtain CSF for cytology weekly);
o
Consolidation:  Weekly for 6 weeks (obtain CSF for cytology weekly);  
o
Maintenance:  Monthly for 6 months (obtain CSF for cytology monthly).   


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3.6
RADIATION THERAPY GUIDELINES
For CNS involvement by lymphoma, radiotherapy should be considered for parenchymal 
brain or chemotherapy resistant leptomeningeal disease. 
3.7
POST-THERAPY EVALUATION
3.7.1
Restaging: 

Chest, abdomen and pelvis CT scans two months following end of treatment, then q3 
months x 12 months, then q6 months x 12 months, and then yearly thereafter. After five 
years, CT scans will no longer be performed.
3.7.2
Laboratory tests: 

CBC/differential, mineral panel, acute care panel, hepatic panel, LDH at restaging visits.

HIV viral load 2 months following treatment, then q 3 months x 1 year, then q 6 months x 
1 year.

FACS lymphocyte analysis (including CD4, CD8,) 2 months following treatment, then q 
3 months x 1 year, then q 6 months x 1 year. FACS analysis will be performed at the 
Clinical Center Laboratory as of amendment M.
3.7.3
Research blood samples will be collected at the same time points as FACS analysis (see 
Section 5 for collection information and schedule)
3.8
COST AND COMPENSATION 
3.8.1
Costs 
NIH does not bill health insurance companies or participants for any research or related clinical 
care that participants receive at the NIH Clinical Center.  If some tests and procedures performed 
outside the NIH Clinical Center, participants may have to pay for these costs if they are not 
covered by insurance company.  Medicines that are not part of the study treatment will not be 
provided or paid for by the NIH Clinical Center.    
3.8.2
Compensation
Participants will not be compensated on this study.
3.8.3
Reimbursement
The NCI will cover the costs of some expenses associated with protocol participation.  Some of 
these costs may be paid directly by the NIH and some may be reimbursed to the 
participant/guardian as appropriate.  The amount and form of these payments are determined by 
the NCI Travel and Lodging Reimbursement Policy.   
3.9
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF-STUDY CRITERIA
Prior to removal from study, effort must be made to have all subjects complete a safety visit 
approximately 30 days following the last dose of study therapy.
3.9.1
Criteria for Removal from Protocol Therapy
o
Completion of protocol treatment
o
Inability to tolerate therapy as outlined in the protocol. 
o
Disease progression requiring new treatment. 


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o
Extraordinary medical circumstances: if at any time the constraints of the protocol are 
judged to be detrimental to the participant's health, remove the participant from study 
and document the reason(s) for withdrawal. 
o
Participant's refusal to continue treatment. In this event, document the reason(s) for 
stopping treatment.
o
Positive pregnancy test
3.9.2
Off Study Criteria

Participant does not follow the instructions given by the study team

Participant voluntary withdrawal

Lost to Follow Up

PI Discretion

Study closes for any reason

Death

Completion of 5 year follow-up
3.9.3
Lost to Follow-up
A participant will be considered lost to follow-up if he or she fails to return for three (3) 
consecutive scheduled visits and is unable to be contacted by the study site staff. 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit:

The site will attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain if the participant wishes to and/or should continue in the study.

Before a participant is deemed lost to follow-up, the investigator or designee will make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, 
if necessary, an IRB approved certified letter to the participant’s last known mailing 
address or local equivalent methods). These contact attempts should be documented in 
the participant’s medical record or study file. 

Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up.
4
SUPPORTIVE CARE 
4.1
CYTOMEGALOVIRUS (CMV)
Ganciclovir is usually the initial treatment choice, but due to its hematological toxicity, it should 
not be used without consulting the PI.  Both cidofovir and foscarnet are effective in CMV, but 
are nephrotoxic, and will not be used if there is evidence of renal dysfunction.  Urinalysis for 
proteinuria and creatinine clearance estimates or measurements made if these agents are to be 
used.  All cases of CMV infection must be discussed with the PI.


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4.2
FUNGAL INFECTIONS
4.2.1
Oral Candidiasis – if asymptomatic, recommend clotrimazole troches.  If symptomatic, 
recommend oral fluconazole.  Fluconazole interacts with many drugs, and can alter 
EPOCH pharmacokinetics and therefore must be held during chemotherapy infusions.
4.2.2
Esophageal Candidiasis – recommend oral fluconazole, but if no response, consider 
amphotericin B. Fluconazole interacts with many drugs, and can alter EPOCH 
pharmacokinetics and therefore must be held during chemotherapy infusions.
4.2.3
Cryptococcus neoformans infection may present as meningitis, pneumonia, or fungemia.  
Recommend amphotericin B and fluconazole. 
4.3
MYCOBACTERIUM DISEASE
4.3.1
Mycobacterium tuberculosis – Inactive versus active infection must be distinguished.  In 
participants with low CD4 counts, 2/3’s present with extrapulmonary disease.  Diagnosis 
may require biopsies in addition to culture.  There is a high incidence of drug resistant 
strains.  Consultation with the infectious disease service is mandatory for these 
participants.  Combination therapy with isoniazid, rifampin, pyrazinamide, ethambutol 
and pyridoxine (vitamin B6) is usually initiated.  These drugs may have a marked impact 
on EPOCH pharmacokinetics, and may cause hepatitis, bone marrow suppression, optic 
neuritis and peripheral neuropathy. Due to potential interactions with EPOCH 
pharmacokinetics, these drugs should be stopped during chemotherapy infusions, if 
possible.  
4.3.2
Mycobacterium avium complex usually occurs in participants with CD4+ count 
<100/mm3.  Disseminated infection presents with fever, weight loss, night sweats, 
diarrhea, anemia, neutropenia, and thus may be difficult to differentiate from “B” 
symptoms.  Sputum and blood cultures should be obtained. Clarithromycin or 
azithromycin in combination with clofazimine or rifampin are recommended.  Due to 
potential interactions with EPOCH pharmacokinetics, these drugs should be stopped 
during chemotherapy infusions, if possible.  
4.4
FEBRILE NEUTROPENIA
A life-threatening complication requiring hospitalization and urgent broad-spectrum antibiotics.
4.5
ANEMIA
If symptomatic or if the hemoglobin falls below 8 mg/dl erythropoietin may be considered.  Red 
blood cell transfusions are sometimes associated with increased HIV replication and 
opportunistic infections, but if necessary, red blood cell transfusion support should be utilized.      
4.6
THROMBOCYTOPENIA 
Should be treated conservatively.  In the absence of bleeding or a planned invasive procedure, 
platelet transfusions should be given for a platelet count below 10,000.  If invasive procedures 
are planned or the participant develops bleeding, platelet transfusions should be administered in 
accordance with standard of practice, usually maintaining a platelet count > 50,000/mm3.
4.7
CENTRAL VENOUS ACCESS
Required for EPOCH administration.  Temporary lines are preferred (removed after completion 


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of each infusion) and include: internal jugular line; PICC lines via the brachial vein.  Other lines 
include semi-permanent HICKMAN, GROSHONG catheters or medi-port implanted devices.  
All devices will have nursing supervision to include participant self-care and cleaning/flushing of 
the devices.
4.8
OMMAYA RESERVOIRS
May be placed for participants requiring repeated CSF sampling and intrathecal chemotherapy.  
These devices will require nursing supervision to include participant self-care and cleaning of the 
devices.
4.9
NUTRITIONAL ASSESSMENT AND PSYCHOLOGICAL SUPPORT
AIDS is commonly complicated by malnutrition.  Participants with weight loss or evidence of 
wasting syndrome should have a nutritional consult and nutritional intake should be optimized 
by either enteral or parental means.  All participants on the study will be informed of and 
encouraged to see a NIH Social Worker for evaluation and support.  


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5
CORRELATIVE STUDIES FOR RESEARCH 
5.1
BIOSPECIMEN COLLECTION
NOTE:  The amount of blood to be drawn from adult participants for research purposes will not 
exceed 10.5 mL/kg or 550 mL, whichever is smaller, over any eight-week period.  
Time Point(s)
Sample
Tube/ 
Volume*
Baseline
(up to 3 days 
prior to C1D1)
Each cycle,
Day 21
(+7 days)
Post-Treatment
2 months (±1 week), 
q3 months x 1 year 
(±2 weeks), 
q6 months x 1 year 
(±4 weeks)
Receiving/ 
Analyzing 
Lab
Storage/ 
Future Use
1 x 8-10mL 
yellow top
X
X
X
Clinical 
Support Lab 
(Leidos)
Lymphomagenesis
(optional)
4-10 x 10mL 
sodium 
heparin tubes 
(green top)
X
Up to 4 times over 
24 months; 
≥3 months between 
draws
Children’s 
National 
Medical 
Center
HIV Genotyping
(select subjects only)
2-4 x 10mL 
EDTA/ 
heparin tubes
X
X
X
Maldarelli 
Lab
*Tube type(s) may be adjusted based upon materials available and/or to ensure the best samples are 
collected for planned research analysis at the time of collection/procedure.
5.1.1
Blood and Tissue for Storage/Future Use
Blood will be drawn at the time points identified in Section 5.1, processed per routine methods, 
and stored in the conditions described below in Section 5.2.  Tissues will be also accessed from 
biopsies or other procedures, no new biopsies are planned as part of this study.  Portions of these 
samples will be used for the analyses outlined in Sections 5.1.4 and 5.1.5, and for future 
identified projects upon regulatory approval (e.g., new amendment to this protocol), as 
appropriate.  
5.1.2
HIV Genotyping
5.1.2.1
Scope of HIV Genotyping
HIV replication is rapid and error-prone in vivo, yielding a genetically diverse virus population 
in infected individuals. Combination antiretroviral therapy suppresses but does not eradicate 
HIV. The mechanism of HIV persistence is unknown, but better understanding of HIV 
persistence will lead to new strategies of HIV eradication. In order to investigate HIV 
persistence, we have been characterizing the genetics of HIV populations in infected individuals 
over time before and after introduction of antiretroviral therapy. It is of great interest to 
investigate the effects of cytotoxic chemotherapy on HIV populations.  In this study, Wilson and 
colleagues39 have demonstrated substantial frequencies of complete and partial responses with 
EPOCH and EPOCH-R chemotherapy delivered in the absence of antiretroviral therapy.  In these 


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studies, participant viral RNA levels increased during chemotherapy, but were all suppressed to 
<50 copies/ml after chemotherapy was completed and antiretroviral therapy was introduced. 
It will be of great interest to characterize HIV populations by performing sensitive HIV 
genotyping prior to, during, and/or following chemotherapeutic regimen.  In these studies, we 
will obtain single genome sequences of HIV present in plasma. We will use phylogenetic and 
other population genetics analytic tools to compare the virus populations present during the 
course of the study period. We will determine whether chemotherapy results in change in overall 
genetic diversity of HIV, whether a shift in HIV populations occurs, and whether specific 
subpopulations of virus are affected more than others. 
5.1.2.2
Methods
Starting with Amendment O (version date 08/08/2013), plasma samples collected from select 
participants will be sent to: 
Frank Maldarelli, M.D. Ph.D.
Head, Clinical Retrovirology Section
HIV Drug Resistance Program
Building 535, Room 108E
1050 Boyles St.
Ft. Detrick
Frederick MD 21702
Phone: 301-846-5611
For each case, HIV RNA will be isolated from plasma samples taken before, during and after 
SC-EPOCH-R therapy.  The isolated RNA will be genotyped using a detailed version of 
standard, commercially available HIV genotyping tests. 
5.1.3
Lymphomagenesis in HIV positive vs HIV negative individuals [Beginning with Amend 
P (version date: 04/16/2014)] Optional
5.1.3.1
Rationale for lymphomagenesis correlative studies 
The incidence of certain types of lymphomas in HIV positive participants is significantly higher 
than in HIV negative individuals. Unlike other HIV-associated malignancies such as Kaposi’s 
Sarcoma, the establishment of ART has not improved these statistics. The mechanism for 
lymphomagenesis in HIV positive vs HIV negative individuals and whether there is a difference 
in tumor response of T cells derived from these populations is largely unknown. 
Cytotoxic T cells (CTL) play a major role in fighting viral infections, including HIV and EBV. 
They also play a role in anti-tumor immunity. The infusion of CD8, single-epitope specific T 
cells have been shown to be safe in HIV participants but currently has not shown long-term 
efficacy. In the cancer setting, the infusion of EBV-specific CTLs has been largely safe and 
successful. Over 90% of HIV-associated Hodgkin’s Lymphoma is EBV+ and 30-40% of HIV-
associated Burkitt Lymphoma is EBV+. 
Therefore, we hypothesize that we can generate polyclonal CTL products that are specific for 
both HIV (gag, pol, and nef) and EBV latency antigens expressed in HL (LMP1, LMP2, and 
EBNA1). We hypothesize that these CTLs can effectively target both HIV infection as well as 
tumor cells which will (1) allow for immune reconstitution following HIV clearance and (2) 
provide direct anti-tumor activity.


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5.1.3.2
Methods
We plan to ex vivo expand T cell lines targeting both HIV and EBV antigens from HIV positive 
and HIV negative participants with Burkitt Lymphoma or Hodgkin Lymphoma (either currently 
receiving treatment or completed treatment). We can achieve this by isolating T cells from 50-
100mL of whole blood and stimulating them with antigen presenting cells pulsed with peptides 
from HIV gag, pol, nef and EBV LMP1, LMP2, and EBNA1. We will then use a variety of 
immunoassays to determine these T cells’ specificity and function. Our goal is to determine 
whether there are differences in the anti-lymphoma response between HIV positive and HIV 
negative participants and ultimately, to determine whether these T cells could have clinical 
efficacy in the setting of adoptive T cell therapy.
5.1.3.3
Samples to be collected

Up to 100 mL of blood per collection. If other research blood is being collected and the 
amount approaches the research blood limit, the amount of blood collected for CNMC 
may be adjusted. The CNMC collaborators need at least 40 mL of blood per collection.

Blood should be collected in sodium heparin green top tubes and kept at room 
temperature

Blood will be used as whole blood or processed to obtain plasma/serum, peripheral blood 
mononuclear cells, or lymphocyte subsets
5.1.3.4
Sample processing

Samples collected from select participants will be coded and sent under an MTA to:
Children’s National Medical Center 
111 Michigan Ave NW
Washington DC 20010

For sample pick up, contact Marcus Dean. If not available, contact one of the other 
individuals as provided below.  
Catherine Bollard
Phone #:202-476-4776
Email: CBollard@childrensnational.org 
Marcus Dean
Phone #: 202-476-4776
Email:  MTDEAN@childrensnational.org 
Russell Cruz
Phone #: 202-476-2046
Email: ccruz@cnmc.org   
Lauren McLaughlin
Phone #:  202-476-3201
Email:  LMcLaugh@childrensnational.org 
5.1.3.5
Clinical information to be provided with samples

Samples and data will be coded

The following participant details will be sent with the samples: 


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o
Age and sex
o
Lymphoma diagnosis and Stage at diagnosis
o
EBV positivity of the tumor
o
Lymphoma treatment received
o
Date lymphoma treatment completed
o
HIV serostatus 
o
HLA-type, if available
o
CD4 Nadir before chemotherapy    
o
Peak HIV Viral Load, if available 
o
HIV viral load at or near time of sample collection, if available
5.1.4
Detecting Minimal Residual Disease (MRD)
5.1.4.1
Rationale for MRD assessment
Detecting Minimal Residual Disease (MRD) can be a powerful tool to monitor participants’ 
response to treatment and early detection of relapse.  It is of research interest to determine if 
circulating tumor DNA before, during or after therapy is predictive of long-term disease-free 
survival. Adaptive Biotechnologies Corp will assess whether immune repertoire data (B-cell 
immunoglobulin receptor sequences or T-cell receptor sequences) from the Human Material 
can be used as biomarkers that correlate with disease-free survival. Adaptive Biotechnologies 
Corp will use a proprietary method, Immune Cell Receptor Sequencing (ICRS) platform, for 
amplifying and analyzing immune cell receptor sequences, allowing unprecedented sensitivity 
and specificity.  Data from experiments conducted by Adaptive Biotechnologies Corp using 
the human material will be provided to NCI and such data provided by Adaptive 
Biotechnologies Corp to NCI may be used by NCI for any purpose.
5.1.4.2
Samples to be sent to Adaptive Biotechnologies Corp 
Bloods from the storage/future use samples collected from select participants at the following 
time points may be sent, if available:

Baseline (pre-treatment) 

After each cycle of therapy 

At each planned follow-up clinic visit until disease progression
5.1.4.3
Sample collection and processing
Portions of the other samples collected, including blood (serum, plasma and/or buffy coat), 
frozen or formalin fixed and paraffin embedded (FFPE) human tissue, and data from select 
participants will be sent.  
5.1.4.4
Shipping information
Only de-identified and coded samples will be shared as described below; see Section 5.2.1 for 
process of sample de-identification, coding, and sample request instructions.  The samples 
and data will be stored in the Clinical Support Laboratory, Leidos Biomedical Research, Inc. 
and sent in batches to Adaptive Biotechnologies Corp at the address listed below.
Adaptive Biotechnologies Corp.
1551 Eastlake Ave E
Suite 200 


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Seattle WA 98102
5.1.5
Comparison of methods of monitoring circulating tumor DNA
5.1.5.1
Rationale for comparing ctDNA methods 
The detection of Minimal Residual Disease (MRD) in aggressive lymphomas can be a 
powerful tool to monitor participants’ response to treatment and early detection of relapse.  
The field of molecular monitoring of circulating tumor DNA (ctDNA) is an emerging field, 
however, and the most effective technique is unknown.  Multiple methods that interrogate the 
peripheral blood for tumor-specific molecules are under development.  Some technologies 
that assay for the VDJ region of the immunoglobulin receptor (i.e. Adaptive Biotechnologies) 
have been clinically validated, but newer technologies are capable of detecting multiple 
somatic mutations in the ctDNA in addition to detecting the VDJ gene sequence.  The ctDNA 
genotyping method may provide additional information that captures a broader range of 
participants and may identify novel patterns of clonal evolution.  One such technology is the 
Cancer Personalized Profiling by Deep Sequencing (CAPP-Seq) method developed by the 
Alizadeh lab at Stanford University.  The CAPP-Seq method is an ultrasensitive capture-
based targeted sequencing method that can be used on lymphoid tissue and cell-free DNA in 
order to define key biological features from the tumor.  It is of research interest to determine 
how the CAPP-Seq method compares with the Adaptive Biotechnologies method (i.e. 
clonoSEQ) for monitoring ctDNA before, during or after therapy.  
The CAPP-Seq sequencing panel (i.e. ‘selector’) was designed to maximize the number of 
participants (and mutations per participant) detected, while simultaneously minimizing the 
panel size and sequencing cost. Genomic regions with recurrent somatic alterations in 
DLBCL were therefore prioritized for selector design. As an initial step, single nucleotide 
variants (SNVs) and indels were collected from multiple whole exome and whole genome 
sequencing studies, spanning a total of 102 DLBCL tumors. A bioinformatics approach was 
then applied to identify recurrently mutated regions of the genome harboring single nucleotide 
variants (SNVs) and/or indels that maximally cover both participants and mutations per 
participant. As a second step, the CAPP-Seq includes reported translocation breakpoints 
involving IGH, BCL2, BCL6 or MYC in order to identify hyper-localized and recurrent 
breakpoint regions. In order to capture MYC translocations, CAPP-Seq incorporates two IGH 
regions covering ~50% of MYC/IGH translocations and a single MYC hotspot encompassing 
15% of MYC/non-IGH translocations as well as 2 more MYC breakpoint hotspots spanning 
~5kb, yielding a final predicted coverage of 90% of all MYC translocations. As a third step, 
CAPP-Seq includes genomic regions encompassing Ig VDJ recombination sites and 
mutations arising from activation-induced cytidine deaminase activity (AID/AICDA). 
Specifically, it includes the 10 most commonly used IgVH regions in DLBCL along with the 
heavy joining cluster consisting of 6 IgJH regions. CAPP-Seq also incorporates several 
aberrant non-Ig AID target genes, including the region spanning the transcription start site and 
first exon of BCL6 as well as the transcription start sites of BCL2, MYC, PIM1 and CD83. 
The final selector design covers 1,053 genomic regions from 268 genes, totaling 242 kb (247 
kb when including additional MYC regions. 
The Alizadeh lab will use the CAPP-Seq method to determine whether the tumor-specific 
genetic aberrations from the human material can be used as biomarkers that correlate with 
disease-free survival. Alizadeh lab will use a proprietary method, CAPP-Seq, for analyzing 


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tumor genomic DNA. Data from experiments conducted by the Alizadeh lab using the Human 
Material will be provided to NCI and such data provided by Alizadeh lab to NCI may be used 
by NCI for any purpose.
5.1.5.2
Samples to be sent to Alizadeh lab
Bloods from the storage/future use samples collected from select participants at the following 
time points may be sent, if available:

Baseline (pre-treatment) 

After each cycle of therapy (if collected)

At each planned follow-up clinic visit until disease progression
5.1.5.3
Sample collection and processing
Portions of the other samples collected, including blood (serum, plasma and/or buffy coat), 
frozen or formalin fixed and paraffin embedded (FFPE) human tissue, and data from select 
participants will be sent.  
5.1.5.4
Shipping information
Only de-identified and coded samples will be shared as described below; see Section 5.2.1 for 
process of sample de-identification, coding, and sample request instructions.  The samples 
and data will be stored in the Clinical Support Laboratory, Leidos Biomedical Research, Inc. 
and sent in batches to Alizadeh lab at the following address:  
Alizadeh Lab
Stanford Cancer Institute/Stanford University
1291 Welch Road
Lorry Lokey Building, SIM1 Rm. G2115
Stanford, CA 94305-5458 
5.2
SAMPLE STORAGE, TRACKING AND DISPOSITION
All specimens obtained in the protocol are used as defined in the protocol.  Samples will be 
ordered in CRIS and tracked through a Clinical Trial Data Management system.  Should a CRIS 
screen not be available, the CRIS downtime procedures will be followed.  Samples will not be 
sent outside NIH without appropriate approvals and/or agreements. 
5.2.1
Procedures for stored specimens 
5.2.1.1
Clinical Support Laboratory, Leidos Biomedical Research, Inc

The Clinical Support Laboratory, Leidos Biomedical Research, Inc. -Frederick, processes 
and cryopreserves samples in support of IRB-approved, NCI clinical trials.  All 
laboratory personnel with access to participant information annually complete the NIH 
online course in Protection of Human Subjects.  The laboratory is CLIA certified for anti-
IL15 and certain cytokine measurements and all laboratory areas operate under a Quality 
Assurance Plan with documented Standard Operating Procedures that are reviewed 
annually.  Laboratory personnel are assessed for competency prior to being permitted to 
work with participant samples.  Efforts to ensure protection of participant information 
include:


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
The laboratory is located in a controlled access building and laboratory doors are kept 
locked at all times. Visitors to the laboratory are required to be accompanied by 
laboratory staff at all times.  

Hard copy records or electronic copies of documents containing participant information 
are kept in the locked laboratory or other controlled access locations.   

An electronic database is used to store information related to participant samples 
processed by the laboratory.  

The database resides on a dedicated program server that is kept in a central, locked 
computer facility.  

The facility is supported by two IT specialists who maintain up to date security features 
including virus and firewall protection.  

Program access is limited to specified computers as designated by the laboratory 
director.  Each of these computers has a password restricted login screen.  

The database sample entry program itself is accessed through a password protected entry 
screen.  

The database program has different levels of access approval to limit unauthorized 
changes to specimen records and the program maintains a sample history.  

Upon specimen receipt each sample is assigned a unique, sequential laboratory accession 
ID number.  All products generated by the laboratory that will be stored either in the 
laboratory freezers or at a central repository facility are identified by this accession ID.

Inventory information will be stored at the vial level and each vial will be labeled with 
both a sample ID and a vial sequence number.  

Vial labels do not contain any personal identifier information.   

Samples are stored inventoried in locked laboratory freezers and are routinely transferred 
to the NCI-Frederick repository facilities for long term storage.    

Access to stored clinical samples is restricted.  Investigators establish sample collections 
under “Source Codes” and the investigator responsible for the collections, the protocol 
Principal Investigator, specifies who has access to the collection.  Specific permissions 
will be required to view, input or withdraw samples from a collection. Sample 
withdrawal requests submitted to approved laboratory staff by anyone other than the 
repository source code owner are submitted to the source code owner for approval.  The 
repository facility will also notify the Source Code holder of any submitted requests for 
sample withdrawal.  

It is the responsibility of the Source Code holder (the NCI Principal Investigator) to 
ensure that samples requested and approved for withdrawal are being used in a manner 
consistent with IRB approval.  

The Clinical Support Laboratory does perform testing services that may be requested by 
clinical investigators including, but not limited to, immunophenotyping by flow 
cytometry and cytokine testing using ELISA or multiplex platforms.  

When requests are submitted by the NCI investigator for shipment of samples outside of 
the NIH it is the policy of the laboratory to request documentation that a Material 
Transfer Agreement is in place that covers the specimen transfer.  The laboratory does 


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not provide participant identifier information as part of the transfer process but may, at 
the discretion of the NCI investigator, group samples from individual participants when 
that is critical to the testing process.   

The NCI investigator responsible for the sample collection is responsible for ensuring 
appropriate IRB approvals are in place and that a Material Transfer Agreement has been 
executed prior to requesting the laboratory to ship samples outside of the NIH. 
5.2.1.2
Maldarelli Laboratory
Under the direction of Dr. Maldarelli, all samples processed by the laboratory will be uniquely 
barcoded, with data entered using a secure computerized database and backup hardcopy process 
per standard laboratory practice.  
Samples are stored in labeled boxes in secured freezers (i.e., -20ºC to -80ºC, or other, as 
appropriate) according to stability requirements; these freezers are located onsite.  Access to 
stored clinical samples is restricted and limited to research personnel for approved analyses only 
(as per the IRB approved protocol).
Upon completion of planned analyses by the Maldarelli lab, leftover samples may be stored in 
the laboratory for future analyses or transferred to the Clinical Support Laboratory, Leidos 
Biomedical Research, Inc.in Frederick, MD.
5.2.2
Study Completion, Future Use and Sample Destruction
The study will remain open so long as sample or data analysis continues.  Following completion 
of the planned analyses, samples will remain in storage as detailed above.
Tissue specimens and derived tissue lysates, RNA and DNA collected in the course of this 
research project may be banked and used in the future to investigate new scientific questions 
related to this study that are not expressly stated in the present protocol. However, this research 
may only be done if the risks of the new questions and the proposed research have undergone 
prospective IRB review and approval. If new risks are associated with the research the Principal 
Investigator must amend the protocol and obtain informed consent from all research subjects.
If, at any time, a participant withdraws from the study and does not wish for their existing 
samples to be utilized, the individual must provide a written request. Following receipt of this 
request, data will be excluded from future distributions, but data that have already been 
distributed for approved research use will not be able to be retrieved; additionally, the samples 
will be destroyed (or returned to the participant, if so requested) and reported per the 
requirements of section 7.2
The PI will record any loss or unanticipated destruction of samples as a deviation. Reporting will 
be per the requirements of section 7.2
5.3
GENETIC/GENOMIC ANALYSIS
5.3.1
Description of the scope of genetic/genomic analysis
At any point in the analyses, normal genome could be analyzed for comparison with other testing 
(e.g., HIV and/or cancer genome).


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5.3.2
Description of how privacy and confidentiality of medical information/biological 
specimens will be maximized
Confidentiality for genetic samples will be maintained as described (Section 5.1.3.5 and 5.2).  In 
addition, a Certificate of Confidentiality has been obtained for this study.
5.3.3
Management of Results
Subjects will be contacted if a clinically actionable gene variant is discovered.  Clinically 
actionable findings for this study are defined as disorders appearing in the American College of 
Medical Genetics and Genomics recommendations for the return of incidental findings that is 
current at the time of primary analysis. (A list of current guidelines is maintained on the CCR 
intranet: https://ccrod.cancer.gov/confluence/display/CCRCRO/Incidental+Findings+Lists).  
5.3.4
Genetic Counseling
Subjects will be contacted with a request to provide a blood sample to be sent to a CLIA 
certified laboratory.  If the research findings are verified in the CLIA certified lab, the subject 
will be offered the opportunity to come to NIH to have genetic education and counseling to 
explain this result; at the time of any such event(s), these activities will be funded by the 
NCI/CCR in consideration of the specific circumstances.  If the subject does not want to come 
to NIH, a referral to a local genetic healthcare provider will be provided (at their expense).
This is the only time during the course of the study that incidental findings will be returned. No 
interrogations regarding clinically actionable findings will be made after the primary analysis.
6
DATA COLLECTION AND EVALUATION
6.1
DATA COLLECTION
The PI will be responsible for overseeing entry of data into a 21 CFR Part 11-compliant data 
capture system provided by the NCI CCR and ensuring data accuracy, consistency and 
timeliness. The principal investigator, associate investigators/research nurses and/or a contracted 
data manager will assist with the data management efforts. Primary and final analyzed data will 
have identifiers so that research data can be attributed to an individual human subject participant.
All adverse events, including clinically significant abnormal findings on laboratory evaluations, 
regardless of severity, will be followed until return to baseline or stabilization of event. 
Document AEs from the first study intervention, Study Day 1 through 30 days after the last agent 
was last administered. 
An abnormal laboratory value will be recorded in the database as an AE only if the laboratory 
abnormality is characterized by any of the following:

Results in discontinuation from the study

Is associated with clinical signs or symptoms 

Requires treatment or any other therapeutic intervention

Is associated with death or another serious adverse event, including hospitalization. 

Is judged by the Investigator to be of significant clinical impact
If any abnormal laboratory result is considered clinically significant, the investigator will provide 
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End of study procedures: Data will be stored according to HHS, FDA and NIH Intramural 
Records Retention Schedule regulations as applicable. 
Loss or destruction of data: Should we become aware that a major breach in our plan to protect 
subject confidentiality and trial data has occurred, this will be reported expeditiously per 
requirements in section 7.2.1
The following exceptions to data collection apply:

As the toxicity profile of EPOCH-R is well defined and published, grade 1 clinical 
adverse events will not be recorded in the database.  

NOTE:  The following was a prior data exception that no longer applies (effective with 
Amendment R) as it is contradictory to C3D guidelines, it is retained here for historical 
purposes only:  Only the highest grade of each event during a cycle of treatment will be 
recorded in the database.
6.1.1
Additional Information

All participants must have signed an Informed Consent and an on-study confirmation of 
eligibility form will be filled out before entering on the study.  

Data was submitted to CTEP using quarterly reports via CDUS.  The final CDUS 
submission was for data collection through March 31, 2010.  The CCR C3D database will 
be used to store and report data.  

Complete records must be maintained on each participant; these will consist of the 
hospital chart with any supplementary information obtained from outside laboratories, 
radiology reports, or physician’s records. A record of tumor measurements will be kept 
for each participant.  These records will serve as the primary source material that forms 
the basis for the research record.  All relevant data will also be entered on a computer 
database from which formal analyses are done. The primary source documentation will 
assure the following:  on-study information, including participant eligibility data and 
participant history; flow sheets, specialty forms for pathology, radiation, or surgery; and 
off-study summary sheet, including a final assessment by the treating physician.
6.2
DATA SHARING PLANS
6.2.1
Human Data Sharing Plan
What data will be shared?
I will share human data generated in this research for future research as follows:
_X_ Coded, linked data in an NIH-funded or approved public repository.  
_X_ Coded, linked data in BTRIS (automatic for activities in the Clinical Center)
How and where will the data be shared? 
Data will be shared through:
_X_ An NIH-funded or approved public repository.  Insert name or names: ClinicalTrials.gov.
_X_ Another public repository.  Insert name or names: dbGaP.
_X_ BTRIS (automatic for activities in the Clinical Center)


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_X_ Publication and/or public presentations.
When will the data be shared?
_X_ At the time of publication or shortly thereafter.
6.2.2
Genomic Data Sharing Plan
Unlinked genomic data will be deposited in public genomic databases such as dbGaP in 
compliance with the NIH Genomic Data Sharing Policy.
6.3
RESPONSE CRITERIA
6.3.1
Complete response (CR)
Disappearance of all signs and symptoms of lymphoma for a period of at least one month. All 
lymph nodes and nodal masses must have regressed to normal size ( 1.5 cm in their greatest 
transverse diameter for nodes > 1.5 cm before therapy).  Previously involved nodes that were 1.1 
to 1.5 cm in their greatest transverse diameter before treatment must have decreased to  1 cm in 
their greatest transverse after treatment or by more than 75% in the sum of the products of the 
greatest diameters.  The spleen, if considered to be enlarged before therapy on the basis of a CT 
scan must have regressed in size and must not be palpable on physical examination. Any 
macroscopic nodules in any organs detectable on imaging techniques should no longer be 
present.
6.3.2
Complete response unconfirmed (CRu)
A residual lymph node mass > 1.5 cm in greatest transverse diameter that has regressed by > 
75% in sum of the products of the greatest diameters, does not change over the last two 
treatments, and any biopsies obtained are negative will be considered to be in CR.  In organs 
involved by disease, any residual lesions that have decreased by > 75% in sum of the products of 
the greatest diameters or are < 1 cm, are consistent with scar, and stable over the last two 
treatments will be considered to fulfill criteria for CR.  
6.3.3
Partial response (PR)
A 50% or greater decrease in the sum of the products of the longest perpendicular diameters of 
all measured lesions lasting for a period of at least one month. No individual lesions may 
increase in size and no new lesions may appear.
6.3.4
Stable disease (SD)
Tumor measurements not meeting the criteria of CR, PR, or PD.
6.3.5
Progression (PD)
Increase of 25% or more in the sum of the products of the longest perpendicular diameters of all 
measured lesions compared to the smallest previous measurements, or the appearance of any new 
lesion(s).  For progressive disease, a biopsy should be performed to determine if the lesion is a 
reactive lymph node or lymphoma.
6.4
TOXICITY CRITERIA
This study will utilize the NCI CTC version 2.0 for toxicity and adverse event reporting.  
Adverse events that occur in the follow up period will not be reported or recorded unless the 
investigator believes they are related to protocol treatment.


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7
NIH REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING PLAN
7.1
DEFINITIONS 
Please refer to definitions provided in Policy 801: Reporting Research Events found at 
https://irbo.nih.gov/confluence/pages/viewpage.action?pageId=36241835#Policies&Guidance-
800Series-ComplianceandResearchEventReportingRequirements.
7.2
OHSRP OFFICE OF COMPLIANCE AND TRAINING/IRB REPORTING
7.2.1
Expedited Reporting
Please refer to the reporting requirements in Policy 801: Reporting Research Events and Policy 
802 Non-Compliance Human Subjects Research found at 
https://irbo.nih.gov/confluence/pages/viewpage.action?pageId=36241835#Policies&Guidance-
800Series-ComplianceandResearchEventReportingRequirements. Note: Only IND Safety 
Reports that meet the definition of an unanticipated problem will need to be reported per these 
policies.
7.2.2
IRB Requirements for PI Reporting at Continuing Review
Please refer to the reporting requirements in Policy 801: Reporting Research Events found at 
https://irbo.nih.gov/confluence/pages/viewpage.action?pageId=36241835#Policies&Guidance-
800Series-ComplianceandResearchEventReportingRequirements. 
7.3
NCI CLINICAL DIRECTOR (CD) REPORTING
Problems expeditiously reported to the OHSRP in iRIS will also be reported to the NCI Clinical 
Director.  A separate submission is not necessary as reports in iRIS will be available to the 
Clinical Director.
In addition to those reports, all deaths that occur within 30 days after receiving a research 
intervention should be reported via email to the Clinical Director unless they are due to 
progressive disease.  
To report these deaths, please send an email describing the circumstances of the death to the 
Clinical Director/designee at NCICCRQA@mail.nih.gov within one business day of learning of 
the death.
7.4
IND SPONSOR REPORTING CRITERIA
NOTE:  This section no longer applies, information is retained for historical reasons only.  
The IND sponsor of this study was CTEP, with applicable reporting requirements ending 
3/15/2010.  
Events requiring report were sent to the Investigational Drug Branch by AdEERS @ 
http://ctep.info.nih.gov/AdEERS/default.htm. 
7.5
NIH REQUIRED DATA AND SAFETY MONITORING PLAN
7.5.1
Principal Investigator/Research Team
The clinical research team will meet on a weekly basis when participants are being actively 
treated on the trial to discuss each participant. Decisions about dose level enrollment and dose 
escalation if applicable will be made based on the toxicity data from prior participants. 


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All data will be collected in a timely manner and reviewed by the principal investigator or a lead 
associate investigator. Events meeting requirements for expedited reporting as described in 7.2.1 
will be submitted within the appropriate timelines. 
The principal investigator will review adverse event and response data on each participant to 
ensure safety and data accuracy. The principal investigator will personally conduct or supervise 
the investigation and provide appropriate delegation of responsibilities to other members of the 
research staff.
8
STATISTICAL CONSIDERATIONS
8.1.1
Racial/gender make-up
Subjects from both genders and all racial/ethnic groups are eligible for this study if they meet the 
eligibility criteria.  To date, there is no information that suggests differences in drug metabolism 
or disease response would be expected in any one participant group.  Efforts will be made to 
extend accrual to a representative population, but in this preliminary study, a balance must be 
struck between participant safety considerations and limitations on the number of participants 
exposed to potentially toxic treatments on the one hand and the need to explore gender and 
ethnic aspects of clinical research on the other.  If differences in outcome that correlate with 
gender or ethnic identity are noted, accrual may be expanded or a follow-up study may be 
written to investigate these differences.  
8.1.2
Determination of sample size
8.1.2.1
Summary and Original Design
The main parameter of interest is the proportion of participants who are progression free at one 
year.  It would be desirable if 70% of participants were without progression after one year from 
starting treatment, and inadequate if this were only 50%. Because of the relatively long time 
required to evaluate this endpoint (potentially a full year after the last participant has been 
accrued), the study will be conducted as a one-stage trial.  Twenty-eight participants will be 
entered into this study; if at least 18 are progression free at the one-year point, then this will 
suggest that the treatment is associated with 91% confidence of having at least 50% progression 
free survival at one year.  (This sample size is determined by using a one stage design with 
alpha=0.1, beta=0.2, p0=0.5 and p1=0.7 36).  Confidence intervals about the 12-month DFS point 
will be made, and a Kaplan-Meier curve of disease free survival will also be constructed.
According to the literature and our experience, 6 cycles of chemotherapy are normally required 
in order to obtain a CR or CRu in this patient population. Based upon data from the first 8 
participants enrolled on the trial, the mean number of cycles has been reduced to 4. We would 
like to provide evidence that the treatment in this protocol is resulting in a marked decline in the 
amount of chemotherapy administered.
We plan to enroll an additional 20 participants onto the study, consistent with the overall ceiling 
of 28. If we hypothesize that the mean number of cycles of chemotherapy will be 4, then with 20 
participants, there is 80% power using a 0.05 level two-sided significance test, to detect a 
difference between a mean of 4 and a mean of 5 cycles of therapy, when the standard deviation is 
1.5. We will determine the overall mean number of cycles given until CR/CRu, and will form an 
appropriate confidence interval about this number, to demonstrate whether this represents a 
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In addition, for purposes of safety, we will monitor the times at which participants experience 
disease progression. If at any time, the cumulative fraction of participants who have progressed 
after achieving a CR/CRu by 6 months exceeds 25%, then consideration will be given to 
modifying the therapy or terminating further accrual to the trial.
No formal comparison with any other group of participants is planned for this particular study. 
This study is being conducted as a small pilot in order to provide information as to whether an 
equivalence trial should be conducted by a multi-center AIDS malignancy trials consortium or 
other cooperative group.  It is recognized that the results from this trial are limited by the lack of 
a concurrent control group, but this is being done deliberately as a precursor to such a study, 
which would require considerably more participants and more institutions in order to be 
completed expeditiously.
Since beginning this study, there has emerged controversy regarding the role of rituximab in the 
treatment of ARL. A recently published randomized study of R-CHOP versus CHOP in ARL 
(Kaplan et al.) concludes that while rituximab is associated with a better tumor response, it is 
associated with an inferior clinical outcome because of toxicity. In our present study, we have 
achieved our initial goal of PFS in favor of at least 70%; current data shows a PFS of 77% at one 
year. This has been achieved with no treatment related deaths and with a median of 3 treatment 
cycles, which is 50% fewer than standard treatment. Given these very favorable results, and the 
need to provide further precision regarding the efficacy and safety of rituximab in ARL, we are 
increasing our accrual ceiling by 15 participants, for a total accrual ceiling of 43 participants. 
This will also allow us to gain further information on the efficacy of SC-EPOCH-R in subgroups 
of participants with low CD4 < 100/mm3 and in whom rituximab was associated with increased 
infectious deaths in the Kaplan et al study.  Hence, this study is important to evaluate the role of 
rituximab, especially in a heavily immunosuppressed population. 
The most recent analysis performed indicated an 81.5% PFS probability at 30 months, and 
77.9% survival at that point. Since these results are favorable, it would be desirable to increase 
the precision of the estimates and to allow further participants to enroll into a study with 
promising results. As such, the accrual ceiling will be set at 50 participants, to permit the 
maximum confidence interval width for PFS to be approximately 22% (from 69% to 91%) if the 
results are maintained. 
The projected accrual rate for the study is at minimum 6 participants per year.  The most 
conservative estimate thus is that it would take at maximum 28 months to meet the accrual 
ceiling.
8.1.2.2
Revised Design
As of December, 2011:  this study enrolled 56 participants. A replacement protocol has recently 
opened for accrual of participants with Burkitt’s lymphoma.  The present study has demonstrated 
successful outcomes for a population of participants with DLBCL, with 84% 5 year PFS and 
68% 5-year OS39. Thus far, we have enrolled 45 participants with HIV+ DLBCL.  To provide 
further information on the efficacy of limited treatment among participants with germinal center 
B-cell like diffuse large B-cell lymphoma (GCB) and non-GCB DLBCL (which has an inferior 
outcome), we wish to increase the accrual by an additional 20 participants to increase the 


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precision of the estimates of clinical outcomes for participants with DLBCL and to maintain a 
referral pattern until a replacement protocol is made available to subsequent participants. 
Thus, the total accrual ceiling as of the amendment dated 12/28/2011 will be 80 participants.
8.1.3
Evaluation of Secondary Objectives
The secondary objectives will be primarily used to address measures of utility of CT and nuclear 
scans with respect to their ability to predict response outcomes by means of sensitivity, 
specificity and predictive value and percent correct.  We recognize that the sample size will be 
limited as it is being driven by the primary endpoint and thus these values will be interpreted 
cautiously.  Non-parametric statistical tests such as the Wilcoxon signed rank test will be utilized 
to compared baseline CD4 cell counts and HIV viral loads with post-treatment values to test 
whether post treatment values differ from baseline.  Although these evaluations will be 
considered exploratory, and no formal correction for multiple comparisons will be employed, the 
results will be interpreted cautiously in view of the number of potential comparisons being 
performed.
9
COLLABORATIVE AGREEMENTS
This study involves a number of Material Transfer Agreements (MTAs). The listing and numbers 
for these will be maintained outside of the protocol. 
10 HUMAN SUBJECTS PROTECTIONS
10.1 RATIONALE FOR SUBJECT SELECTION
Persons with HIV infection are at increased risk of aggressive non-Hodgkin’s lymphoma.  For 
the age group under 19 years, there is nearly a 300-fold excess in cases above that expected in 
the HIV-negative age-matched population, and a 60-fold excess overall for all age groups 37.  
There are no established guidelines for treatment of the pediatric patient population with HIV-
NHL.  Maternal transmission of HIV has been substantially decreased as a result of antiretroviral 
therapy.  Therefore, this protocol will include participants  age 18 years.  No selection will be 
based on race, ethnicity, or gender.
10.2 PARTICIPATION OF CHILDREN
Participants under the age of 18 are excluded because inclusion of an occasional younger 
participant will not provide generalizable information that would justify their inclusion on this 
study. Pediatric patients with B cell lymphoma are rare and are treated on pediatric studies.
10.3 PARTICIPATION OF SUBJECTS UNABLE TO GIVE CONSENT
Adults unable to give consent are excluded from enrolling in the protocol.  However, it is 
possible that subjects enrolled in the protocol may permanently lose the capacity to consent for 
themselves during the course of this study.  For this reason and because there is a prospect of 
direct benefit from research participation (Section 10.5), all subjects ≥ age 18 will be offered the 
opportunity to fill in their wishes for research and care, and assign a substitute decision maker on 
the “NIH Advance Directive for Health Care and Medical Research Participation” form so that 
another person can make decisions about their medical care in the event that they become 
incapacitated or cognitively impaired during the course of the study. 


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Note: The PI or AI will contact the NIH Ability to Consent Assessment Team (ACAT) for 
evaluation to assess ongoing capacity of the subjects and to identify an LAR, as needed. 
Please see section 10.6.1 for consent procedure. 
10.4 EVALUATION OF BENEFITS AND RISKS/DISCOMFORTS
The investigational nature and objectives of this trial, the procedures and treatments involved and 
their attendant risks and discomforts, potential benefits, and potential alternative therapies will be 
carefully explained to the participant or the participant’s surrogate, and a signed informed 
consent document will be obtained.
The potential benefit is that the protocol therapy may result in long-term lymphoma remission 
without the high potential for lethal complications associated with standard therapy. 
The potential risk is that the protocol therapy may not result in long-term lymphoma remission.
The potential risks of genetic testing are as outlined in the informed consent document 
(included/revised with Amendment R; version date:  04/26/2017).  This study has a Certificate of 
Confidentiality, which helps to protect participant’s research information. The researchers 
involved in this study cannot be forced to disclose the identity or any information collected in 
this study in any legal proceedings at the federal, state, or local level, regardless of whether they 
are criminal, administrative, or legislative proceedings. However, the participant or the 
researcher may choose to voluntarily disclose the protected information under certain 
circumstances. Furthermore, federal agencies may review participant’s records under limited 
circumstances, such as a DHHS request for information for an audit or program evaluation or an 
FDA request under the Food, Drug and Cosmetics Act. The Certificate of Confidentiality will 
not protect against the required reporting by hospital staff of information on suspected child 
abuse, reportable communicable diseases, and/or possible threat of harm to self or others. The 
procedures involved in this protocol, with their attendant risks and discomforts and potential 
benefits will be carefully explained to the participant.
10.5 RISKS/BENEFITS ANALYSIS
As outlined in the introduction, standard therapy for HIV-NHL results in a median survival less 
than 18 months for good prognosis patients, and downwards of 6 months for poor prognosis 
patients.  This study is aimed at developing a strategy to effectively eradicate the lymphoma 
without untoward damage to the immune system resulting from the therapy.  Standard therapy is 
not effective at either of these goals.  Based on preliminary evidence of EPOCH alone, and on 
preliminary data from rituximab plus CHOP, it is reasonable to predict that the strategy outlined 
in this protocol will have a high likelihood of greater anti-lymphoma activity while at the same 
time ameliorating therapy associated immune damage.
10.5.1 Risks of Exposure to Ionizing Radiation
This research study involves up to nine (9) CT scans (C/A/P) and up to six (6) PET/CTs. Subjects 
undergoing these scans will be exposed to up to 17.1 rem. 
The CT scans that participant will get in this study will expose them to the roughly the same 
amount of radiation as 57 years of background radiation. The risk of getting cancer from the 


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radiation exposure in this study is 1.7 out of 100 (1.7 %) and of getting a fatal cancer is 0.9 out of 
100 (0.9%) 
10.5.2 Risks related to Imaging
The radiation risks of the FDG and CT scans are discussed above.  In addition to radiation risks, 
CT scans that employ contrast may cause allergic reactions, injection site reactions abdominal 
discomfort and fainting.  MRIs carry no radiation risks but are contraindicated in participants with 
metal in their bodies. In patients that receive gadolinium contrast with MRIs, allergic reactions, 
injection site reactions and kidney damage may occur. 
10.5.3 Risk related to blood sampling
Side effects of blood draws include pain and bruising, lightheadedness, and rarely, fainting. 
10.5.4 Risks related to Bone Marrow Biopsy 
The risks associated with bone marrow biopsies are pain and bleeding at the biopsy site. Rarely, 
there is a risk of infection at the sampling site.
10.5.5 Risks related to Lumbar Puncture
The risks associated with lumbar puncture may include pain or bleeding at the site of needle 
insertion (the low back), infection, and headache. Most people tolerate this treatment without 
serious side effects.
10.6 CONSENT PROCESSES AND DOCUMENTATION
The informed consent document will be provided as a physical or electronic document to the 
participant or consent designee(s) as applicable for review prior to consenting. A designated 
study investigator will carefully explain the procedures and tests involved in this study, and the 
associated risks, discomforts and benefits. In order to minimize potential coercion, as much time 
as is needed to review the document will be given, including an opportunity to discuss it with 
friends, family members and/or other advisors, and to ask questions of any designated study 
investigator. A signed informed consent document will be obtained prior to entry onto the study.
The initial consent process as well as re-consent, when required, may take place in person or 
remotely (e.g., via telephone or other NIH approved remote platforms used in compliance with 
policy, including HRPP Policy 303) per discretion of the designated study investigator and with 
the agreement of the participant/consent designee(s). Whether in person or remote, the privacy of 
the subject will be maintained. Consenting investigators (and participant/consent designee, when 
in person) will be located in a private area (e.g., clinic consult room). When consent is conducted 
remotely, the participant/consent designee will be informed of the private nature of the 
discussion and will be encouraged to relocate to a more private setting if needed.  
Consent will be documented with required signatures on the physical document (which includes 
the printout of an electronic document sent to participant) or as described below, with a manual 
(non-electronic) signature on the electronic document.  When required, witness signature will be 
obtained similarly as described for the investigator and participant.
Manual (non-electronic) signature on electronic document:
When a manual signature on an electronic document is used for the documentation of consent 
at the NIH Clinical Center, this study will use the following to obtain the required signatures:


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
Adobe platform (which is not 21 CFR Part 11 compliant); or,  

iMedConsent platform (which is 21 CFR Part 11 compliant)
During the consent process, participants and investigators will view individual copies of the 
approved consent document on screens at their respective locations (if remote consent); the 
same screen may be used when in the same location but is not required.  
Both the investigator and the participant will sign the document using a finger, stylus or mouse. 
Note: Refer to the CCR SOP PM-2, Obtaining and Documenting the Informed Consent Process 
for additional information (e.g., verification of participant identity when obtaining consent 
remotely) 
found 
at:   
https://ccrod.cancer.gov/confluence/pages/viewpage.action?pageId=73203825.
10.6.1 Consent Process for Adults Who Lack Capacity to Consent to Research Participation
For participants addressed in section 10.3, an LAR will be identified consistent with Policy 403 
and informed consent obtained from the LAR, as described in Section 10.6. 
10.6.2 Request for Waiver of Consent for Screening Activities
Prior to the subject signing the consent for this study pre-screening activities listed in section 
2.2.1 may be performed. 
We request a waiver of consent for these activities as they involve only minimal risk to the 
subjects.  A waiver will not adversely affect the rights and welfare of the subjects given that the 
activities are only intended to determine suitability for screening for participation in research 
protocols.  These activities could not practicably be carried out without the wavier as central 
recruiting services, utilized in the NIH Clinical Center, perform pre-screening activities for 
multiple studies and obtaining consent for each one is beyond their resources.  The subjects will 
be provided with additional pertinent information after participation as they will be informed 
whether or not they are eligible to sign a consent for additional screening.
11 REGULATORY AND OPERATIONAL CONSIDERATIONS 
11.1 STUDY DISCONTINUATION AND CLOSURE
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause. Written notification, documenting the reason for study suspension or 
termination, will be provided by the suspending or terminating party to sponsor and regulatory 
authorities. If the study is prematurely terminated or suspended, the Principal Investigator (PI) 
will promptly inform study participants, the Institutional Review Board (IRB), and sponsor and 
will provide the reason(s) for the termination or suspension. Study participants will be contacted, 
as applicable, and be informed of changes to study visit schedule.
 Circumstances that may warrant termination or suspension include, but are not limited to:

Determination of unexpected, significant, or unacceptable risk to participants

Demonstration of efficacy that would warrant stopping   

Insufficient compliance to protocol requirements

Data that are not sufficiently complete and/or evaluable

Determination that the primary endpoint has been met

Determination of futility


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Study may resume once concerns about safety, protocol compliance, and data quality are 
addressed, and satisfy the sponsor, IRB and as applicable, Food and Drug Administration (FDA).
11.2 QUALITY ASSURANCE AND QUALITY CONTROL
Each clinical site will perform internal quality management of study conduct, data and biological 
specimen collection, documentation and completion.  An individualized quality management 
plan will be developed to describe a site’s quality management.
Quality control (QC) procedures will be implemented beginning with the data entry system and 
data QC checks that will be run on the database will be generated. Any missing data or data 
anomalies will be communicated to the site(s) for clarification/resolution.
Following written Standard Operating Procedures (SOPs), the monitors will verify that the 
clinical trial is conducted and data are generated and biological specimens are collected, 
documented (recorded), and reported in compliance with the protocol, International Conference 
on Harmonisation Good Clinical Practice (ICH GCP), and applicable regulatory requirements 
(e.g., Good Laboratory Practices (GLP), Good Manufacturing Practices (GMP)). 
The investigational site will provide direct access to all trial related sites, source data/documents, 
and reports for the purpose of monitoring and auditing by the sponsor, and inspection by local 
and regulatory authorities.
11.3 CONFLICT OF INTEREST POLICY
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical.  Therefore, any actual conflict of interest of persons who 
have a role in the design, conduct, analysis, publication, or any aspect of this trial will be 
disclosed and managed. Furthermore, persons who have a perceived conflict of interest will be 
required to have such conflicts managed in a way that is appropriate to their participation in the 
design and conduct of this trial.  The study leadership in conjunction with the National Cancer 
Institute has established policies and procedures for all study group members to disclose all 
conflicts of interest and will establish a mechanism for the management of all reported dualities 
of interest.
11.4 CONFIDENTIALITY AND PRIVACY 
Participant confidentiality and privacy is strictly held in trust by the participating investigators, 
their staff, and the sponsor(s). This confidentiality is extended to cover testing of biological 
samples and genetic tests in addition to the clinical information relating to participants. 
Therefore, the study protocol, documentation, data, and all other information generated will be 
held in strict confidence. No information concerning the study or the data will be released to any 
unauthorized third party without prior written approval of the sponsor. 
All research activities will be conducted in as private a setting as possible.
The study monitor, other authorized representatives of the sponsor, representatives of the 
Institutional Review Board (IRB), and/or regulatory agencies may inspect all documents and 
records required to be maintained by the investigator, including but not limited to, medical 
records (office, clinic, or hospital) and pharmacy records for the participants in this study. The 
clinical study site will permit access to such records.


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The study participant’s contact information will be securely stored at the/each clinical site for 
internal use during the study. At the end of the study, all records will continue to be kept in a 
secure location for as long a period as dictated by the reviewing IRB, Institutional policies, or 
sponsor requirements.
Study participant research data, which is for purposes of statistical analysis and scientific 
reporting, will be transmitted to and stored at the NCI CCR. This will not include the 
participant’s contact or identifying information. Rather, individual participants and their research 
data will be identified by a unique study identification number. The study data entry and study 
management systems used by the clinical site(s) and by NCI CCR research staff will be secured 
and password protected. At the end of the study, all study databases will be archived at the NIH.
To further protect the privacy of study participants, a Certificate of Confidentiality has been 
issued by the National Institutes of Health (NIH).  This certificate protects identifiable research 
information from forced disclosure. It allows the investigator and others who have access to 
research records to refuse to disclose identifying information on research participation in any 
civil, criminal, administrative, legislative, or other proceeding, whether at the federal, state, or 
local level. By protecting researchers and institutions from being compelled to disclose 
information that would identify research participants, Certificates of Confidentiality help achieve 
the research objectives and promote participation in studies by helping assure confidentiality and 
privacy to participants.
12 PHARMACEUTICAL INFORMATION
There is no IND associated with the use of any of the commercial agents used in this study. 
This study meets the criteria for exemption for an IND as this investigation is not intended to 
support a new indication for use or any other significant change to the labeling; the drugs are 
already approved and marketed and the investigation is not intended to support a significant 
change in advertising; and the investigation does not involve a route of administration or dosage 
level in use in a patient population or other factor that significantly increases the risks (or 
decreases the acceptability of the risks) associated with the use of the drug product.
12.1 RITUXIMAB
Refer to the FDA approved package insert for complete product information.
12.1.1 Supply
Commercially available: 

CTEP held IND until amendment dated 03-15-10

CTEP supplied until amendment dated 03-15-10
Rituximab is provided in pharmaceutical grade glass vials containing 10 mL (100mg) or 50 mL 
(500) mg at a concentration of 10 mg of protein per milliliter.  Please refer to the FDA- approved 
package insert for rituximab for product information, extensive preparation instructions, and a 
comprehensive list of adverse events.


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12.1.2 Storage
Rituximab for clinical use should be stored in a secure refrigerator at 2º to 8°C. 
12.1.3 Preparation
Rituximab will be diluted to a final volume of 0.9% Sodium Chloride or 5% Dextrose Injection 
to prepare a standard product with concentration of 2 mg/ml.  Caution should be taken during the 
preparation of the drug, as shaking can cause aggregation and precipitation of the antibody
12.1.4 Stability
After dilution, rituximab is stable at 2-8 degrees C (36-46 degrees F) for 24 hours and at room 
temperature for an additional 24 hours.
12.1.5 Administration
A peripheral or central intravenous line will be established. During rituximab infusion, a 
participant's vital signs (blood pressure, pulse, respiration, temperature) should be monitored 
according to the standard of care. Medications readily available for the emergency management 
of anaphylactoid reactions should include: epinephrine (1:1000, 1 mg/mL) for subcutaneous 
injection, diphenhydramine hydrochloride for intravenous injection, and resuscitation equipment.
Prophylaxis against hypersensitivity and infusion-related reactions associated with rituximab will 
include acetaminophen 650 mg and diphenhydramine hydrochloride 50-100 mg administered 30 
to 60 minutes prior to starting rituximab. Participants will also receive their first dose of 
prednisone 60 mg/m2 (or a glucocorticoid equivalent dose of an alternative steroid) at least 60 
minutes before rituximab treatment commences.
Rituximab will be administered as an intravenous infusion at 375 mg/m2 on day 1 of each cycle 
of EPOCH, immediately prior to starting etoposide + doxorubicin + vincristine administration. 
For Low Risk Participants receiving EPOCH-RR, Rituximab will also be administered on day 5 
of each cycle, following etoposide + doxorubicin + vincristine but prior to cyclophosphamide 
administration. Rituximab infusions will be administered to participants primarily in an 
outpatient clinic setting.  
First dose:
The initial dose rate at the time of the first rituximab infusion should be 50mg/hour (25 mL/hr) 
for the first 30 minutes. If no toxicity is seen, the dose rate may be escalated gradually in 50 
mg/hour (25 mL/h) increments at 30-minute intervals) to a maximum of 400 mg/hour (maximum 
rate = 200 mL/h). 
Second and Subsequent Doses (select the appropriate administration timing):
90-minute Administration
If the first dose of rituximab was well tolerated, subsequent doses may be administered over 90 
minutes with 20% of the total dose given in the first 30 minutes, and remaining 80% of the total 
dose administered over the subsequent 60 minutes; e.g.:


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Two-Step Rate Escalation
Volume to administer (X mL)
1st portion (0 – 30 minutes)
2nd portion (30 – 90 minutes)
Special Note: The 90-minute infusion scheme is not recommended for participants with 
clinically significant cardiovascular disease or high circulating lymphocyte counts (≥5000/mcL).
Standard Administration for Second & Subsequent Infusions
Participants who tolerate initial treatment without experiencing infusion-related adverse effects 
but for whom the 90-minute infusion scheme during subsequent treatments is considered 
inappropriate, may receive subsequent rituximab doses at the Standard Rate for Subsequent 
Infusions, which is as follows:
Begin at an initial rate of 100 mg/hour (50 mL/h) for 30 minutes. If administration is well 
tolerated, the administration rate may be escalated gradually in 100-mg/hour (50-mL/h) at 30-
minute intervals to a maximum rate of 400 mg/hour (maximum rate = 200 mL/h).
CAUTION:  DO NOT ADMINISTER AS AN INTRAVENOUS PUSH OR BOLUS.  
12.1.6 Safety Profile
No dose-limiting effects were observed in the Phase I/II studies.  Reported adverse events 
including fever, chills, headache, nausea, vomiting, rhinitis, asthenia, and hypotension, occurred 
primarily during rituximab infusions and typically responded to an interruption of the infusion 
and resumption at a slower rate.  
Fatal Infusion Reactions:  Severe and fatal cardiopulmonary events, including angioedema, 
hypoxia, pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, and 
cardiogenic shock, have been reported.  These severe reactions typically occurred during the first 
infusion with time to onset of 30-120 minutes.
Cardiac Events:  Patients with preexisting cardiac conditions, including arrhythmia and angina, 
have had recurrences of these cardiac events during rituximab infusions.
Tumor Lysis Syndrome:  Tumor lysis syndrome, some with fatal outcome, has been reported and 
is characterized in patients with a high number of circulating malignant cells (≥25,000 ul) by 
rapid reduction in tumor volume, renal insufficiency, hyperkalemia, hypocalcemia, 
hyperuricemia, and hyperphosphatemia.
Renal Events:  Rituximab has been associated with severe renal toxicity including acute renal 
failure requiring dialysis and in some cases, has led to death.  Renal toxicity has occurred in 
patients with high numbers of circulating malignant cells (≥25,000/mm2 ) or high tumor burden 
who experience tumor lysis syndrome and in patients administered concomitant cisplatin.
Mucocutaneous Reactions:  Severe bullous skin reactions, including fatal cases of toxic 
epidermal necrolysis and paraneoplastic pemphigus, have been reported in patients treated with 
rituximab.  The onset of reaction has varied from 1 to 13 weeks following rituximab exposure.
Total Dose (mg)
2
0.2 X mL (over 30 min)
Total Dose (mg)
2
0.8 X mL (over 60 min)


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Hematologic Events:  In clinical trials, Grade 3 and 4 cytopenias were reported in 48% of 
patients treated with rituximab; these include: lymphopenia (40%), neutropenia (6%), leukopenia 
(4%), anemia (3%), and thrombocytopenia (2%).  The median duration of lymphopenia was 14 
days (range, 1 to 588 days) and of neutropenia was 13 days (range, 2 to 116 days).  A single 
occurrence of transient aplastic anemia (pure red cell aplasia) and two occurrences of hemolytic 
anemia following Rituximab therapy were reported. 
In addition, there have been a limited number of post-marketing reports of prolonged 
pancytopenia, marrow hypoplasia, and late onset neutropenia. 
Infectious Events:  Rituxan induced B-cell depletion in 70% to 80% of patients with NHL and 
was associated with decreased serum immunoglobulins in a minority of patients; the 
lymphopenia lasted a median of 14 days (range, 1-588 days).  Infectious events occurred in 31% 
of patients: 19% of patients had bacterial infections, 10% had viral infections, 1% had fungal 
infections, and 6% were unknown infections.  Serious infectious events (Grade 3 or 4), including 
sepsis, occurred in 2% of patients.
Hepatitis B Reactivation:  Hepatitis B virus (HBV) reactivation with fulminant hepatitis, hepatic 
failure, and death has been reported in some patients with hematologic malignancies treated with 
rituximab.  The majority of patients received rituximab in combination with chemotherapy.  The 
median time to the diagnosis of hepatitis was approximately four months after the initiation of 
rituximab and approximately one month after the last dose.
Other Serious Viral Infections:  The following additional serious viral infections, either new, 
reactivated or exacerbated, have been identified in clinical studies or post-marketing reports. The 
majority of patients received Rituxan in combination with chemotherapy or as part of a 
hematopoietic stem cell transplant. These viral infections included JC virus (progressive 
multifocal leukoencephalopathy [PML]), cytomegalovirus, herpes simplex virus, parvovirus 
B19, varicella zoster virus, West Nile virus, and hepatitis C. In some cases, the viral infections 
occurred up to one year following discontinuation of Rituxan and have resulted in death.
Progressive multifocal leukoencephalopathy (PML)
PML is a rare disease caused by the reactivation of latent JC virus in the 
brain.  Immunosuppression allows reactivation of the JC virus which causes demyelination and 
destruction of oligodendrocytes resulting in death or severe disability.  Rare cases of PML, some 
resulting in death, have been reported in patients with hematologic malignancies who have 
received rituximab.  The majority of these patients had received rituximab in combination with 
chemotherapy or as part of a hematopoietic stem cell transplant.  Cases of PML resulting in 
death have also been reported following the use of rituximab for the treatment of autoimmune 
diseases. The reported cases had multiple risk factors for PML, including the underlying disease 
and long-term immunosuppressive therapy or chemotherapy.  Most cases of PML were 
diagnosed within 12 months of their last infusion of rituximab. 
Physicians should consider PML in any patient presenting with new onset neurologic 
manifestations. Consultation with a neurologist, brain MRI, and lumbar puncture should be 
considered as clinically indicated.  In patients who develop PML, rituximab should be 
discontinued and reductions or discontinuation of any concomitant chemotherapy or 
immunosuppressive therapy should be considered.


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Bowel Obstruction and Perforation:  Abdominal pain, bowel obstruction and perforation, in some 
cases leading to death, were observed in patients receiving Rituxan in combination with 
chemotherapy for DLBCL. In post-marketing reports, which include both patients with low-
grade or follicular NHL and DLBCL, the mean time to onset of symptoms was 6 days (range 
1−77) in patients with documented gastro-intestinal perforation. Complaints of abdominal pain, 
especially early in the course of treatment, should prompt a thorough diagnostic evaluation and 
appropriate treatment.
Immunogenicity:  Patients may develop a human anti-chimeric antibody (HACA) response with 
rituximab treatment.  The clinical significance of this is unclear.
Pregnancy:  B-cell lymphocytopenia generally lasting less than 6 months can occur in infants 
exposed to rituximab in utero.
Immunization:  Response rates may be reduced with non live vaccines.
Additional Safety Signals:  The following serious adverse events have been reported to occur in 
patients following completion of rituximab infusions: arthritis, disorders of blood vessels 
(vasculitis, serum sickness and lupus-like syndrome), eye disorders (uveitis and optic neuritis), 
lung disorders including pleuritis and scarring of the lung (bronchiolitis obliterans), that may 
result in fatal outcomes, and fatal cardiac failure.
See the rituximab Investigator Brochure for additional details regarding safety experience with 
rituximab.
12.2 DOXORUBICIN
Refer to the FDA approved package insert for complete product information.
12.2.1 Supply
Commercially available in 10, 20, 50, 100 and 150 mg vials with 50, 100, 250, 500 and 750mg, 
of lactose, respectively.
12.2.2 Toxicities
Myelosuppression, stomatitis, alopecia, nausea and vomiting, and acute and chronic cardiac 
toxicity, manifested as arrhythmias or a congestive cardiomyopathy, the latter uncommon at total 
cumulative doses less than 500 mg/m2. The drug causes local necrosis if infiltrated into 
subcutaneous tissue. Please refer to the package insert for a complete listing of all toxicities.  
12.3 VINCRISTINE
Refer to the FDA approved package insert for complete product information.
12.3.1 Supply
Commercially available in 1 mg, 2 mg, and 5 mg vial sizes. Each ml contains 1 mg of 
vincristine, 100 mg mannitol, 1.3 mg methylparaben, and 0.2 mg propylparaben. Drug should be 
stored at 2º-8oC and should be protected from light. 
12.3.2 Toxicities
Peripheral neuropathy, autonomic neuropathy, and alopecia. Local necrosis if injected 
subcutaneously. Please refer to the package insert for a complete listing of all toxicities.


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12.4 ETOPOSIDE
Refer to the FDA approved package insert for complete product information.
12.4.1 Supply
Commercially available as a concentrate for parenteral use in 100 mg vials; each ml contains 20 
mg etoposide, 2 mg citric acid, 30 mg benzyl alcohol, 80 mg polysorbate 80, 650 mg of 
polyethylene glycol 300, and 30.5% alcohol. 
12.4.2 Toxicities
Myelosuppression, nausea, vomiting, anaphylactoid reactions, alopecia, and hypotension if 
infusion is too rapid. Please refer to the package insert for a complete listing of all toxicities.
12.5 ETOPOSIDE/ DOXORUBICIN/VINCRISTINE ADMINISTRATION 
Stability studies conducted by the Pharmaceutical Development Section, Pharmacy Department, 
NIH Clinical Center, have demonstrated that admixtures of vincristine, doxorubicin, and 
etoposide in 0.9% Sodium Chloride Injection, USP (0.9%NS) at concentrations, respectively, of 
1, 25, and 125 mcg/mL; 1.4, 35, and 175 mcg/mL; 2, 50, and 250 mcg/mL; and 2.8, 70, 350 
mcg/mL are stable for at least 36 hours at room temperature when protected from light. Also, 
admixtures containing vincristine, doxorubicin, and etoposide concentrations of 1.6, 40, and 200 
mcg/mL are stable for at least 30 hours at 32°C.
For this study, etoposide, doxorubicin, and vincristine comprising a daily dose (a 24-hour 
supply) will be diluted in 0.9%NS. Product containers will be replaced every 24 hours to 
complete the planned duration of infusional treatment. Product volumes will be determined by 
the amount of etoposide present in a 24-hour supply of medication. For daily etoposide doses 
≤130 mg, admixtures will be diluted in approximately 500 mL 0.9%NS.  For daily etoposide 
doses >130 mg, admixtures will be diluted in approximately 1000 mL 0.9%NS.
Etoposide + doxorubicin + vincristine admixtures will be administered by continuous IV 
infusion over 96 hours with a suitable rate controller pump via a central venous access device.
12.6 CYCLOPHOSPHAMIDE 
Refer to the FDA approved package insert for complete product information.
12.6.1 Supply
Commercially available in white crystalline formulation for intravenous injection, in vials 
containing 100 mg, 200 mg, 500 mg, 1gm, and 2 gm. 
12.6.2 Storage and preparation
Intact vials are stable at room temperature (not to exceed 30oC). Reconstitute with appropriate 
amounts of 0.9% NaCl to produce a final concentration of 20 mg/ml.  Discard solution after 24 
hours at room temperature.  Stable up to 6 days if refrigerated (2º-8oC). 
12.6.3 Administration
Cyclophosphamide will be diluted in 100 mL of D5W or 0.9% NaCl and infused over 30 
minutes or according to institutional standard.  Participants will be instructed to drink an 
adequate amount of fluids and empty their bladders frequently during cyclophosphamide 
administration. 


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12.6.4 Toxicities 
Myelosuppression, nausea and vomiting, hemorrhagic cystitis, and alopecia. Cystitis can be 
largely prevented by maintaining a good state of hydration and good urine flow during and after 
drug administration using the following.  Please refer to the package insert for a complete listing 
of all toxicities.  
12.6.5 Hydration Guidelines
All participants should receive 0.9%NS at the following volumes (based on cyclophosphamide 
dose levels) and rates with half the specified volume given before starting cyclophosphamide 
administration and half the volume given after completion of the cyclophosphamide 
administration.  
Cyclophosphamide
Dosage Levels
Fluid Volume and Administration Rate
1 & 2
1000 mL 0.9%NS @ 300 – 500 mL/h
Levels 3, 4, & 5
2000 mL 0.9%NS @ 300 – 500 mL/h
Levels 6
2500 mL 0.9%NS @ 300 – 500 mL/h
12.7 PREDNISONE
Refer to the FDA approved package insert for complete product information.
12.7.1 Supply
Commercially available in a large number of oral dosage strengths including pills and liquid 
formulations. Tablets should be stored in well-closed containers at temperatures between 15-
30oC. 

Doses:  Prednisone utilization will be simplified by using only 20- and 50-mg tablets 
to produce individual doses and by stratifying prednisone doses by a participant’s 
body surface area (BSA), as follows:
BSA (m2)
Each Dose
1.25 – 1.49
80 mg
1.5 – 1.83
100 mg
1.84 – 2.16
120 mg
2.17 – 2.41
140 mg
2.42 – 2.6
150 mg
2.61 – 2.69
160 mg
2.7 – 3
170 mg


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12.7.2 Toxicities
Proximal muscle weakness, glucose intolerance, thinning of skin, redistribution of body fat, 
Cushingoid facies, immunosuppression, and propensity to gastrointestinal ulceration. Please refer 
to the package insert for a complete listing of all toxicities. 
12.8 FILGRASTIM (G-CSF)
Refer to the FDA approved package insert for complete product information.
12.8.1 Supply
Commercially available in single use vials containing 480 mcg/vial (300 mcg/ml, 1.6 ml vial). 
Should be stored at 2º-8oC (do not freeze and do not shake) and is stable for at least 1 year at this 
temperature. Filgrastim will be given by subcutaneous injection; participant or other caregiver 
will be instructed on proper injection technique.
12.8.2 Toxicities
Rare anaphylactic reactions with the first dose; bone pain at sites of active marrow with 
continued administration. Local reactions at injection sites. Constitutional symptoms, increased 
alkaline phosphatase, LDH, uric acid; worsening of pre-existing inflammatory conditions. Please 
refer to the package insert for a complete listing of all toxicities.
12.9 HYDROCORTISONE, DEXAMETHASONE
These drugs are commercially available. 
12.9.1 Hydrocortisone is a commercially available corticosteroid available as preparations that 
should be stored at less than 40C (preferably between 15 - 30C).  Reconstituted 
solutions should be stored at 25C or below, and unused reconstituted solutions should be 
discarded after 3 days.  
12.9.2 Dexamethasone is a synthetic glucocorticoid.  Preparations for intravenous injection 
should generally be stored a temperature less than 40C (preferably between 15 - 30C).  
It must be protected from light and freezing.  It may be administered parenterally, or 
orally as tablets, elixir, solution, or concentrate.   
12.10 METHOTREXATE
Refer to the FDA approved package insert for complete product information
12.10.1
 Supply
Commercially available folic acid antagonist, and only the preservative-free preparation may be 
used for intrathecal injection.
12.10.2
 Storage
It should be stored at 15-30C and protected from light. Prior to intrathecal or intraventricular 
injection, the prescribed dose of methotrexate should be reconstituted/diluted with preservative-
free 0.9% sodium chloride to a total volume of 5 mL.  Prepared methotrexate doses should be 
utilized within 4 hours of preparation.


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12.10.3
 Toxicities
It can cause leukopenia, and as such leucovorin may be administered 24 hours after each dose.  It 
can cause headaches, drowsiness, and blurred vision.  It can also cause a transient acute 
neurologic syndrome manifested by confusion, hemiparesis, seizures, and coma. Please refer to 
the package insert for a complete listing of all toxicities.
12.11 CYTARABINE
Refer to the FDA approved package insert for complete product information
12.11.1
 Supply
A commercially available pyrimidine nucleoside antimetabolite.
12.11.2
 Storage
Cytarabine should be stored at –15-30C, and used within 2 years of the date of manufacture.  
Prior to intrathecal injection it is reconstituted with preservative free 0.9% sodium chloride, and 
should be utilized within 4 hours of preparation.  Prior to intrathecal or intraventricular injection, 
the prescribed dose of cytarabine should be reconstituted/diluted with preservative-free 0.9% 
sodium chloride to a total volume of 5 mL.
12.11.3
 Toxicities
It can cause myelosuppression, fever, dizziness, somnolence, and arachnoiditis. Please refer to 
the package insert for a complete listing of all toxicities.
12.12 LEUCOVORIN
A commercially available calcium salt of folinic acid, which is a metabolite of folic acid.  
Leucovorin calcium powder for injection and tablets should be stored at 15-30C and protected 
from light.  When reconstituted with sterile water for injection, it should be used immediately, or 
when reconstituted with bacteriostatic water, within 7 days.  It must not be given intrathecally.  
Given IV or orally, it is usually non-toxic in therapeutic doses.  Hypersensitivity reactions have 
been reported.  


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14 APPENDICES
14.1 APPENDIX A:  EVALUATIONS ROADMAP
NOTE:  See Section 5 for applicable windows and additional information.  
Evaluations Roadmap
Pre treatment
During treatment
Confirmation of aggressive 
histology NHL
Confirm HIV serology
Laboratory eligibility assessment
HIV viral load 
Lymphocyte FACS analysis
Research bloods
Staging: 
   CNS
   Bone marrow
   Peripheral sites
      PET
      CT
Restage following cycles 2-6
See Schema in Study Design 
(Section 3.1)
End of therapy research 
studies/samples:
HIV viral load
Lymphocyte FACS analysis
Research bloods
Restage with CT at two months, 
then q3 months x 1 year, then q6 
months x 1 year, and then yearly 
thereafter.  CT scans stop after 5 
years.
HIV viral load
Lymphocyte FACS analysis 
Research bloods at same time 
points FACS is obtained.
       Post treatment


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