Clinical trial NCT01555541
Conditions: Diffuse Large Cell Lymphoma Relapsed/Refractory
Keywords: relapsed refractory DLBCL lymphoma B-cell diffuse
Sponsor: C. Babis Andreadis
Start date: 2012-05-25; Completion date: 2021-07-01
Enrollment: 19 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The goal of this clinical trial is to show that incorporating ofatumumab instead of rituximab in combination with etoposide and cytarabine (OVA) is successful in collecting autologous stem cells for use in an autologous stem cell transplantation (autoSCT) and to examine its effectiveness in eliminating residual diffuse large B-Cell Lymphoma (DLBCL) in patients.

Detailed description:
Patients with relapsed Diffuse Large B-cell Lymphoma (DLBCL) who are refractory to or relapse within 12 months of first-line rituximab-based therapy, have poor outcomes with conventional approaches to autologous stem cell transplantation as detailed above. The investigators hypothesize that the intensive mobilization strategy developed can overcome some of the obstacles to successful autologous stem cell transplantation (ASCT) by both eliminating residual disease following salvage therapy and by facilitating stem cell collection. Even though there is clinical experience in the cooperative group setting with intensive pre-ASCT mobilization, it has never been prospectively validated in DLBCL and concerns exist as to its ability to improve outcomes with ASCT in this high-risk, and heavily pretreated group of patients. Furthermore, most patients in the study site's registry treated with intensive mobilization were rituximab-naïve and the findings may not translate in the rituximab-refractory population. The investigators also believe that ofatumumab, a novel monoclonal antibody against a distinct cluster of differentiation antigen 20 (CD20) epitope may in fact overcome rituximab resistance in DLBCL patients and through more effective complement dependent cytotoxicity (CDC) may eliminate minimal residual disease in the patient and contaminating tumor cells in the stem cell graft.

General Design

This is a single-institution, single-arm, prospective phase II study. Patients with high-risk DLBCL (defined as either achieving less than complete remission (CR) to initial rituximab-containing therapy or relapsing within 12 months of initial therapy) will be enrolled on this study and will undergo staging prior to receiving intensive mobilization with ofatumumab, etoposide, and high-dose ara-C (OVA). Following successful stem cell collection, patients will proceed to standard autologous transplantation with cyclophosphamide, 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), and etoposide (CBV) preparative regimen. Response evaluation will occur after salvage therapy, following intensive mobilization therapy (d42), at day +90 after ASCT, and at 6, 12 and 24 months thereafter. Event-free, progression-free, and overall survival will also be assessed until 48 months. The primary study endpoint is mobilization-adjusted complete metabolic response rate (maCR) following OVA. Subjects who are not chemosensitive to salvage therapy (i.e. do not achieve a partial response or complete response) will be re-evaluated after an additional salvage regimen. If they are still not chemosensitive at this point, they will be withdrawn from the study and replaced.

Arms: arm 1: None
Interventions: intervention 1: Ofatumumab intervention 2: Etoposide intervention 3: Cytarabine
Intervention descriptions: intervention 1: 1000 mg IV days 0, 7, 14, 21 intervention 2: 10 mg/Kg IV over 24 hours daily, days 1-4 intervention 3: 2000 mg/m2 IV twice daily, days 1-4

Protocol documents:
ICF_001.pdf: 
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Dr. Charalambos Andreadis
University of California, San Francisco
Consent to Participate in a Research Study
CC# 112525: A phase II study of intensive consolidation and stem cell mobilization therapy with 
ofatumumab, etoposide, and high-dose ara-C (OVA), followed by autologous stem cell 
transplantation in high-risk patients with relapsed/refractory Diffuse Large B-Cell Lymphoma
Introduction
This is a clinical trial, a type of research study.  Dr. Charalambos Andreadis and his associates in 
the Adult Lymphoma and Stem Cell Transplantation Program at UCSF Medical Center will 
explain the trial to you. This trial is being supported by a Grant and study medication from the 
pharmaceutical company Novartis.
Clinical trials include only people who choose to take part.  Please take your time to make your 
decision about participating.  You may discuss your decision with your family and friends and 
with your health care team.  If you have any questions, you may ask your study doctor.
You are being considered for this clinical trial because you have relapsed or progressive diffuse 
large B-Cell Lymphoma (DLBCL) and you are undergoing “Salvage Therapy” (standard second-
line chemotherapy treatment) followed by an autologous stem cell transplantation (autoSCT), 
which is the appropriate therapy for you.
Why is this study being done?
Patients with relapsed or progressive DLBCL can be potentially cured with autoSCT.  However, 
patients who have received prior therapy containing rituximab and who have either never 
achieved a complete response, or who progressed within 12 months of achieving a complete 
response, are at higher risk of treatment failure and have a lower likelihood of cure with 
traditional autoSCT.
At UCSF, we have developed an ‘augmented’ form of chemotherapy given prior to autoSCT.  
This therapy is given following standard salvage therapy and consists of etoposide (VP-16) and 
high-dose ara-C.  In this study, we are combining it with ofatumumab in a regimen abbreviated 
as OVA. The aim of using this additional course of chemotherapy (OVA) is to decrease the 
amount of residual disease in your body (small amount of cancer cells that might remain after 
salvage therapy) and to eliminate any contaminating cancer cells from being collected with your 
stem cells for autoSCT.
The basis for this approach to treatment is that a similar augmented therapy (consisting of 
rituximab, etoposide, and ara-C), has been used at UCSF for over 10 years with good results.  
Like rituximab, ofatumumab is an antibody (a substance that can bind to proteins such as those 
found on cancer cells).  We will now try combining etoposide and ara-C with ofatumumab, 
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which binds to cancer cells at a different location than rituximab, and may potentially overcome 
the cancer cell’s resistance to rituximab.
You are being asked to participate in this study because based on the specific characteristics of 
your disease, the study doctors feel that you may benefit from this augmented chemotherapy.
Etoposide, and ara-C are FDA approved therapies for lymphoma.  However, they are not 
approved for use in this combination (OVA).  All other treatments, including salvage therapy, 
stem cell collections and stem cell infusions are part of standard therapy for lymphoma.
Ofatumumab (Arzerra®) is FDA approved for the treatment of patients with chronic 
lymphocytic leukemia (CLL) refractory to fludarabine and alemtuzumab.
The goal of this clinical trial is to show that OVA is successful in collecting autologous stem 
cells for use in autoSCT and to examine its effectiveness in eliminating residual DLBCL in 
patients with your risk factors. If this clinical trial is successful it will lead to a larger trial in the 
future to study this treatment regimen in many institutions across the United States.
Novartis, the company that is providing ofatumumab, is also providing financial support to 
UCSF to conduct this study.
How many people will take part in this study?
About 24 patients will be involved in this study at UCSF Medical Center. 
What will happen if I take part in this research study?
Before you begin the main part of the study . . .
You will need to have the following exams, tests or procedures to find out if you can be in the 
main part of the study.  This is done to help determine whether or not you may benefit from the 
study and if you will able to undergo further intensive treatment.  If any of these tests are found 
to be abnormal, you may not be allowed to participate in this study.
The following procedures are part of your normal care and would be done even if you did not 
join the study:

Medical history and physical examination

Laboratory/Blood tests (about 2 teaspoons of blood will be taken to look at your blood 
counts, organ function, and your immune function)
The following procedures are not part of your normal care and are being done solely for this 
study:
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
Blood sample for Hepatitis B and C testing (about 1 teaspoon):
Your blood will be tested for hepatitis B and C.  Patients who test positive for Hepatitis B 
will be tested for ongoing infection with a test called Hepatitis B viral load.  Patients with 
a positive viral load will not be allowed to participate.  If the results of Hepatitis B viral 
load testing do not suggest ongoing infection, you will need to have Hepatitis B viral load 
testing every 2 months while on the study.  If your results are later found to be positive, 
you will obtain appropriate therapy for hepatitis and you may not be allowed to continue 
on study treatment.  Based on your baseline risk, your doctor may prescribe antiviral 
medication for Hepatitis to prevent you from developing active, ongoing infection.  
Patients who test positive for Hepatitis C will be excluded from the study.  
All Hepatitis testing done throughout the study will be done solely for the study (it is not 
part of normal care)

Tissue samples:
As part of your regular care, you had a blood and/or tissue sample taken to diagnose your 
cancer.  If there is any sample left over that is no longer needed for your care, the study 
doctor will keep some of it for research tests to look for differences in DLBCL cancer 
cells.  Some of your sample will also be kept for residual disease testing (to compare 
them to samples that may be taken later in the study).
Salvage Therapy:
Salvage therapy (standard second-line chemotherapy treatment) is not part of this study; it is part 
of your regular care.  However you will need to have responded to salvage therapy before being 
able to continue on to the main part of the study.  After undergoing salvage therapy, you will 
have the following procedures to see if you responded to salvage therapy and if you are still 
eligible for the study:
The following procedures are part of your normal care:

Medical history and physical examination

Laboratory/Blood tests

Echocardiogram or MUGA scan:
You will have one of these exams to determine how well your heart squeezes blood.
o
Echocardiogram: For this exam, you will be asked to lie on your left side while a 
technician places a probe with gel on your chest to create images of your heart.  This 
procedure will take about 45-60 minutes.
o
MUGA scan: For this exam, a small blood sample will be taken, mixed with a 
radioactive substance, and injected back into your body.  You will then wait for about 
60 minutes for the radioactive substance to circulate throughout your body.  After this 
time, you will lie flat on a scanning bed while the scanner takes images of your heart.  
You will need to lie still for about 10-20 minutes so that the images are clear.  The 
procedure will take about 90 minutes.
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
DLCO (diffusing capacity of the lung for carbon monoxide) test:
This exam determines how well oxygen passes into your blood from the lungs and how 
well carbon dioxide passes from your blood into your lungs.  This exam is done to see 
how well your lungs are working.  For this exam, a clip will be put on your nose and you 
will be asked to inhale (breath in) a small amount of “tracer” gas (carbon monoxide) 
through a mouthpiece.  After inhaling the tracer gas, you will hold your breath for 10 
seconds, and then blow it out (exhale).  The exhaled gas will be tested to see how much 
of it was absorbed from your lungs.  The procedure will take about 30 minutes.  If you 
are a smoker, you will be asked to not smoke for 4 to 6 hours before this exam.

Lumbar puncture:
This exam (commonly referred to as a “spinal tap”) involves using a needle to take a 
sample of cerebrospinal fluid (the fluid surrounding your brain and spinal cord).  It is 
done to see if your cancer has spread to your brain and/or spinal cord.  For this exam, you 
will lie down sideways and a local anesthetic will be given through a small needle into 
the skin. You will be asked to lie still and breathe slowly, as a large needle for the lumbar 
puncture is pushed into the spinal canal and the cerebrospinal fluid is withdrawn into a 
syringe.  After the needle is removed, you will have to lie still for a short while to prevent 
headaches (a common side effect of this procedure).  For the rest of the day, you should 
lie down for several hours, drink plenty of fluids, and report any symptoms of headache 
or dizziness to your doctor. This procedure will take about 30 minutes.
This procedure will only be done on patients who have a history of cancer in the brain or 
spinal cord, or if the doctor suspects it may have spread there.

Bone marrow aspiration and biopsy:
A bone marrow aspiration involves using a needle to remove a sample of fluid from your 
bone marrow; a bone marrow biopsy involves using a needle to remove a piece of your 
bone marrow.  These procedures are done to evaluate the cancer in your bones.  The 
doctor will insert the needles into your hip bone to remove the fluid and marrow samples 
(about 2 teaspoons).  You will receive medicine to numb the surface of your skin where 
the needles will be inserted.  This procedure will take about 15-30 minutes.
Samples of your tissue will be kept for research studies to look for differences in DLBCL 
cancer cells and to compare to samples which may be taken later (to see if there is any 
residual disease present in your body).

FDG-PET scan and CT scan or PET/CT scan:
The FDG-PET scan is done to show how the organs and cells work in your body and to 
show activity of the cells in your tumor.  The exam will begin with an injection of a 
radioactive substance.  You will then wait for about 30 minutes for the radioactive 
substance to circulate throughout your body.  After this time you will lie down on a 
scanning bed, which will move you into the scanner (a large ring, similar to a big 
doughnut hole).  The scanner will take images of your body.  You will need to remain 
very still so that the images are clear.  This procedure will take about 1 hour.  You will 
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need to fast (not eat) for 6 hours before your exam, and you will need to drink at least 2 
large glasses of water before the exam.
The CT or PET/CT scan makes detailed pictures of your body tissue and organs and is 
done to see if your cancer has spread.  In order to get clearer pictures, you may be given 
“contrast material” (a special dye that makes it easier to see your organs and tissues).  
The contrast material may be given orally (by mouth), intravenously (by needle into a 
vein), or rectally (into your lower bowels; this is less likely).  For the exam, you will lie 
flat on a scanning bed that will move you into the scanner.  You will need to lie still and 
may be asked to hold your breath for a few seconds so that the images are clear.  This 
procedure will take about 30 minutes.
The following procedures are not part of your normal care and are being done solely for this 
study:

Blood sample for research tests:
About 2 teaspoons of blood will be drawn and used for residual disease testing.

Pregnancy test:
If you are a woman who is able to have children, you will have a serum pregnancy test 
(women who are pregnant or breastfeeding are not eligible for this study)

EKG:
This exam shows the electrical activity of your heart.  Wires or “leads” will be attached 
to your chest with an adhesive and you will be asked to lie still while the machine prints 
out an electrical “record” of your heart activity.  This procedure will take about 15-30 
minutes.
After undergoing all these procedures, it is possible that you may not be able to participate in the 
study.  If this happens, the study doctor will discuss other treatment options with you.
During the main part of the study...
If the exams, tests and procedures above show that you can be in the main part of the study, and 
you choose to take part, then you will undergo the following tests and procedures.
Treatment will consist of two sequential steps: initial chemotherapy (OVA augmented therapy) 
with stem cell collection, followed by high dose chemotherapy and stem cell re-infusion or 
transplantation. A summary (schema) showing the parts of the study can be found on the last 
page of this consent form.
Step 1 - Chemotherapy and Stem Cell Collection
For the first step, you will be admitted to the hospital for approximately four weeks.
Because you will be having many blood draws, infusions of medication, and transfusions during 
this study, you will have an intravenous catheter (called a central venous catheter) placed into 
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one of the large veins in your neck or arm.
You will receive therapy with ofatumumab on the first day of treatment (and weekly thereafter, 
for a total of 4 doses).  Ofatumumab is given as an intravenous (IV) infusion over several hours. 
Before each infusion of ofatumumab, you will be given medication to help to reduce any 
infusion reactions. These may include anti-histamines, steroids and pain relievers. You will be 
checked closely, and if you do have any infusion reactions these will be treated.
On the first day of treatment, you will also have the following procedures:

Medical history and physical examination

Laboratory/Blood tests daily (about 2 teaspoons)

Research blood test (about 2 teaspoons) to look at differences in your cancer cells
You will receive chemotherapy with etoposide and ara-c for the next four days of the 
hospitalization. The drug etoposide is given as an IV injection continuously over 24 hours for 
four days (96 hours).  The drug ara-C (cytarabine) is given intravenously over 2 hours twice a 
day for four days (for a total of 8 doses).  You will be given medications to prevent nausea and 
vomiting, fevers, rashes, pain or any other side effects from the chemotherapy.  Because 
chemotherapy will lower your blood cell counts, you may be given antibiotics, blood/platelet 
transfusions, and nutritional support as needed.
After 2 weeks of hospitalization you will receive G-CSF (also called neupogen) injections to 
help the white blood cells recover more quickly and to stimulate the release of "stem cells" from 
the bone marrow into the blood.  G-CSF will be given daily by subcutaneous (under the skin) 
injection.  After approximately 7 days of G-CSF injections, the blood cell counts will begin to 
rise.  Once the white blood cell count reaches an adequate level, you will begin the stem cell 
collection process. This process, called "leukapheresis", and is performed daily until adequate 
stem cells are collected.  The process requires that an additional catheter (called a “Quinton” 
catheter) be placed into one of the large blood veins in the neck. The Quinton catheter is attached 
to an apheresis machine. The machine draws some of your blood into the machine, spins the 
blood and separates the blood into various components (white blood cells, red blood cells and 
platelets). The white blood cells, including the circulating stem cells, will be collected into a bag 
while the remainder of the blood cells are returned to you through the catheter. Each collection 
procedure takes 3 to 4 hours.  The leukapheresis procedure will be repeated daily until enough 
stem cells have been collected and saved for the second phase of treatment.  A small amount of 
these stem cells (less than 5% of the total) will be saved and stored at a UCSF Laboratory for 
research studies (the stem cells will be analyzed to see if any leftover cancer cells can be found)
During treatment with OVA (about 4 weeks), you will also have the following procedures:

Laboratory/Blood tests (about 2 teaspoons daily)

Research blood test  (day 21or later)
o
To see how the drug is absorbed by your body (about 2 teaspoons)
o
For residual disease testing (1 teaspoon)
Once the stem cells have been collected and you have recovered from the side effects of 
chemotherapy you will be discharged from the hospital.  This completes Step 1. In order to 
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proceed to Step 2, you must have recovered completely from the effects of Step 1 and must have 
no evidence of active infection.  If there are any signs of organ dysfunction or recurrent 
lymphoma, you may not be able to continue with this study.
Six weeks after starting the first step of treatment, you will be evaluated to make sure you are 
still in remission and to make sure that your internal organs (heart, liver, kidney and lungs) are in 
satisfactory condition to proceed with further intensive treatment.  Your evaluation will include 
the following:

Medical history and physical examination

Laboratory/blood tests (2 teaspoons)

Research blood tests:
o
To see how the drug is absorbed by your body (2 teaspoons)
o
To look at differences in your cancer cells (2 teaspoons)
o
For residual disease testing (2 teaspoons) 

Blood sample for Hepatitis B testing

FDG-PET scan and CT or PET/CT scan

Bone marrow biopsy (if your bone marrow was previously affected by lymphoma)
While on Step 1, if your disease progresses after starting OVA treatment and the intention of 
your treatment team is to proceed  with autologous stem cell transplantation in the future, you 
will still be followed at regular intervals starting at month 3 of the schedule listed in “after you 
have completed treatment” section below.  If you do not intend to have a transplant, you will be 
followed by Dr. Andreadis or his staff during the first two years after treatment.  They will 
continue to obtain your records from your local doctor or contact you every 3 months for 2 years 
to see how you are doing.
Step 2 - Autologous Stem Cell Transplantation
If you are able to continue with treatment, you will then be admitted to the hospital to proceed 
with the second step in the treatment, the autologous stem cell transplant.  You will be 
hospitalized continuously for 3-5 weeks. As with the first hospitalization, you will have a central 
venous catheter placed into one of the large veins in your neck or arm.
Stem cell transplant will take place on “Day 0”.  Before this happens, you will receive 
chemotherapy 6 days, 4 days, and 2 days before day 0 (designated as day -6, day -4, and day -2).
You will have routine laboratory/blood tests on each day of chemotherapy.
You will receive high-dose ‘CBV’ chemotherapy, which consists of 3 drugs (Cyclophosphamide, 
BCNU, and VP-16).  BCNU (carmustine) will be administered intravenously over 2 hours (day -
6).  After 1 day of rest, you will receive VP-16 (etoposide) intravenously over 4 hours (day -4).  
After another day of rest, you will receive cyclophosphamide (Cytoxan®) intravenously over 1 
hour (day -2).
After a day of rest from the CBV chemotherapy, you will receive an IV infusion of your stem 
cells (day 0), which were saved in Step 1 of treatment.  The stem cell infusion is given through 
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your IV catheter like a transfusion.
During the remainder of your time in the hospital you will be given blood/platelet transfusions, 
antibiotics, and nutritional support to prevent or treat the side effects of treatment (similar to that 
during Step 1).  Six days after starting the stem cell infusion, you will receive daily subcutaneous 
injections of G-CSF to help your white blood cells recover more quickly; G-CSF injections will 
continue until your white blood cells have recovered.  After your body has healed from the 
effects of the high-dose chemotherapy, you will be discharged from the hospital.
While on Step 2, if your disease progresses after starting CBV treatment, you will still be 
followed by Dr. Andreadis or his staff.  They will review continue to obtain your records from 
your local doctor or contact you every 3 months during the first two years after treatment to see 
how you are doing.  
After you have completed treatment . . .
After being discharged from the hospital you will continue to require close observation and 
outpatient treatment.  You will be required to return to UCSF for the following tests and 
procedures:
At 1 and 2 months:

Medical history and physical examination

Laboratory/blood tests (2 teaspoons)

Blood sample for Hepatitis B testing (1 teaspoon)
At 3 months:

Medical history and physical examination

Blood test for routine safety tests (2 teaspoons)

Research blood tests:
o
To see how the drug is absorbed by your body (2 teaspoons)
o
To look at differences in your cancer cells (2 teaspoons)
o
For residual disease testing (2 teaspoons) 

Blood sample for Hepatitis B testing

FDG-PET scan and CT or PET/CT scan

Bone marrow biopsy (if your bone marrow was previously affected by lymphoma)

DLCO test (this is a study procedure)
At 6, 12, and 24 months:

Medical history and physical examination

Laboratory/blood tests (2 teaspoons)

Research blood tests:
o
To see how the drug is absorbed by your body (2 teaspoons)
o
To look at differences in your cancer cells (2 teaspoons)
o
For residual disease testing (2 teaspoons)

Blood sample for Hepatitis B testing (1 teaspoon)
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
FDG-PET scan (this is a study procedure.  It will be done at 6 months only if the previous 
scan done at 3 months showed evidence of your disease) CT or PET/CT scan
If the study doctor suspects that you cancer has returned, you will be asked to come in for the 
following tests and procedures:

Medical history and physical examination

Laboratory/blood tests

FDG-PET and CT or PET/CT scan 

Bone marrow biopsy (if your bone marrow was previously affected by lymphoma).  
Samples of your tissue will be kept for research studies to look for differences in DLBCL 
cancer cells. (this is a study procedure)
After the follow-up procedures above, you may be contacted by Dr. Andreadis or his staff during 
the first five years after treatment to see how you are doing.  The UCSF staff will also continue 
to obtain your records from your local doctor for 5 years.
How long will I be in the study?
Treatment and post-treatment procedures will last approximately 26 months.  Afterwards, the 
researchers would like to check up on you for 5 years after your treatment to see how well you 
are doing.
Can I stop being in the study?
Yes. You can decide to stop at any time. Tell the study doctor if you are thinking about stopping 
or decide to stop. He or she will tell you how to stop your participation safely.
It is important to tell the study doctor if you are thinking about stopping so any risks from the 
transplant treatment can be evaluated by your doctor. Another reason to tell your doctor that you 
are thinking about stopping is to discuss what follow-up care and testing could be most helpful 
for you.
The study doctor may stop you from taking part in this study at any time if he/she believes it is in 
your best interest, if you do not follow the study rules, or if the study is stopped.
What side effects or risks can I expect from being in the study?
All cancer treatments are associated with risks.  Side effects may be mild, moderate, or severe.  
This research study may involve risks we don’t know about yet.  Everyone taking part in the 
study will be watched carefully for any side effects.  AutoSCT is a difficult and risky procedure.  
All possible attempts will be made to keep you as safe and comfortable as possible but there will 
be periods during the treatments and hospitalizations when you will be uncomfortable.  Many 
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side effects go away soon after you complete the treatment and hospitalizations. In some cases, 
side effects can be serious, long lasting, or may never go away. There is also a risk of death 
(depending on the state of your lymphoma and your general health, the risk of dying due to 
treatment is believed to be less than 4 %).  The treatment you receive may prove to have more 
side effects than other treatments.  This will not be known until after the study is completed and 
the data has been analyzed.
If you experience any side effects, you must tell your doctor, who may give you other drugs to 
ease any discomfort you may experience.  In addition, if a severe reaction to the drug occurs, 
your doctor may need to stop the study treatment.
STEP 1: (Consolidation chemotherapy)
During the first chemotherapy treatment with ofatumumab, etoposide and ara-c, you will likely 
experience the following side effects:
Risks and side effects related to ofatumumab (Ofatumumab has been given to patients with 
arthritis, leukemia, multiple sclerosis and certain other types of blood cancer) include those 
which are:
Likely

skin rash

allergic reactions, sometimes severe with swelling of face or mouth

difficulty breathing, shortness of breath, chest tightness, cough

low blood pressure (can cause light-headedness when you stand up

flushing, high temperature

excessive sweating

shaking or shivering

rapid heart beat

nausea

diarrhea

back pain

high blood pressure

itchy, bumpy rash (hives)

throat pain or irritation

lack of energy

stuffy nose

low levels of white blood cells (which may increase risk of infection and fever)

low levels of red blood cells (anemia)

low levels of platelets in the blood (which may cause wound healing problems or 
bleeding)

cold sores
Less Likely

infections of the lungs or airways (respiratory tract) such as pneumonia 
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
infections of the ear, nose or throat 

blood infections 

urinary tract infections 

shingles 

increase in potassium, phosphate and uric acid in the blood that can cause kidney 
problems (tumor lysis syndrome)

problems with blood clotting

the bone marrow failing to produce enough red or white blood cells 

rash or darkening of the skin
Rare but serious

A condition called “progressive multifocal leukoencephalopathy” (PML).  PML is a rare 
but serious and life threatening brain condition, that has been reported with medicines 
similar to ofatumumab, including rituximab.  PML may include memory loss, trouble 
thinking, difficulty walking, or loss of vision.  If any of these symptoms develop, you 
will be evaluated immediately with appropriate tests and a neurological consultation.  
Any further therapy with ofatumumab will be discontinued.

Severe skin reactions such as toxic epidermal necrolysis (serious and life threatening 
reaction which causes large areas of peeling skin and blisters to form on the mucous 
membranes lining the mouth, throat, anus, genitals, and eyes) may be observed with 
monoclonal antibodies and may also be observed in association with ofatumumab.  In 
some cases this reaction may be fatal

Sudden and severe Hepatitis B virus (HBV) infection can occur in patients newly 
exposed to HBV following treatment with ofatumumab, which can be fatal.  Your study 
doctor will discuss with you whether or not vaccination for hepatitis B infection should 
be considered.  If you have had hepatitis B, ofatumumab could cause your hepatitis B to 
become active again.  Your blood will be monitored regularly for this condition.  
Additionally, your doctor may treat you with a suitable anti-viral medicine to help 
prevent this.

Blockage of the small intestine, which can cause abdominal pain, nausea, vomiting, or 
decreased appetite

Cytokine-related infusion reactions or post injection systemic reactions: Cytokines are 
substances in your blood that allow cells to talk to each other.  These can be released and 
cause infusion reactions or post injection systemic reactions, particularly during or 
following the first dose of ofatumumab.  Infusion reactions tend to decrease with 
subsequent doses of ofatumumab.  Most of the infusion / injection site reactions reported 
with ofatumumab have been mild or moderate; however, infusion reactions may be 
severe or even lead to death.  You will receive medicines before the infusion / injection to 
reduce the risk of these reactions on your treatment days.  

In the setting of an infusion reaction these events can rarely occur: Fluid collection in the 
lungs and change in heart rhythm. Patients with decreased lung function may be at 
greater risk of side effects that affect the lungs. Change in heart rhythm may be 
associated with decreased blood flow to the heart which may lead to chest pain and heart 
attack.
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Risks and side effects related to the cytarabine include those which are:
Likely

Nausea, vomiting and decreased appetite

Fever/chills

Rash or darkening of the skin

Low Blood Counts (low white blood cells, red blood cells and platelets)

Complete hair loss

Mouth sores and difficulty swallowing

Diarrhea
Less Likely

Eye irritation with redness or pain on the surface of the eye

Damage to the liver, usually reversible

Damage to the lungs, usually reversible

Inflammation around the heart causing pain

Inflammation of the pancreas

Numbness or burning in the feet or hands

Infection

Headache or dizziness
Rare but serious

Brain damage resulting in slurred speech, difficulty with coordination and walking. This 
usually consists of a temporary (2-5 days) loss of coordination and temporary difficulty 
in speech or thinking.  However in rare cases (less than 2%) these changes may be 
permanent, disabling or even fatal.

Allergic reactions causing swelling around the face, low blood pressure or difficulty 
breathing

Kidney dysfunction requiring dialysis

Bladder dysfunction possibly requiring placement of a catheter in the bladder
Risks and side effects related to the etoposide include those which are:
Likely

Nausea and vomiting

Fevers/chills

Rash

Low Blood Counts (low white blood cells, red blood cells and platelets)

Weakness or tiredness (malaise)

Mouth sores

Abdominal cramps

Diarrhea

Low blood pressure (may be serious)

Sterility (unable to have children)
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Less Likely

Liver dysfunction

Kidney damage

Nerve damage

Fluid buildup in the lungs or legs

Infection
Rare but serious

Secondary cancer

Abnormal heart rhythm

Numbness or burning in the feet or hands

Severe allergic reaction causing severe skin rash with blistering

Toxic reaction in the tissues surrounding the IV catheter 

Inflammation of the lungs with chronic damage to the lungs

Visual changes

Severe high blood pressure
STEP 2: (Transplant Chemotherapy) 
During the transplant chemotherapy treatment with BCNU, etoposide, and cyclophosphamide, 
you may experience the following side effects:
(Risks and side effects related to etoposide are listed above)
Risks and side effects related to the BCNU (Carmustine) include those which are:
Likely

Low blood pressure, fast heartbeat, chest pain and headache during infusion

Disorientation, dizziness

Nausea, anorexia and vomiting

Transient eye flushing, blurry vision

Mouth sores, crampy abdominal pain and diarrhea

Low Blood Counts

Malaise

Complete hair loss
Less Likely

Chest pain

Facial Flushing

Abdominal pain

Mouth irritation

Infection
Rare but serious

BCNU lung injury.  This can develop anytime between drug administration and as late as 
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4 years afterwards.  It presents as shortness of breath, cough, fever, and chest pain.  
Additional testing such as lung function tests and CT scans may be needed to diagnose 
this condition.  If treated early it is largely reversible but it can rarely progress to 
pulmonary fibrosis, which is permanent lung damage that can be fatal.

Liver damage, most often reversible

Kidney dysfunction, rarely requiring dialysis

Allergic reaction
Risks and side effects related to the Cyclophosphamide include those which are:
Likely

Nausea, anorexia and vomiting

Mouth sores, crampy abdominal pain and diarrhea

Low Blood Counts

Malaise

Hair loss

May cause sterility
Less Likely

Facial flushing

Headache

Skin Rash

Nasal and sinus congestion during infusion
Rare but serious

Lung damage, causing shortness of breath

Heart damage, sometimes irreversible causing fatigue and shortness of breath

Bladder damage, rarely leading to permanent scarring or even death. Frequent urination, 
pain with urination, blood with urination, or bladder spasms can occur. Catheterization of 
the bladder (insertion of a tube into the bladder) and medications to help with bladder 
function may be needed.

SIADH, a condition that affects electrolyte balance in your body and results in water 
retention.  It is temporary and treatable with restriction of water intake.

Can cause secondary cancers
General Side Effects from this high-dose chemotherapy:
The high dose chemotherapy combination is expected to cause damage to hair, skin and the 
lining of the mouth and intestines.  Hair loss will be complete but is usually temporary.  In some 
cases the hair will not grow back completely or at all. During the first 1 to 2 weeks after stem 
cell transplantation there will be severe sores in the mouth.  These may be painful enough to 
require morphine or other narcotics for pain control. In addition to causing mouth sores, the 
combination chemotherapy affects the entire intestine.  This may lead to long periods of nausea 
or vomiting, diarrhea or crampy abdominal pain and inability to eat for several weeks. In time, 
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the body will naturally heal from all or most of these high dose chemotherapy related toxicities 
and this recovery will take approximately 1 to 3 weeks.
During the re-infusion of blood stem cells you will experience a number of side effects related to 
the chemical DMSO which is mixed with the stem cells in order to allow it to be safely frozen 
and thawed.  The stem cell infusion takes place over 30-60 minutes.  Typical side effects are 
nausea, vomiting, headache, flushing, chest tightness and pressure and abdominal cramps.  You 
will receive anti-nausea medicines to try to minimize these effects and they should be gone 
within several hours after the infusion is completed. 
Complications from Low Blood Counts
Most of the danger associated with high dose chemotherapy is due to the complications 
associated with low blood counts.  During both treatment steps you are expected to have low 
blood counts. These treatments will temporarily stop your own bone marrow from producing 
normal blood cells.  There will be a period of approximately 2 to 3 weeks when the blood 
counts will be low.  Low white blood counts can lead to problems with infections.  You will 
receive antibiotics to prevent infection and additional medications to treat an infection if it 
occurs.  Despite aggressive treatment, occasionally an infection can become overwhelming 
and you could even die from infection.  You will require transfusions of red blood cells 
because of anemia.  You will also require transfusions of platelets to prevent bruising and 
bleeding.  In cases where your body does not accept platelet transfusions from other people, 
there may be a risk of serious or even fatal bleeding.
Damage to Internal Organs
There are certain inherent risks in receiving very high dose chemotherapy of this type.  
Damage to internal organs can occur as a direct toxicity of this treatment.  If this damage 
occurs, it may be disabling or even fatal.  Usually, no specific treatment for these 
complications is available. This high dose therapy is also damaging to the reproductive 
system and there is a high likelihood (more than 95% chance) that you will be permanently 
sterile. Damage to the nerves may occur causing burning or tingling and rarely pain in the 
hands and feet. 
Failure to Engraft
The high dose chemotherapy that you will receive will permanently damage the bone marrow 
so that it will never grow back.  Restoration of your bone marrow function and blood counts 
will require the growth (engraftment) of your own infused stem cells.  The engraftment rate 
with autologous transplantation is approximately 99%.  If engraftment fails, there will be 
insufficient platelets, white cells and red cells to prevent bleeding and infection.  If 
uncorrected this condition could be fatal.  Initial therapy for this problem includes the use of 
bone marrow growth factors.  Re-transplantation may or may not be possible and you could 
potentially die of this complication.
Failure to Control Malignant Disease
Despite the intensity of this treatment program there is still a chance that it will not 
completely control your cancer or that the disease may recur after some period of control.
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If your cancer is in remission but recurs after the transplant, further treatment may be 
available. Should the cancer recur your doctor will describe the options of further therapy.
Risk of Second Cancers
Patients who receive treatment with high-dose chemotherapy have an increased risk of 
getting second cancers, including leukemia or lymphoma after the transplant procedure. The 
risk may be as high as 5-10% of developing a second cancer within 20 years of the 
procedure. You should receive routine screening for cancer if you receive this treatment.
Side Effects of Supportive Care Medications
You will receive medicine before the infusion/injection to reduce the risk of infusion/injection 
reactions on your treatment days. Overall, these medicines given before the infusion/injection are 
well tolerated.
Voriconazole is used to prevent fungal infections.  Voriconazole can cause side effects including 
those which are:
Likely

Nausea and vomiting

Diarrhea and abdominal cramps

Visual changes with color changes and difficulty with bright light

hallucinations

Headache

Fever/Chills

Rash
Less Likely

Low white blood cell count

Swelling in the feet

Fast heart beat

Liver inflammation with elevated liver tests 
Severe

Severe allergic reaction with low blood pressure and difficulty breathing

Severe skin rash with blistering

Abnormal heart rhythm with possible death

Kidney failure, possibly requiring dialysis
Fluconazole is used to prevent fungal infections.  Fluconazole can cause side effects including 
those which are:
Likely

Nausea and vomiting

Diarrhea
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
Headache

Rash
Less Likely 

Liver inflammation with elevated liver tests 

Abdominal cramps with pain

Dizziness

Taste changes
Rare but Serious

Allergic reaction causing low blood pressure or shortness of breath

Seizures

Low white blood cells with infection

Low blood platelets with possible bleeding

Severe rash with possible blistering

Abnormal heart rhythm with possible death

Swelling due to allergic reaction
Moxifloxacin is used to prevent bacterial infections. Moxifloxacin can cause side effects 
including those which are:
Likely

Nausea and vomiting

Diarrhea and crampy abdominal pain

Headache

Dizziness
Less Likely

Liver inflammation with elevated liver tests 

Rash

Joint aches

Infection in the colon called pseudo-membranous colitis causing severe diarrhea and 
cramps
Rare but Serious

Seizures

Abnormal heart beating

Allergic reaction causing low blood pressure or shortness of breath

Psychosis and depression

Low white blood cells with infection

Low blood platelets with possible bleeding

Reversible kidney failure possibly requiring dialysis

Severe rash with possible blistering
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Acyclovir is used to prevent viral infection including lip and mouth ulcers from herpes simplex 
and shingle infections from varicella zoster (the chicken pox virus).  Acyclovir can cause side 
effects including those which are:
Likely

Nausea and vomiting

Diarrhea and crampy abdominal pain

Headache

Dizziness
Less Likely

Malaise or fatigue

Rash

Joint aches

Lightheadedness

Confusion
Rare but Serious

Seizures or coma

Kidney problems

Low white blood cell counts with infection

Low blood platelets with bleeding
Neupogen (G-CSF) is a growth factor used to stimulate the growth of white blood cells.  
Neupogen can cause side effects including those which are:
Likely

Nausea and vomiting

Fever or chills

Headache

Chest and sternal pain

Elevated white blood cells

Bone pain

Bruising and pain at the injection site
Less Likely

Liver inflammation with elevated liver tests 

Kidney problems

Diarrhea and/or abdominal/flank pain

Elevated uric acid levels with possible gout

Enlarged spleen

Fatigue with or without anemia

Low blood platelets with possible bleeding

Low blood pressure
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Rare but Serious

Rupture of the spleen requiring surgery

Severe pneumonia/inflammation of the lungs 

The side effects of Neupogen can often be controlled with acetaminophen (Tylenol) or 
other pain medication, but occasionally Neupogen must be discontinued due to side 
effects.
Corticosteroids: The following side effects may occur with short term use of corticosteroids: 
fluid retention, acne, constipation, mood swings, sleeping problems, sweating, headache, 
dizziness, feeling sick to your stomach, stomach pain, bloating, and blurry vision.
Antihistamines: An antihistamine, such as cetirizine, will be given to you in this study. Use 
caution when driving a car or operating potentially dangerous machinery because sleepiness may 
occur. Also avoid alcohol or other drugs that can further decrease alertness.  The most common 
side effect is sleepiness. Dizziness, fainting, headache, confusion, nausea, flushing, fatigue, rash, 
and dry mouth may also occur. Short-term increases in liver tests that suggest possible liver 
damage have occurred infrequently.  
Acetaminophen/Paracetamol:  Acetaminophen/paracetamol will be given to you in this study. 
Side effects from acetaminophen are rare.  Your doctor will instruct you on the maximum daily 
dose of acetaminophen.  Taking more than the recommended amount may cause liver damage.  
You should not take two or more products that contain acetaminophen at the same time unless 
directed by a physician.  Your doctor should be informed about blood thinners, isoniazid (INH), 
and medications for pain, fever, and coughs.  Tell your doctor if you drink three or more 
alcoholic beverages every day. Notify your doctor if any rash, hives, swelling of the face and 
throat, or difficulty breathing or swallowing occurs.
Procedure Risks
Risks of Blood Draw
If you have a blood draw from your arm, you may feel some discomfort when the needle is 
placed in the vein. Sometimes a bruise may develop where the blood was drawn or the needle 
was placed for treatment, and occasionally infection, clotting, or bleeding may develop at the 
puncture site.
Risks of Intravenous Access (central catheter placement)
You will have several catheters placed into your vein.  Likely complications include discomfort, 
pain, bruising, and/or bleeding at the catheter insertion site. Occasional complications of the 
central venous catheter include blood clot formation, a punctured lung and infection. Rare 
complications include air embolus and death.
Risks of Bone Marrow Aspiration and Biopsy
There may be some temporary pain or discomfort associated with these procedures.  While 
complications are extremely rare, excessive bleeding and infections at the site of the biopsy can 
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occur.
Risks of Lumbar Puncture
Can cause a headache approximately 20% of the time.  This headache tends to be worse when 
you sit up as opposed to when you lay flat.  This headache can be treated with pain medicines as 
well as increasing your intake of fluids especially caffeinated fluids.  There can be some local 
pain in the lower back where the needle entered your skin.  Infection of the spinal fluid is 
extremely rare.  Bleeding into the lower back area which might affect your spinal nerves is also 
very rare.
Risks of Radiology Tests
The amount of radiation you will be exposed to is relatively small. These doses of radiation 
could be potentially harmful, but the risks are so small that they are difficult to measure. If you 
have had a lot of x-ray already, you should discuss this with your study doctor.
Risks of FDG-PET scan
This scan involves the risks of radiation (see above). The contrast material (radioactive form of 
glucose) is used. This substance can be easily eliminated from the body either through 
radioactive decomposition or excreted through urine.
Risks of CT scan
This scan involves the risks of radiation (see above).  If contrast material (iodine dye) is used, 
there is a slight risk of developing an allergic reaction, from mild (itching, rash) to severe 
(difficulty breathing, shock, or rarely, death).  Rarely, the contrast material may cause nausea, 
vomiting or a headache.  The contrast material may also cause kidney problems, especially if you 
are dehydrated or have poor kidney function.  The study doctors will ask you about any allergies 
or related conditions before the procedure.  If you have any of these problems, you may not be 
allowed to have a CT scan with contrast.  If you are taking metformin (or similar drugs by mouth 
to treat high blood sugar), such treatment will be stopped for 2-3 days around the time a scan is 
planned in order to avoid kidney side effects.
Having a CT scan may mean some added discomfort for you.  In particular, you may be bothered 
by feelings of claustrophobia when placed inside the CT scanner, or by lying in one position for 
a long time.  If contrast material is used, you may feel discomfort when it is injected by vein.  
You may feel warm and flushed and get a metallic taste in your mouth.
Risks of EKG
You may experience an allergic reaction to the adhesive used to attach the electrodes to the skin.  
These symptoms are generally mild and clear up on their own.  Please let your doctor know if 
you are aware of any allergies.
Risks of Echocardiogram
This exam might cause you to be uncomfortable from the pressure of the probe on your chest or 
lying still for the examination.
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Risks of MUGA scan
This scan involves the risks of radiation (see above).  You may develop bruising where the 
needle is placed in your veins to administer the radioactive substance.  You may be 
uncomfortable lying flat.  You may have an allergic reaction to the radioactive substance.
Risks of DLCO
You may feel uncomfortable when your nose is clipped shut or when the mouthpiece is placed in 
your mouth.
Risk to an Unborn Child
Females:
It is possible that these chemotherapy agents may cause unknown side effects to an unborn child 
now or in the future due to exposure in the womb. There may also be a risk to the child if he/she 
is breastfeeding.
If you are a woman who is able to become pregnant, you will need to have a negative pregnancy 
test before starting treatment. You will not be able to participate in this research study if you are 
pregnant, or if you are breastfeeding.  Your participation in this study requires that you use an 
acceptable means of birth control throughout the study and for one year after completing 
treatment. Examples of effective birth control are: a condom or a diaphragm with spermicidal 
jelly, oral, injectable, or implanted birth control, or abstinence.
If you are a man you must agree to use condoms during intercourse or to remain abstinent during 
the study and for one year after completing treatment. This is to prevent the possibility of a 
pregnancy from sperm that might have been damaged by treatment.
If you become pregnant while participating in this study or father a child, you must contact your 
doctor immediately. Your doctor will advise you of the possible risks to the unborn child and 
discuss options for managing the pregnancy.  Because of possible risks to an unborn child, the 
study drug will be stopped permanently for pregnant participants.
Some males (ask your study doctor if this applies to you):
You should not father a baby while you are on this study. If you are engaging in sexual 
intercourse with a woman of childbearing potential, you should use a highly effective method of 
birth control.  Check with the study doctor about what kind of birth control methods to use and 
for how long to use them.  Some methods may not be approved for use during this study.  You 
must tell the doctor right away if your partner gets pregnant.   If your partner gets pregnant 
during the study, you may be asked questions about the pregnancy and the baby.
Unknown Risks
For studies involving experimental treatments, there may be unknown risks associated with the 
treatment. If you believe you have been injured, or if you have any unusual symptoms, you 
should report them to the study doctor.  The researchers will let you know if they learn anything 
that might make you change your mind about participating in the study.
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For more information about risks and side effects, ask your study doctor.
Are there benefits to taking part in the study?
Taking part in this study may or may not make your health better.  While doctors hope therapy 
with OVA will be more useful against your cancer compared to the usual treatment, there is no 
proof of this.  We do know that the information from this study will help doctors learn more 
about autologous transplantation using OVA as a treatment for lymphoma.  This information 
could help future cancer patients.
What other choices do I have if I do not take part in this study?
Your other choices may include:

Getting treatment or care for your cancer without being in a study.  This may include 
autologous transplantation and/or chemotherapy such as RICE (rituximab, ifosfamide, 
carboplatin, etoposide) or rituximab plus cyclophosphamide.  Your study doctor will 
discuss any available treatment options with you.

To not receive any therapy at all.  You would still be able to receive supportive care or 
comfort care. This type of care helps reduce pain, tiredness and tries to improve the way 
you feel without directly treating the lymphoma.  You may be able to receive specific 
lymphoma therapy in the future if desired.

You may be able to receive other experimental lymphoma treatments either at UCSF or at 
another facility.
Please talk to your doctor about your choices before deciding if you will take part in this study.
Will my medical information be kept private?
We will do our best to make sure that the personal information in your medical record is kept 
private.  However, we cannot guarantee total privacy.  Your personal information may be given 
out if required by law.  If information from this study is published or presented at scientific 
meetings, your name and other personal information will not be used.
Organizations that may look at and/or copy your medical records for research and data analysis 
include:

Novartis Pharmaceuticals Corporation (the drug supplier) and its authorized agents.

The U.S. Food and Drug Administration (FDA), National Cancer Institute (NCI), and 
other government agencies in the United States and other countries, which are involved in 
keeping research safe for people.

The Committee on Human Research (UCSF’s institutional review board, which is 
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involved in protecting your rights as a participant in this study)

The UCSF Helen Diller Family Comprehensive Cancer Center

The Bone Marrow Transplant Registry, and their representatives

The University of California
A UCSF medical record will be created as a result of your participation in this study.  This 
consent form, and some of the results from your research tests, will be included in your medical 
record.  Information from your records will be entered in a database.  Therefore, your other 
UCSF doctors may become aware of your participation
California regulations require laboratories to report new cases of HIV, hepatitis B, and hepatitis 
C infection to the county public health department. The reports include the patient’s name, social 
security number, and other identifying information. Information about these new infections is 
used to track these diseases statewide and nationwide. Other than this required reporting, your 
results will be treated confidentially by the study staff. Personally identifying information will 
not be reported to other departments or agencies
What are the costs of taking part in this study?
Treatments and tests, not standard of care, that are performed strictly because of study 
participation will be funded by Novartis This will include EKGs, certain FDG-PET and CT 
scans, biopsy samples for research, DLCO tests, and certain blood tests.  The study drug, 
ofatumumab, will also be provided free of charge by Novartis.
The doctors and hospital will bill you or your insurance company for tests and procedures that 
are considered part of your usual care, just as they would if you were not participating in this 
study.  This includes chemotherapy infusions and supportive care medications.
It is possible that your insurance company will refuse to pay for these tests and procedures even 
after you have already received treatment, and you will have to pay for your care.  Every attempt 
will be made to obtain insurance approval for treatment before the study investigations and 
treatments are administered.  You will be given the opportunity to meet with a financial advisor 
from the hospital to determine the maximum dollar amount that you will be expected to pay.
For more information on clinical trials and insurance coverage, you can visit the National Cancer 
Institute's website at  http://cancer.gov/clinicaltrials/understanding/insurance-coverage.  You can 
print a copy of the "Clinical Trials and Insurance Coverage" information from this website.  
Another way to get the information is to call 1-800-4-CANCER (1-800-422-6237) and ask them 
to send you a free copy.
IRB NUMBER: 11-07843
IRB APPROVAL DATE: 02/14/2017
IRB EXPIRATION DATE: 02/13/2018


ICF 01-17-2017
Page 24 of 26
UCSF CC# 112525
Protocol v.10 01-17-2017
Dr. Charalambos Andreadis
Will I be paid for taking part in this study?
You will not be paid for taking part in this study.
What happens if I am injured because I took part in this study?
It is important that you tell your study doctor, Dr. Charalambos Andreadis, if you feel that you 
have been injured because of taking part in this study.  You can tell the doctor in person or call 
him/her 
.
Treatment and Compensation for Injury: If you are injured as a result of this study, the 
University of California will provide necessary medical treatment. The costs of the treatment 
may be billed to you or your insurer just like any other medical costs, or covered by the 
University of California, depending upon a number of factors. The University does not 
normally provide any other form of compensation for injury.  For further information about 
this you may call the office of the Committee on Human Research at (415) 476-1814 or 
write: Committee on Human Research, UCSF, Box 0962, San Francisco, CA 94143.
What are my rights if I take part in this study?
Taking part in this study is your choice. You may choose either to take part or not to take part in 
the study. If you decide to take part in this study, you may leave the study at any time. No matter 
what decision you make, there will be no penalty to you and you will not lose any of your regular 
benefits. Leaving the study will not affect your medical care. You can still get your medical care 
from our institution.
We will tell you about new information or changes in the study that may affect your health or 
your willingness to continue in the study.
In the case of injury resulting from this study, you do not lose any of your legal rights to seek 
payment by signing this form
Who can answer my questions about the study?
You can talk to your study doctor about any questions or concerns you have about this study.  
Contact your study doctor, Dr. Charalambos Andreadis, or one of his associates 
.
For questions about your rights while taking part in this study, call the office of the Committee 
on Human Research, UCSF's Institutional Review Board (a group of people who review the 
research to protect your rights) at 415-476-1814.
IRB NUMBER: 11-07843
IRB APPROVAL DATE: 02/14/2017
IRB EXPIRATION DATE: 02/13/2018


ICF 01-17-2017
Page 25 of 26
UCSF CC# 112525
Protocol v.10 01-17-2017
Dr. Charalambos Andreadis
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
CONSENT
You have been given copies of this consent form and the Experimental Subject’s Bill of Rights 
to keep.  You will be asked to sign a separate form authorizing access, use, creation, or 
disclosure of health information about you.
PARTICIPATION IN RESEARCH IS VOLUNTARY.  You have the right to decline to 
participate or to withdraw at any point in this study without penalty or loss of benefits to which 
you are otherwise entitled  If you wish to participate in this study, you should sign below.
____________________________________
______________________
Signature of Patient
Date
____________________________________
______________________
Name of Patient
Date
______________________________
______________________
Signature of Person Obtaining Consent
Date
______________________________
______________________
Name of Person Obtaining Consent
Date
____________________________________
______________________
Witness (only required if the participant is 
Date
a non-English speaker)
IRB NUMBER: 11-07843
IRB APPROVAL DATE: 02/14/2017
IRB EXPIRATION DATE: 02/13/2018


ICF 01-17-2017
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UCSF CC# 112525
Protocol v.10 01-17-2017
Dr. Charalambos Andreadis
STUDY SCHEMA
Determination of Eligibility to Enter Study
Step 1:
Consolidation chemotherapy/Intensive Mobilization (3-5 weeks)
Ofatumumab (days 0,7,14,21) + Ara-C (days 1-4) + Etoposide (days 1-4)
Neupogen starts day +14
Stem cells collected when WBC >10,000/uL
Interim Assessment at 6 weeks from start of Step 1
If study continuation criteria met, proceed to next step (at least 2 weeks after discharge from step 
1)
If disease progresses and
Intent is to proceed to transplantation in the future, proceed to follow-up period starting at 
three months
No intention for transplantation, follow-up will occur every 3 months by study team for 
up to 2 years
Step 2:
 Transplantation (3-5 weeks)
Day -6: Enter hospital, receive BCNU
Day -2: Receive etoposide
Day -2: Receive cyclophosphamide
Day 0: Receive infusion of own stem cells
Day +6: Start Neupogen (G-CSF), until count recovery
Approximately Day 14-21: discharged from hospital
If disease progresses, follow-up will occur every 3 months by study team for up to 
2 years
Follow-up period
First month following discharge: “House arrest”, limited contact with people
Monthly (at least) clinic visits
 Three months: Response Assessment
Months 6, 12, 24: Clinic visit and response assessment
Telephone or chart review every 6 months for up to 5 years
IRB NUMBER: 11-07843
IRB APPROVAL DATE: 02/14/2017
IRB EXPIRATION DATE: 02/13/2018

Prot_SAP_002.pdf: 
A phase II study of intensive consolidation and stem cell mobilization therapy with 
ofatumumab, etoposide, and high-dose ara-C (OVA), followed by autologous stem 
cell transplantation in high-risk patients with relapsed/refractory Diffuse Large B-
Cell Lymphoma 
Protocol Number:  CC #112525 
IND Number:  114,047 
Version Number:  10.0 
Version Date:  January 17, 2017 
Study Drugs:  Ofatumumab, etoposide, cytarabine 
Principal Investigator (Sponsor-Investigator) 
Charalambos Andreadis, MD, MSCE  
UCSF Comprehensive Cancer Center 
Co-Investigators 
Lawrence Kaplan, MD 
Catherine Smith, MD 
Rebecca Olin, MD 
Weiyun Ai, MD 
Lloyd Damon, MD 
Karin Gaensler, MD 
Aaron Logan, MD, PhD 
Thomas Martin III, MD 
Peter Sayre, MD 
Neil Shah, MD 
Jeffrey Wolf, MD 
Gabriel Mannis, MD 
Statistician 
Jimmy Hwang, PhD 
Revision History 
Final 
Version 1.0 
06-01-2011
Amendment #1 
Version 2.0 
07-28-2011
Amendment #2 
Version 3.0 
10-15-2011
Amendment #3 
Version 4.0 
12-21-2011
Amendment #4 
Version 5.0 
02-01-2013
Amendment #5 
Version 6.0 
05-23-2016
Amendment #6 
Version 7.0 
08-26-2016
Amendment #7 
Version 8.0 
09-19-2016
Amendment #8 
Version 9.0 
11-22-2016
Amendment #9 
Version 10.0 
01-17-2017
Protocol Version #10.0 
Protocol #112525 
01-17-2017
NCT# 01555541


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Table of Contents 
PRINCIPAL INVESTIGATOR ........................................................................................................................................................ I 
CO-INVESTIGATORS .................................................................................................................................................................. I 
STUDY SUMMARY ....................................................................................................................................... 1 
1 
INTRODUCTION ................................................................................................................................ 4 
1.1 
DLBCL ......................................................................................................................................... 4 
1.2 
INTENSIVE MOBILIZATION ................................................................................................................ 4 
1.3 
FDG-PET AS A PREDICTIVE MARKER IN RELAPSE ............................................................................. 5 
1.4 
OFATUMUMAB ................................................................................................................................ 5 
1.4.1 
Safety....................................................................................................................................... 6 
1.4.2 
Efficacy .................................................................................................................................... 7 
2 
STUDY OBJECTIVES ........................................................................................................................ 9 
3 
STUDY DESIGN ................................................................................................................................. 9 
3.1 
GENERAL DESIGN .......................................................................................................................... 9 
3.2 
PRIMARY STUDY ENDPOINTS .......................................................................................................... 9 
3.3 
SECONDARY STUDY ENDPOINTS ..................................................................................................... 9 
4 
SUBJECT SELECTION AND WITHDRAWAL................................................................................. 11 
4.1 
INCLUSION CRITERIA..................................................................................................................... 11 
4.2 
EXCLUSION CRITERIA ................................................................................................................... 11 
4.3 
SUBJECT RECRUITMENT AND SCREENING ...................................................................................... 11 
4.4 
EARLY WITHDRAWAL OF SUBJECTS ............................................................................................... 11 
4.5 
DATA COLLECTION AND FOLLOW-UP FOR WITHDRAWN SUBJECTS ................................................... 11 
5 
ON STUDY EVALUATION ............................................................................................................... 11 
5.1 
REGISTRATION ............................................................................................................................. 11 
5.2 
SALVAGE RESPONSE ASSESSMENT ............................................................................................... 11 
5.3 
DAY 0 OF OVA ............................................................................................................................. 11 
5.4 
ALL OTHER DAYS OF OVA ............................................................................................................. 11 
5.5 
DAY 42 EVALUATION (+/- 4 DAYS) ................................................................................................. 11 
5.6 
CBV ADMINISTRATION .................................................................................................................. 11 
5.7 
DAY +30’ AND +60’ EVALUATION (+/- 4 DAYS) ................................................................................ 11 
5.8 
DAY +90’ EVALUATION (+/- 4 DAYS)............................................................................................... 11 
5.9 
MONTH 6, 12, AND 24 EVALUATION (+/- 4 WEEKS) .......................................................................... 11 
5.10 
AT TIME OF SUSPECTED RELAPSE/PROGRESSION .......................................................................... 11 
6 
FOLLOW-UP PHASE ....................................................................................................................... 11 
7 
TREATMENT REGIMEN .................................................................................................................. 11 
7.1 
INTENSIVE MOBILIZATION REGIMEN (OVA) .................................................................................... 11 
7.1.1 
Ofatumumab Administration at 1000mg IV on days 0,7,14, and 21. ..................................... 11 
7.2 
PERIPHERAL BLOOD STEM CELL (PBSC) COLLECTION ..................................................... 11 
7.3 
HIGH-DOSE THERAPY WITH STEM CELL RESCUE (CBV) ................................................................. 11 
7.4 
OPTIONAL RADIOTHERAPY ............................................................................................................ 11 
8 
MEASUREMENT OF EFFECT ......................................................................................................... 11 
8.1 
DEFINITION OF ADEQUATE STEM CELL COLLECTION ....................................................................... 11 
8.2 
DEFINITION OF ENGRAFTMENT ...................................................................................................... 11 
8.3 
LYMPHOMA RESPONSE ASSESSMENT (REVISED IWG CRITERIA [12]) ................................................ 11 
8.4 
SURVIVAL-TIME PARAMETERS ........................................................................................................ 11 
9 
SAFETY AND ADVERSE EVENTS ................................................................................................. 11 


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9.1 
SAFETY DEFINITIONS .................................................................................................................... 11 
9.2 
TIME PERIOD AND FREQUENCY OF DETECTING AND REPORTING SAES ........................................... 11 
9.3 
SPECIAL REPORTING CONSIDERATIONS ......................................................................................... 11 
10 
STUDY DRUG AND CHEMOTHERAPEUTIC AGENTS ................................................................... 11 
10.1 
OFATUMUMAB (ARZERRA) ............................................................................................................. 11 
10.2 
ETOPOSIDE (VESPID®; VP-16) ..................................................................................................... 11 
10.3 
G-CSF (FILGRASTIM; NEUPOGEN®) .............................................................................................. 11 
10.4 
CYTARABINE (CYTOSAR-U®; ARA-C; CYTOSINE ARABINOSIDE) ....................................................... 11 
11 
STATISTICAL CONSIDERATIONS ................................................................................................... 11 
11.1 
SAMPLE SIZE ............................................................................................................................... 11 
11.2 
STATISTICAL METHODS ................................................................................................................. 11 
11.3 
ACCRUAL AND ESTIMATED DURATION OF STUDY ............................................................................ 11 
11.4 
DLBCL SUBTYPING ...................................................................................................................... 11 
11.5 
MINIMAL RESIDUAL DISEASE TESTING ........................................................................................... 11 
11.6 
DATA SAFETY MONITORING PLAN .................................................................................................. 11 
12 
DATA MANAGEMENT AND STUDY TERMINATION ...................................................................... 11 
12.1 
DATA AND PROTOCOL MANAGEMENT ............................................................................................. 11 
12.2 
TERMINATION OF STUDY ............................................................................................................... 11 
13 
STUDY FINANCES ............................................................................................................................ 11 
13.1 
FUNDING SOURCE ........................................................................................................................ 11 
13.2 
CONFLICT OF INTEREST ................................................................................................................ 11 
14 
REFERENCES ................................................................................................................................... 11 
15 
ATTACHMENTS ................................................................................................................................ 11 
15.1 STUDY PROCEDURES ........................................................................................................................ 11 
15.2 CALCULATION OF SAAIPI ................................................................................................................... 11 
15.3 HIGH DOSE THERAPY WITH STEM CELL RESCUE (CBV) ...................................................................... 11 


OVA in High-Risk Relapsed/Refractory DLBCL 
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Study Summary 
 
Title 
A phase II study of intensive consolidation and stem cell mobilization therapy 
with Ofatumumab, etoposide, and high-dose ara-C (OVA), followed by 
autologous stem cell transplantation in high-risk patients with relapsed/refractory 
Diffuse Large B-Cell Lymphoma 
Study Design 
Phase II, single institution pilot study 
Study Duration 
24 months accrual, 24 months followup 
Objectives 
Primary Objective: 
To demonstrate the ability of Ofatumumab in combination with etoposide and 
cytarabine to mobilize peripheral blood stem cells and lead to a high compelte 
metabolic response rate prior to autologous stem cell transplantation in rituximab 
pre-treated patients with high-risk relapsed or refractory DLBCL. 
Secondary Objectives: 
2.2.1 To evaluate stem cell engraftment following successful mobilization. 
2.2.2 To determine PFS following treatment with Ofatumumab in combination 
with etoposide and high-dose ara-C (OVA) and subsequent autologous stem cell 
transplantation. 
2.2.3 To measure the effect of OVA on other clinically meaningful endpoints. 
2.2.4 To measure the FDG-PET conversion rate from PR to CR following OVA 
and its association with clinical outcomes. 
2.2.5 To examine potential relationships between Ofatumumab concentration 
and clinical outcomes. 
2.2.6 To study the safety and tolerability of OVA. 
2.2.7 To store tumor tissue for future molecular subtyping. 
2.2.8 To evaluate minimal-residual disease testing in the setting of 
transplantation. 
Number of Subjects 
24 patients 
Main Eligibility 
Criteria 
KEY INCLUSION CRITERIA 
Diagnosis of CD20+ WHO diffuse large B-cell lymphoma or primary mediastinal 
B-cell lymphoma. Transformation of previously-diagnosed low-grade lymphoma 
is excluded. 
Refractory to or relapse following a rituximab/anthracycline first-line regimen 
High-risk disease as defined by one of the following: 
• 
First relapse after CR within 12 months of initiation of front-line 
therapy 
• 
Less than CR to front-line therapy 
• 
sAAIPI of 2 or higher at the time of relapse (see attachment 14.2) 
Receipt of no more than three prior chemotherapy regimens. Monoclonal 
antibody therapy and involved field radiotherapy are not included in this number. 
Prior use of ofatumumab is allowed if there has been no disease progression 
following that therapy (i.e. ofatumumab-based salvage regimens allowed) 
KEY EXCLUSION CRITERIA 
Progression following prior ofatumumab salvage therapy 
 
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Active central nervous system or meningeal involvement by lymphoma. Patients 
with a history of CNS or meningeal involvement must be in a documented 
remission by CSF evaluation and contrast MRI imaging for at least 3 months 
prior to study entry. 
Bone marrow involvement with more than or equal to 15% lymphoma cells 
following salvage therapy. 
Evidence of myelodysplasia on any bone marrow biopsy prior to initiation of 
therapy. 
Known HIV infection 
Positive serology for Hepatitis B (HB) defined as a positive test for HbsAg and a 
detectable HBV DNA viral load. If negative for HBsAg but HBcAb positive 
(regardless of HBsAb status), a HBV DNA test will be performed and if positive 
the subject will be excluded. If HBV DNA is negative, subject may be included 
but must undergo at least every 2-month HBV DNA PCR testing from the start of 
treatment during the treatment course. Prophylactic antiviral therapy may be 
initiated at the discretion of the investigator. 
Positive serology for hepatitis C (HC) defined as a positive test for HCAb, in 
which case reflexively perform a HCV PCR to confirm the result 
Receipt of live virus vaccination within 4 weeks prior to planned initiation of study 
treatment. 
Study Product, 
Dose, Route, 
Regimen 
Ofatumumab 1000 mg IV on days 0,7,14,21 
Given concurrently with: 
Etoposide 10 mg/Kg IV over 24 hours daily, days 1-4 
Cytarabine 2000 mg/m2 IV twice daily, days 1-4 
Statistical 
Methodology 
This is a single-institution, single-arm, open-label Phase II study of Ofatumumab 
in combination with etoposide and high-dose cytarabine as an intensive 
consolidation and stem cell mobilization regimen in patients with 
relapsed/refractory diffuse large B-cell lymphoma. The primary efficacy endpoint 
of the study is the mobilization-adjusted complete response rate (maCR) which 
is defined as the proportion of patients achieving complete response to the 
treatment upon successful stem cell mobilization, defined as at least 2 x10^6 
CD34+cells/Kg of actual body weight. Secondary endpoints include time to 
neutrophil and platelet engraftment following ASCT, PFS in this high-risk patient 
population and other survival-time measures of clinical efficacy, i.e. OS, TTP, 
EFS, and CR/Pr proportion at day +90. Our study will also measure the FDG- 
PET conversion rate from PR to CR following OVA and correlate post-OVA PET 
results with PFS, TTP, and OS. We will examine potential relationships between 
Ofatumumab concentration at selected time points and PFS, TTP, OS. We will 
perform MRD testing at baseline, at the time of stem cell collection, and following 
ASCT, and will correlate the results to clinical endpoints. Finally, safety will be 
evaluated with regard to infusion-related reactions, B-cell number, 
hypogammaglobulinemia, and long-term hematologic toxicity. 
Patients who have received a single infusion of study drug (day 0 of OVA) will be 
included in the statistical analyses. We are planning to accrue 24 subjects over 
the course of 2 years with an additional 2-year follow-up.  In terms of the 


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composite primary endpoint, the historical CR rate after 2 cycles of salvage 
therapy among high risk, rituximab refractory patients is between 25% and 50% 
of the overal responses (i.e CR/(CR+PR).[8, 19, 20] Furthermore, the chance of 
a mobilization failure among complete an dpartial responders observed in the 
CORAL study is 15%.[9] We thus expect the null value of the composite 
endpoint of maCR to be 25% (~40% CR-15% mobilization failure). Given the 
excellent historical CR rates with intensive consolidation and the very low risk of 
mobilization failures, we expect the alternative maCR rate to be 50%. Based on 
the exact probability with type I error of 10% and 1-sided test, a sample size of 
N=24 in the single arm study will have > 80% power to detect the maCR rate for 
the following hypothesis: H0: p0<25% (40%CR/15%mobilization-failure) vs Ha: 
p1>50% (55%CR/5%mobilization-failure under OVA). The following table shows 
statistical power for the test of the null hypothesis under the assumed maCR of 
25% and for various mobilization-adjusted complete response rates with 24 
subjects (alpha=10% under 1-sided exact test): 
 
maCR rate 
Statistical Power 
25% vs 40% 
51% 
25% vs 45% 
70% 
25% vs 50% 
84% 
25% vs 55% 
93% 
25% vs 60% 
97% 
 
An interim analysis for futility and safety will be performed when 12 subjects are 
enrolled. We will define the futility as >50% stem cell mobilization failure as 
excessive and unacceptable. If six or fewer (< 50%) subjects have adequate 
stem cell mobilization, the enrollment will not continue and the study will be 
closed for treatment futility. Otherwise we will enroll 12 additional patients to 
complete study for full maCR efficacy analysis. At the same time as the interim 
analysis for futility, we will also perform an interim evaluation for safety, which is 
defined as >30% SAE as too toxic and unacceptable. If 4 or more (>30%) of the 
first 12 patients treated are observed to have protocol-defined unacceptable 
toxicity, the study will be closed for lack of safety. If the stem cell collection 
success rate is less than 50%, the probability of early stopping due to futility is 
61%. If the toxicity rate is greater than 30%, the probability of early stopping due 
to safety is 64%. 


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1 Introduction 
 
This document is a protocol for a human research study. This study is to be conducted according to US 
and international standards of Good Clinical Practice (FDA Title 21 part 312 and International Conference 
on Harmonization guidelines), applicable government regulations and Institutional research policies and 
procedures. 
 
1.1 DLBCL 
 
Diffuse Large B-cell Lymphoma (DLBCL) is the most common lymphoma worldwide. Even though 
rituximab/anthracycline-containing chemotherapy (e.g. R-CHOP) can cure a significant proportion of 
patients with this disease in the modern era, approximately 40% are either refractory to  front-line 
treatment or relapse following therapy.[1-3] The standard of care for these relapsed/refractory patients 
involves salvage chemotherapy (e.g. R-ICE, R-DHAP, R-ESHAP, etc) followed by autologous stem cell 
transplantation (ASCT) in patients who are chemosensitive to salvage.[4] 
 
The obstacles to curing patients following a relapse are several. These include: 1) poor response to 
salvage therapies, and thus ineligibility for subsequent ASCT; 2) inadequate mobilization of stem cells in 
these densely pre-treated patients; and 3) residual disease following salvage therapy.[5, 6] Historically, 
patients at high-risk for treatment failure include those refractory to initial therapy or relapsed within 12 
months of treatment initiation [7] and those with a high age-adjusted international prognostic index at the 
time of relapse (sAAIPI). [8] More recently, the international CORAL study has also identified prior 
treatment with rituximab to be significantly associated with inferior response rates to rituximab-containing 
salvage therapy and inferior long-term survival outcomes after ASCT.[9] This effect appears to be limited 
to those patients who relapse within 12 months of initiation of therapy, and 2-year PFS in this population 
starting from initiation of salvage therapy was only 15%. Out of the 187 patients in that group, only 68 
(36%)made it to transplantation, and this subgroup had a 2-year PFS of 39% following ASCT. [9] 
Additionally, 15% of responding patients didn’t make it to ASCT solely due to inadequate stem cell 
collection. 
 
1.2 Intensive Mobilization 
 
We have developed an intensive approach for treating relapsed patients with high-risk aggressive 
lymphoma prior to transplantation. [10] Following 2-3 cycles of salvage therapy at relapse, high-risk 
patients undergo an additional cycle of therapy with either etoposide, cyclophosphamide, and rituximab 
(CER) or etoposide, cytarabine, and rituximab (EAR) to further decrease tumor burden and to provide in- 
vivo purging of the stem cell graft. Stem cells are then collected following this regimen as opposed to 
standard mobilization (high-dose cyclophosphamide or R-ICE) used for the low-risk patients. In our 
reported cohort, treatment with intensive mobilization was well-tolerated and resulted in excellent stem- 
cell mobilization with no collection failures. Moreover, event-free survival among the high-risk patients 
with DLBCL going to ASCT after CER or EAR was comparable to that of low-risk patients treated with 
standard mobilization (Figure 1a) and overall survival was significantly improved (Figure 1b). In this high- 
risk cohort, our observed 4-year EFS and OS rates are 67% and 76% respectively, comparing very 
favorably to the reported rates from CORAL (4-year PFS 39%).[10] 


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1.3 FDG-PET as a predictive marker in relapse 
 
PET imaging using fluorodeoxyglucose (18F) has been conclusively shown to predict response duration, 
progression-free, and overall survival at the completion of first-line therapy in patients with DLBCL and 
other lymphomas.[11] It has consequently been incorporated in the response assessment criteria for 
lymphoma and has become the standard of clinical care.[12] Several studies are underway to address 
the utility of interim PET in tailoring frontline therapy for selected groups of patients. 
In the relapse setting, there is evidence to suggest that FDG-PET assessment following salvage 
therapy is also predictive of outcomes following ASCT. [13-18] Specifically, patients in PET+ PR prior to 
ASCT have long-term disease-free survival rates in the order of 30-40% compared to 70-80% for the 
PET- CR patients. Historically, PET response data are limited in the setting of salvage therapy for high- 
risk patients with DLBCL. Based on the available studies, we believe the PET-negative CR rate following 
2 cycles of salvage to be between 25% and 50% among overall responders in this high-risk group of 
patients [CR/(CR+PR)= 25-50%].[8, 19, 20] We hypothesize that if we can improve the PET- CR rate 
with intensive consolidation therapy and thus achieve a PET-negative response prior to ASCT, we will 
improve long-term outcomes in this group of patients. The ability of tailored therapy for PET+ patients to 
improve long-term transplantation-related outcomes has been validated in relapsed Hodgkin Lymphoma. 
[21] 
 
1.4 Ofatumumab 
 
Ofatumumab is a type I, human IgG1k antibody that binds to a novel epitope of CD20 that encompasses 
the small extracellular loop and the N-terminal region of the second large extracellular loop.[22] It binds 
to a different epitope from rituximab and because of the avidity and proximity of CD20 binding, it may lead 
to better complemet-dependent cytotoxicity (CDC).[22, 23] Although the mode of action of the two mAbs 
is similar, nonclinical data indicate that ofatumumab may have a greater potential for effector activity, 
particularly on tumor cells expressing low levels of CD20. Another potential advantage is the predicted 
low level of immunogenicity for a human anti-human antibody (HAHA) response to ofatumumab in 
comparison to the human anti-chimeric antibody (HACA) response to rituximab. An in vitro human tissue 
cross-reactivity study has confirmed that ofatumumab binding is restricted to B cells within the peripheral 
blood circulation and human lymphoid tissues, suggesting there is little likelihood of non- 
pharmacologically mediated effects.[24] 
a 
b 
p=NS 
p=0.04 
Figure 1: Event-free (a) and overall (b) survival among 43 patients with DLBCL who 
underwent  autologous  stem  cell  transplantation  per  protocol. 
Reproduced  from 
Damon et al [10] 


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1.4.1 Safety 
 
1.4.1.1 
Preclinical Studies 
Intravenous (IV) administration to monkeys for up to 7 months profoundly decreased circulating B cells 
and resulted in moderate germinal center and follicular atrophy in the lymph nodes, Peyer’s patches and 
spleen. Following clearance of ofatumumab, repletion of B cell counts and a reversal of the tissue 
changes noted during the study were observed. There were no other ofatumumab-related systemic 
effects (including effects on the delayed type hypersensitivity response) or histopathological changes in 
monkeys following chronic exposure to ofatumumab. However, a minor reduction in the magnitude of the 
immunoglobulin G (IgG) response to the keyhole limpet haemocyanin (KLH) antigen was noted in 
monkeys dosed at 20 and 100 mg/kg. 
 
There were 5 unscheduled deaths in the intravenous 7-month repeat dose study. Three out of 42 
monkeys succumbed to a probable C. jejuni infection; a common yet problematic fecal-oral transmitted 
pathogen in monkeys. This infection was not considered to be ofatumumab treatment-related and no 
increase in susceptibility to infection has been reported in the clinical studies. Haemolytic anaemia 
occurred in 2 out of 42 monkeys in the 7-month study. Both of these monkeys had a positive direct 
Coombs’ test indicative of the presence of anti-drug antibodies (ADAs). It is most likely that the hemolytic 
anemia was due to a strong ADA response to ofatumumab, which induced immune complex formation. 
Binding of immune complexes to the surface of the red blood cells is thought to have resulted in 
sequestration of the coated red cells in the spleen causing the hemolytic anemia. ADAs have been 
detected in several monkey toxicity studies following both IV and SC administration. However,  no 
toxicities directly associated with the ADAs have been reported and an ADA response in monkeys is not 
considered indicative of an ADA response in humans.[25] 
 
No maternal toxicity, adverse effects on embryofetal development or teratogenicity occurred  in  the 
monkey embryofetal development study at doses up to 100 mg/kg. The effect on human pregnancy is 
unknown. Precautions will be undertaken to avoid pregnancy and adequate contraception will be used 
while using ofatumumab. 
 
 
1.4.1.2 
Clinical Studies in Humans 
Over 1000 patients have been exposed to ofatumumab in hematologic malignancy clinical trials. Infusion 
reactions in the IV program are common adverse events (AEs) that are generally mild to moderate in 
severity, and have been mitigated by premedication and slower IV administration. Severe infusion 
reactions have been reported, and have occasionally led to temporary interruption or withdrawal of 
ofatumumab. 
 
Infectious events including lower respiratory tract infections and cytopenias that include neutropenia, 
anemia, and thrombocytopenia have been observed in oncology trials with ofatumumab, but these events 
are commonly reported with the diseases under study and/or other concomitant therapies. Neutropenia 
and serious infections have also been reported in RA studies, but these generally occurred at a similar 
frequency between the ofatumumab and placebo groups. 
 
A total of 59% (48/81) of patients had infusion-related reactions after the start of and up to 24 hours after 
any of the 8 ofatumumab infusions. Investigators considered infusion reactions to be drug-related in 44% 
(36/81) of patients. Infusion reactions primarily occurred during Infusion 1 (40%) and Infusion 2 (22%), 
and decreased with subsequent infusions. The most common infusion-related reactions, regardless of 
causality, were rash (10%), anaphylactoid events (9%), hypersensitivity (7%), edema (7%), anorexia 
(6%), nausea (6%), and cardiac events (6%). Infusion-related reactions were predominantly (96%) Grade 
1-2 in severity. Four subjects (5%) experienced infusion-related reactions ≥ Grade 3 in severity (2 
subjects anaphylactoid events, 1 subject bradycardia and convulsion 1 subject facial edema,  rash, 
nausea, and altered taste). All subjects recovered.[24] 


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In study GEN415 [26], a total of 81 subjects diagnosed with DLBCL were treated with 8 weekly infusions 
of ofatumumab (1st dose: 300 mg; 2nd – 8th dose: 1000 mg). All subjects received oral acetaminophen 
and IV antihistamine prior to each infusion and IV glucocorticoid prior to the first and second infusions. 
The protocol defined AE reporting period was from the first infusion (Visit 2/Week 0) to Visit 18 (Month 24 
of follow-up) or time of withdrawal (treatment and follow-up). SAEs were reported through Month 60 
(treatment, follow-up and extended follow-up). The safety cut-off for the interim safety analysis was 28 
Feb 2010. 
 
Of all 81 subjects, 78 (96%) experienced AEs during treatment and follow-up. The most commonly 
reported AEs are shown below. The most common AEs experienced overall were diarrhea (14 subjects, 
17%), fatigue (12 subjects, 15%), edema, peripheral (each 12 subjects, 15%), neutropenia (11 subjects, 
14%), abdominal pain, constipation, nausea (each 10 subjects, 12%), pyrexia, anemia, leukopenia (each 
9 subjects, 11%), and dyspnea, anorexia (each 8 subjects, 10%). 
 
AEs experienced by Greater than or equal to 10% of DLBCL 
 
 
 
1.4.1.3 
Pharmacokinetics, Product Metabolism, and Pharmacodynamics in Humans 
Pharmacokinetic data are currently available from four completed studies (Study 001, Study 402, Study 
403, and Study 148), three concluded studies (Study 405, Study 407, and Study GEN414/OMS115102 
[48-week interim analysis completed]), and four ongoing studies (Study 406, Study 409, Study 
GEN410/OFA110635 [completed to 24 weeks], and Study OFA110867 [Day 169 interim analysis 
completed]). Ofatumumab was administered by IV infusion in all studies except Study OFA110867, in 
which it was given by SC injection. 
 
Measurable concentrations of ofatumumab were detected in all actively treated subjects, except for some 
subjects who received low doses in Study OFA110867. After repeated IV administration, clearance and 
volume of distribution values were low, and half-life values were long for ofatumumab, as seen with other 
monoclonal antibodies. Statistically significant increases in AUC, Cmax, and t½ values and decreases in 
CL values were found between the first and the last infusion. These findings are likely due to the rapid 
and sustained depletion of CD20+ B cells after first infusion, leaving a reduced number of B cells 
available for the antibody to bind at the following infusions. Subcutaneous administration of a single dose 
of ofatumumab ≥30 mg in subjects with RA similarly resulted in rapid and sustained B-cell depletion. 
 
1.4.2   Efficacy 
 
1.4.2.1 Follicular Lymphoma 
As of 21 December 2010, efficacy results are available from one completed study (Study Hx-CD20-001) 
and 2 concluded studies in Follicular Lymphoma (FL); Study Hx-CD20-405 and Study Hx-CD20-409 [24]. 


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In Study Hx-CD20-001 (N=40), overall response (OR) in evaluable subjects with FL in all ofatumumab 
dose groups was 41% (300 mg, n=10: 63%; 500 mg, n=10: 33%; 700 mg, n=10: 20%; and 1000 mg, 
n=10: 50%) and included 4 (10%) subjects with complete response (CR), 3 (8%) subjects with complete 
response unconfirmed (CRu), and 8 (20%) subjects with partial response (PR). A total of 19 (48%) 
subjects had stable disease (SD), and 3 subjects had progressive disease (PD). The median time to 
progression (TTP) for all subjects was 8.8 months and the median duration of response was 29.9 months. 
The median time to next FL therapy was not reached during the study. 
 
In Study Hx-CD20-405, 116 subjects were treated with two dose levels (500 mg, n=30; 1000 mg, n=86) of 
single-agent ofatumumab. The overall response rate (ORR) in the total population was 11%. This group 
of subjects was highly refractory with 65% refractory to their last chemotherapy. Subjects in the study had 
previously received a median of 4 prior treatment regimens. The 1000 mg dose group (n=86) 
demonstrated an ORR of 10% (1 CR, 8 PR). In addition, 50% of subjects in the 1000 mg treatment arm 
had SD. The ORR among subjects in both treatment arms who were refractory to prior rituximab 
monotherapy (n=27) was 22%. The ORR rate in subjects refractory to rituximab in combination with 
chemotherapy was 7%, and the ORR among subjects refractory to rituximab maintenance was 9%. The 
median duration of response was 6 months, and the median progression free survival (PFS) for all 
subjects was 6 months. 
 
In Study Hx-CD20-409 (N=58), subjects with previously untreated FL were randomized to two dose levels 
of ofatumumab in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone): 
300 mg of ofatumumab (cycle 1) followed by 500 or 1000 mg of ofatumumab (cycles 2-6), in combination 
with CHOP, every 3 weeks for 6 cycles. Results demonstrated an ORR of 90%, CR 24%, and CRu 45% 
in the 500 mg group (n=29). In subjects treated with 1000 mg of ofatumumab (n=29), the ORR was 100% 
including 38% CR and 17% CRu. Two subjects had SD and 1 subject had PD. 
 
1.4.1.2    Diffuse large B-cell lymphoma 
Cilessen et al demonstrated that DLBCL cell lines and rituximab-resistant DLBCL cells from 10 patients 
were effectively killed by ofatumumab. [27] As of 21 December 2010, efficacy results are available from 1 
conculded study in relapsed Diffuse Large B-Cell Lymphoma (DLBCL) (GEN415/OMB111776). In study 
GEN415 [26], patients (n=81) with relapsed DLBCL, ineligible for transplant or relapsed after autologous 
transplant were treated with 300mg, followed by seven weekly 1000mg infusions of ofatumumab as single 
agent. Notably, the median number of prior therapies in that study was 3 and 96% of the patients had 
received prior treatment with rituximab. The ORR for the single agent was 11% (3 CR and 6 PR). [26] 
 
1.5 Study Rationale and Selection of Primary Endpoint 
Patients with relapsed DLBCL who are refractory to or relapse within 12 months of first-line rituximab- 
based therapy, have poor outcomes with conventional approaches to autologous stem cell transplantation 
as detailed above. We hypothesize that the intensive mobilization strategy developed at our institution 
can overcome some of the obstacles to successful ASCT by both eliminating residual disease following 
salvage therapy and by facilitating stem cell collection. Even though there is clinical experience in the 
cooperative group setting with intensive pre-ASCT mobilization, it has never been prospectively validated 
in DLBCL and concerns exist as to its ability to improve outcomes with ASCT in this high-risk, and heavily 
pretreated group of patients. Furthermore, most patients in our registry treated with intensive mobilization 
were rituximab-naïve and the findings may not translate in the rituximab-refractory population. We also 
believe that ofatumumab, a novel monoclonal antibody against a distinct CD20 epitope may in fact 
overcome rituximab resistance in DLBCL patients and through more effective CDC may eliminate minimal 
residual disease in the patient and contaminating tumor cells in the stem cell graft. 
 
We thus propose a pilot phase II study that will incorporate ofatumumab instead of rituximab in 
combination with etoposide and cytarabine (OVA) as an intensive mobilization regimen in high-risk 
patients with DLBCL undergoing ASCT. We have chosen our primary endpoint, mobilization-adjusted 
PET negative CR rate, as a criterion for maximum benefit prior to ASCT, i.e. improving mobilization rates 
compared to traditional mobilization and increasing the depth of response.  This is consistent with the 
primary endpoint of the CORAL study, i.e. mobilization-adjusted response rate.   If our approach is 


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successful, we would plan to validate this strategy in a multi-institution / cooperative group setting in this 
patient population. 
 
 
2 Study Objectives 
2.1 
Primary Objective: To demonstrate the ability of Ofatumumab in combination with etoposide 
and cytarabine to mobilize peripheral blood stem cells and lead to a high complete metabolic response 
rate prior to autologous stem cell transplantation in rituximab pre-treated patients with high-risk 
relapsed or refractory DLBCL. 
 
2.2 
Secondary Objectives: 
2.2.1 To evaluate stem cell engraftment following successful mobilization. 
2.2.2 To determine PFS following treatment with Ofatumumab in combination with etoposide and high- 
dose ara-C (OVA) and subsequent autologous stem cell transplantation. 
2.2.3 To measure the effect of OVA on other clinically meaningful endpoints. 
2.2.4 To measure the FDG-PET conversion rate from PR to CR following OVA and its association with 
clinical outcomes. 
2.2.5 To examine potential relationships between Ofatumumab concentration and clinical outcomes. 
2.2.6 To study the safety and tolerability of OVA. 
2.2.7 To store tumor tissue for future molecular subtyping. 
2.2.8 To evaluate minimal-residual disease testing in the setting of transplantation. 
 
 
3 Study Design 
3.1 General Design 
This is a single-institution, single-arm, prospective phase II study. Patients with high-risk DLBCL (defined 
as either achieving less than CR to initial rituximab-containing therapy or relapsing within 12 months of 
initial therapy) will be enrolled on this study and will undergo staging prior to receiving intensive 
mobilization with ofatumumab, etoposide, and high-dose ara-C (OVA). Following successful stem cell 
collection, patients will proceed to standard autologous transplantation with cyclophosphamide, BCNU, 
and etoposide (CBV) preparative regimen. Response evaluation will occur after salvage  therapy, 
following intensive mobilization therapy (d42), at day +90 after ASCT, and at 6, 12 and 24 months 
thereafter. Event-free, progression-free, and overall survival will also be assessed until 48 months. The 
primary study endpoint is mobilization-adjusted complete metabolic response rate (maCR) following OVA. 
Subjects who are not chemosensitive to salvage therapy (i.e. do not achieve a PR or CR) will be re- 
evaluated after an additional salvage regimen. If they are still not chemosensitive at this point, they will 
be withdrawn from the study and replaced. 
 
3.2 Primary Study Endpoints 
 
To demonstrate the ability of OVA to both: 
i) mobilize at least 2 x10^6 CD34+cells/Kg of actual body weight peripheral blood stem cells, and 
ii) result in a metabolic CR on day 42 assessment 
 
3.3 Secondary Study Endpoints 
3.3.1 
Estimate additional mobilization parameters: Percent of patients collecting ≥2, ≥5 and ≥10 x10^6 
CD34+cells/Kg with one collection; median # collections to achieve ≥2, ≥5 and ≥10 x10^6 CD34+cells/Kg; 
Time to neutrophil and platelet engraftment following ASCT. 
3.3.2 To determine PFS following treatment with Ofatumumab in combination with etoposide and high- 
dose ara-C (OVA) and subsequent autologous stem cell transplantation. 
3.3.3 To measure the effect of OVA on other clinically meaningful endpoints including OS, time to 
progression or relapse (TTP), EFS, CR/PR proportion at day +90. 


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3.3.4 To measure the FDG-PET conversion rate from PR to CR following OVA and correlate post-OVA 
PET results with PFS, TTP, OS. 
3.3.5 To examine potential relationships between Ofatumumab concentration at selected time points and 
PFS, TTP, OS. 
3.3.6 To study the safety and tolerability of OVA including: infusion-related reactions, B-cell number, 
hypogammaglobulinemia, and long-term hematologic toxicity. 
3.3.7 To store tumor tissue for future molecular subtyping. 
3.3.8 To evaluate minimal-residual disease testing in the setting of transplantation. 
 
 
 


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4 Subject Selection and Withdrawal 
4.1 Inclusion Criteria 
Patients fulfilling ALL of the following criteria are eligible for entry to the study: 
 
4.1.1 Diagnosis of refractory or relapsed biopsy-proven CD20+ diffuse large B-cell lymphoma or primary 
mediastinal B-cell lymphoma. 
 
4.1.2 Age 18 years or older 
 
4.1.3 Refractory to or relapse following a rituximab/anthracycline first-line regimen 
 
4.1.4 High-risk disease as defined by one of the following: 
• 
First relapse after CR within 12 months of initiation of front-line therapy 
• 
Less than CR to front-line therapy 
• 
sAAIPI of 2 or higher at the time of relapse (see attachment 14.2) 
 
4.1.5 Receipt of no more than three prior chemotherapy regimens. Monoclonal antibody therapy alone 
and involved field radiotherapy are not included in this number. Prior use of ofatumumab is allowed if 
there has been no disease progression following that therapy (i.e. ofatumumab-based salvage regimens 
are allowed) 
 
4.1.6 ECOG performance status ≤ 2. 
 
4.1.7 Patient must be consented to the study prior to salvage assessment 
 
Eligibility to proceed to OVA 
a. 
Chemosensitive disease as defined by at least a partial response to salvage therapy by 
PET/CT criteria. 
b. 
Bone marrow with less than 15% lymphoma cells following salvage therapy. No evidence 
of myelodysplasia. 
c. 
Patients must have adequate organ function with serum creatinine <2.0 mg/dL, total 
bilirubin ≤2X ULN, and AST ≤3X ULN. 
d. 
Neutrophils >1,000/μL and platelets >100,000/μL prior to day 0 
e. 
No active uncontrolled infection. 
 
 
4.2 Exclusion Criteria 
Patients fulfilling ANY of the following criteria are NOT eligible for entry to the study: 
 
4.2.1 Presence of disease transformation from a previously diagnosed low-grade lymphoma. 
 
4.2.2 Progression following prior ofatumumab-based therapy. 
 
4.2.3 Active central nervous system or meningeal involvement by lymphoma. Patients with a history of 
CNS or meningeal involvement must be in a documented remission by CSF evaluation and contrast MRI 
imaging for at least 3 months prior to study entry. 
 
4.2.4 Evidence of myelodysplasia on any bone marrow biopsy. 
 
4.2.5 Treatment with any known non-marketed drug substance or experimental therapy within 5 terminal 
half-lives or 4 weeks prior to enrollment, whichever is longer, or currently participating in any other 
interventional clinical study. 


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4.2.6 Other past or current malignancy. Subjects who have been free of malignancy for at least 3 years, 
or have a history of completely resected non-melanoma skin cancer, or successfully treated in situ 
carcinoma are eligible. 
 
4.2.7 Chronic or current infectious disease requiring systemic antibiotics, antifungal, or antiviral treatment 
such as, but not limited to, chronic renal infection, chronic chest infection with bronchiectasis, tuberculosis 
and active Hepatitis C. 
 
4.2.8 History of significant cerebrovascular disease in the past 6 months or ongoing event with active 
symptoms or sequelae. 
4.2.9 Known HIV infection. 
4.2.10 Clinically significant cardiac disease including unstable angina, acute myocardial infarction within 
six months prior to randomization, congestive heart failure (NYHA III-IV), and arrhythmia unless controlled 
by therapy, with the exception of extra systoles or minor conduction abnormalities. 
4.2.11 Significant concurrent, uncontrolled medical condition including, but not limited to, renal, hepatic, 
gastrointestinal, endocrine, pulmonary, neurological, cerebral or psychiatric disease which in the opinion 
of the investigator may represent a risk for the patient. 
4.2.12 Positive serology for Hepatitis B (HB) defined as a positive test for HbsAg and a detectable HBV 
DNA viral load. If negative for HBsAg but HBcAb positive (regardless of HBsAb status), a HBV DNA test 
will be performed and if positive the subject will be excluded. If HBV DNA is negative, subject may be 
included but must undergo at least every 2-month HBV DNA PCR testing from the start of treatment 
during the treatment course. Prophylactic antiviral therapy may be initiated at the discretion of the 
investigator. 
 
4.2.13 Positive serology for hepatitis C (HC) defined as a positive test for HCAb, in which case reflexively 
perform a HCV PCR to confirm the result. 
4.2.14 Pregnant or lactating women. Women of childbearing potential must have a negative pregnancy 
test at screening. 
4.2.15 Women of childbearing potential, including women whose last menstrual period was less than one 
year prior to screening, unable or unwilling to use adequate contraception from study start to one year 
after the last dose of protocol therapy. Adequate contraception is defined as hormonal birth control, 
intrauterine device, double barrier method or total abstinence. 
4.2.16 Male subjects unable or unwilling to use adequate contraception methods from study start to one 
year after the last dose of protocol therapy. 
 
4.2.17 Subjects who have received live virus vaccination within the 4 weeks prior to planned initiation of 
study treatment. 
 
4.3 Subject Recruitment and Screening 
Patients will be identified by the principal investigator and sub-investigators in the malignant 
hematology/BMT clinic at UCSF and be registered on this study. Subjects can enter the study any time 
after a documented relapse. 
 
4.4 Early Withdrawal of Subjects 
UCSF retains the right to terminate the study at any time. 
UCSF retains the right to terminate an individual study patient’s participation in the study due to the 
following: 
1. Noncompliance with study procedures 
2. Concomitant use of any study drug or procedure without prior approval from the Principal Investigator 
3. Unanticipated adverse medical experiences in this or other studies indicating a potential health hazard 
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4. Study patient’s withdrawal from protocol 
5. No evidence of response (PR or CR) to salvage therapy.  Subjects will be allowed to proceed to a 
different salvage regimen and will be re-evaluated following this. If still without a PR or CR, they will be 
withdrawn for this reason and replaced. 
 
4.5 Data Collection and Follow-up for Withdrawn Subjects 
If a subject withdraws consent to participate in the study prior to day 0 of OVA, he or she will be replaced. 
If a subject withdraws consent on day 0 of OVA or later, attempts will be made to obtain permission to 
record at least survival data up to the protocol-described end of subject follow-up period qt 24 months. 
For the latter subjects, we will continue to record disease-specific data, adhering to the protocol as much 
as possible. This data will be obtained (with the subject’s permission) from local treating physicians if the 
subject is no longer followed at UCSF. 
 
 
5   On Study Evaluation 
5.1 Registration 
 
5.1.1 
History 
including 
demographics, 
detailed 
description 
of 
prior 
anti-lymphoma 
therapy, 
complications associated with therapy (i.e. infections, liver toxicity) and any ongoing medical 
problems. Complete medication list. Complete physical examination including vital signs and 
ECOG performance status. 
 
5.1.2 
Laboratory studies: 
a. 
Hematology: CBC, differential, platelets. 
b. 
Chemistries:  Bilirubin, AST, ALT, alkaline phosphatase, creatinine, electrolytes, LDH, 
glucose, albumin, total protein. 
c. 
PT/PTT 
d. 
Serum Pregnancy Testing 
e. 
Serologies: HBsAb, HBcAb, HbsAg, HCAb. 
f. 
Subjects who are HBcAb positive must undergo HBV DNA PCR testing. 
 
5.1.3 
20 unstained slides or tissue block from the time of relapse (preferred) or initial diagnosis, if either 
available, will be acquired. Ten slides will be used for minimal-residual disease (MRD) test 
calibration and the rest will be stored for future DLBCL subtyping. 
 
5.1.4 
10 cc of peripheral blood for baseline MRD testing 
 
5.2 Salvage Response Assessment 
TO BE COMPLETED AFTER SALVAGE THERAPY 
Salvage therapy is standard treatment for relapsed diffuse large cell lymphoma patients. These regimens 
can consist of different agents, such as R-ICE, R-DHAP, R-Gem/Ox, and others. Salvage therapy is done 
outside of this protocol; however, a response to salvage therapy is required prior to proceeding with OVA 
therapy, per eligibility criteria. 
 
5.2.1 
Interim history, concomitant medications, and complete physical examination including vital signs. 
 
5.2.2 
Laboratory studies: 
a. 
Hematology: CBC, differential, platelets. 
b. 
Chemistries:  Bilirubin, AST, ALT, alkaline phosphatase, creatinine, electrolytes, LDH, 
glucose, albumin, total protein. 


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5.2.3 
Bone marrow aspirate and biopsy within 8 weeks of the end of salvage therapy, and before the 
start of OVA. This should include morphology and standard cytogenetics. Required to proceed to 
OVA. 
 
5.2.4 
Lumbar puncture with cell count, differential and protein within 8 weeks IF patient has had prior 
CNS involvement or has suspicion of CNS disease. 
 
5.2.5 
FDG-PET and CT Neck, Chest, Abdomen, Pelvis with PO/IV contrast or PET/CT within 4 weeks 
from initiation of last cycle of salvage therapy. 
 
5.2.6 
12-lead EKG 
 
5.2.7 
Cardiac ejection fraction by Echo or MUGA within 8 weeks of salvage response assessment. 
Required to proceed to transplant, but not to OVA. 
 
5.2.8 
Pulmonary  function  testing  with  DLCO  within  8  weeks  of  salvage  response  assessment. 
Required to proceed to transplant, but not to OVA. 
 
5.2.9 
10cc of peripheral blood for MRD testing. Sendout. 
 
OVA STEP 
 
5.3 
Day 0 of OVA 
OVA therapy will begin within 2 weeks following Salvage Response Assessment. 
 
5.3.1 
Interim history, concomitant medications, and complete physical examination including vital signs. 
 
5.3.2 
Laboratory studies: 
a. 
Hematology: CBC, differential, platelets. 
b. 
Chemistries: Bilirubin, AST, ALT, alkaline phosphatase, creatinine, electrolytes, calculated 
creatinine clearance, glucose, albumin, uric acid, LDH. PT and Fibrinogen. Quantitative IgG, IgA, 
IgM. 
c. 
Peripheral blood CD19+ B-cell determination by flow cytometry. 
 
5.3.3 
Ofatumumab administration (see section 6.1.1) 
 
5.4 All other days of OVA 
 
5.4.1 
Laboratory studies until completion of apheresis: 
Daily 
CBC, differential, platelets, electrolytes, creatinine. 
Twice-weekly 
Bilirubin, alkaline phosphatase, AST, ALT. 
 
5.4.2 
Etoposide and Cytarabine administration on days 1-4 (see sections 6.1.2 – 6.1.4) 
 
5.4.3 
Ofatumumab administration on days 7,14,21 (see section 6.1.1) 
 
5.4.4 
GCSF administration daily, starting on day 14 and continued until stem cell collection (see section 
6.1.5) 
 
5.4.5 
Ofatumumab pharmacokinetic evaluation within 24 hours after end of infusion on day 21 
 
5.4.6 
4 PBMC cryovials will be stored at the time of first leukapheresis for future studies.   4 cc of 
apheresis product on day 21 or later will be used for MRD testing. 


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5.5 Day 42 Evaluation (+/- 4 days) 
 
5.5.1 
History and complete physical examination including vital signs and ECOG performance status. 
 
5.5.2 
Laboratory studies: 
a. 
Hematology: CBC, differential, platelets. 
b. 
Chemistries:  Bilirubin, AST, ALT, alkaline phosphatase, creatinine, electrolytes, LDH, 
glucose, albumin, and total protein, and quantitative IgG, IgA, IgM. 
c. 
Peripheral blood CD19+ B-cell determination by flow cytometry. 
d. 
Ofatumumab pharmacokinetic evaluation 
e. 
Subjects who are baseline HBcAb positive must undergo HBV DNA PCR testing. 
 
5.5.3 
Bone marrow aspirate and biopsy IF positive for lymphoma at baseline. This should include 
morphology and standard cytogenetics. 
 
5.5.4 
FDG-PET and CT Neck, Chest, Abdomen, Pelvis with PO/IV contrast or PET/CT. 
 
5.5.5 
10 cc of peripheral blood for MRD testing. 
 
5.6 CBV Administration 
 
Laboratory studies: 
Daily 
CBC, differential, platelets, electrolytes, glucose, creatinine. 
Twice-weekly 
Bilirubin, alkaline phosphatase, AST, ALT. 
 
TREATMENT PER INSTITUTIONAL STANDARD OF CARE.  See Section 14.3 for UCSF recommended 
Standard of Care. 
 
5.7 Day +30’ and +60’ Evaluation (+/- 4 days) 
 
5.7.1 
History and complete physical examination including vital signs and ECOG performance status. 
 
5.7.2 
Laboratory studies: 
a. 
Hematology: CBC, differential, platelets. 
b. 
Chemistries:  Bilirubin, AST, ALT, alkaline phosphatase, creatinine, electrolytes, LDH, 
glucose, albumin, and total protein. 
c. 
Subjects who are baseline HBcAb positive must undergo HBV DNA PCR testing. 
 
5.8 Day +90’ Evaluation (+/- 4 days) 
 
5.8.1 
History and complete physical examination including vital signs and ECOG performance status. 
 
5.8.2 
Laboratory studies: 
a. 
Hematology: CBC, differential, platelets. 
b. 
Chemisties:  Bilirubin,  AST,  ALT,  alkaline  phosphatase,  creatinine,  electrolytes,  LDH, 
glucose, albumin, and total protein, and quantitative IgG, IgA, IgM. 
c. 
Peripheral blood CD19+ B-cell determination by flow cytometry. 
d. 
Ofatumumab pharmacokinetic evaluation 
e. 
Subjects who are baseline HBcAb positive must undergo HBV DNA PCR testing. 
 
5.8.3 
Bone marrow aspirate and biopsy within 2 weeks IF positive for lymphoma at baseline. This 
should include morphology and standard cytogenetics. 
 
5.8.4 
FDG-PET and CT Neck, Chest, Abdomen, Pelvis with PO/IV contrast or PET/CT within 2 weeks. 


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5.8.5 
Pulmonary Function Testing with DLCO within 2 weeks. 
 
5.8.6 
10 cc of peripheral blood for MRD testing. 
 
5.9 Month 6, 12, and 24 Evaluation (+/- 4 weeks) 
 
5.9.1 
History and complete physical examination including vital signs and ECOG performance status. 
 
5.9.2 
Laboratory studies: 
a. 
Hematology: CBC, differential, platelets. 
b. 
Chemistries:  Bilirubin, AST, ALT, alkaline phosphatase, creatinine, electrolytes, LDH, 
glucose, albumin, and total protein, and quantitative IgG, IgA, IgM. 
c. 
Peripheral blood CD19+ B-cell determination by flow cytometry. 
d. 
Ofatumumab pharmacokinetic evaluation at 6 months or time of relapse, whichever occurs 
earlier. 
e. 
Subjects who are baseline HBcAb positive must undergo HBV DNA PCR testing at 
month 6. 
 
5.9.3 
FDG-PET IF positive on day+90’ will be repeated at month 6. 
 
5.9.4 
CT Neck, Chest, Abdomen, Pelvis with PO/IV contrast or PET/CT. 
 
5.9.5 
10 cc of peripheral blood for MRD testing. 
 
5.10 At Time of Suspected Relapse/Progression 
 
5.10.1 History and complete physical examination including vital signs and ECOG performance status. 
 
5.10.2 Laboratory studies: 
a. 
Hematology: CBC, differential, platelets. 
b. 
Chemistries:  Bilirubin, AST, ALT, alkaline phosphatase, creatinine, electrolytes, LDH, 
glucose, albumin, and total protein. 
 
5.10.3 FDG-PET and CT Neck, Chest, Abdomen, Pelvis with PO/IV contrast or PET/CT. 
 
5.10.4 Bone marrow aspirate and biopsy IF indicated. This should include morphology and standard 
cytogenetics. 
 
5.10.5 Tumor tissue (20 unstained slides or tissue block) from biopsy confirming relapse, if feasible, will 
be acquired and stored for future testing. 
 
5.10.6 10 cc of peripheral blood for MRD testing. 
 
 
6 Follow-up Phase 
 
I. 
If a subject has progressive disease prior to day 0 of OVA, he/she will be replaced. 
II. 
If patients progress between day 0 of OVA and day -6 of CBV, and the intent is to proceed to an 
autologous stem cell transplant in the future, they will be followed at regular intervals starting on 
day +90 as specified in the protocol for post-transplant follow-up (Sections 5.8,5.9,5.10). 
III. 
If patients progress between day 0 of OVA and day -6 of CBV and the intent is not to proceed 
with transplant or if they progress any time after day -6 of CBV, they will be followed for survival 
only every 3 months for up to 2 years or death, whichever occurs sooner. 


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IV. 
Patients who do not progress in the first 24 months, will be followed for disease status and 
survival every 6 months, until 5 years. 
 
 
7 Treatment Regimen 
7.1 Intensive Mobilization Regimen (OVA) 
 
7.1.1 Ofatumumab Administration at 1000mg IV on days 0,7,14, and 21. 
 
Pre-medication before each ofatumumab infusion must be given within 30 minutes to 2 hours 
prior to the treatment: 
Table 1   Pre-medication Requirements prior to Ofatumumab Infusions 
Infusion 
# 
Acetaminophen 
(po) 
or equivalent 
Antihistamine (iv 
or po) 
diphenhydramine 
or equivalent 
Glucocorticoid 
(iv) 
prednisolone 
or equivalent 
1st 
1000 mg 
50 mg 
50 mg 
2nd 
1000 mg 
50 mg 
50 mg 
3rd 
and 
4th 
1000 mg 
50 mg 
0 – 50 mg1 
If the 2nd infusion has been completed without the subject experiencing any grade = 3 AEs, pre- 
medication with glucocorticoid may be reduced or omitted before the 3rd or 4th infusion at the 
discretion of the investigator. 
 
First Infusion of 1000 mg Ofatumumab, day 0 
The initial rate of the first infusion of 1000 mg ofatumumab (1 mg/mL) should be 12 mL/h. If no 
infusion reactions occur the infusion rate should be increased every 30 minutes, to a maximum of 
400 mL/h, according to Table 2. If this schedule is followed, the infusion duration will be 
approximately 4.6 hours. 
 
Table 2: 
Infusion rate at 1st ofatumumab infusion (1000 mg) 
 
Time 
mL/hour 
0 – 30 minutes 
12 
31 – 60 minutes 
25 
61 – 90 minutes 
50 
91 – 120 minutes 
100 
121 - 150 minutes 
200 
151 - 180 minutes 
300 
181+ minutes 
400 
 
If an infusion reaction develops, the infusion should be temporarily slowed or interrupted. Upon 
restart, the infusion rate should be half of the infusion rate at the time the infusion was paused. If, 
however, the infusion rate was 12 mL/hour before the pause, the infusion should be restarted at 
12 mL/hour. Thereafter, the infusion rate may be increased according to the judgment of the 
investigator, in the manner described in this section. 
 
 
Subsequent Infusions of 1000 mg Ofatumumab, days 7,14, and 21 
If the previous infusion has been completed without grade ≥ 3 infusion-associated AEs, the 
subsequent infusion of the 1000 mg of ofatumumab (1 mg/mL) can start at a rate of 25 mL/hour 


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and should be doubled every 30 minutes up to a maximum of 400 mL/h, according to Table 3. 
Duration of the infusion will be approximately 4 hours if this schedule is followed. If the previous 
infusion has been completed with grade ≥ 3 infusion-associated AEs, the subsequent infusion 
should start at a rate of 12 mL/hour according to Table 2. 
 
Table 3: 
Infusion rate at subsequent ofatumumab infusions 
 
Time 
mL/hour 
0 – 30 minutes 
25 
31 – 60 minutes 
50 
61 – 90 minutes 
100 
91 – 120 minutes 
200 
121+ minutes 
400 
 
During infusion the patient should be monitored closely and appropriate measurements should be 
performed whenever judged necessary. 
 
7.1.2 
Etoposide 10 mg/kg IV continuous infusion over 24 hrs for 4 days (total course dose 40 
mg/kg). 
 
Dose should be based on corrected weight, calculated as follows: Ideal + 25% of the difference 
between actual and ideal weight. If actual is less than ideal weight, use actual weight. 
 
Etoposide infusion should be mixed in normal saline at a concentration of 0.4-0.5 mg/ml. The 
infusion volume will be approximately 1.39 ml/kg/hour and should be rounded to the nearest 500- 
1000 ml and infused through a central venous catheter. 
 
7.1.3 
Cytarabine (ara-C) 2,000 mg/m2 IV over 2 h q 12 h x 8 doses Days 1-4. 
 
Cytarabine dosage should be based on corrected weight, calculated as follows: Ideal weight + 
25% of the difference between actual and ideal weight. If actual weight is less than ideal weight, 
use actual weight. 
 
Begin first cytarabine infusion at the end of first hour of etoposide. Cytarabine doses should be 
mixed in 250 ml of D5W. 
 
7.1.4 
To prevent neurotoxicity from high-dose cytarabine (HDAC), cytarabine doses will be adjusted 
according to renal function. 
 
 
The dose of cytarabine will be reduced to 1000 mg/m2/dose if creatinine is 1.5-1.9 mg/dL 
or if there is an increase from baseline creatinine at start of cytarabine of 0.6-1.1 mg/dL 
(example: baseline creatinine 0.8 mg/dL increase to 1.4 mg/dL (difference of 0.6 mg/dL)), 
decrease cytarabine to 1000 mg/m2/dose. 
 
The dose of cytarabine will be reduced to 100 mg/m2/day by continuous infusion if 
creatinine > 2.0 mg/dL or if there is an increase from baseline > 1.2 mg/dL and 4 or fewer 
cytarabine doses have been administered. The infusion will end at the completion of the 96- 
hour etoposide infusion. If 5 or more cytarabine doses have been administered, then 
discontinue cytarabine. 
 
If cytarabine neurotoxicity develops or is suspected (dysmetria, dysdiadochokinesis, 
truncal/gait ataxia, dysarthria, and/or cerebral/psychiatric abnormalities not explainable by 
other medications), stop cytarabine immediately. If 4 or fewer of 8 planned high-dose 
cytarabine doses have been delivered, cytarabine should be changed to 100 mg/m2/day as 
continuous IV infusion to end at the conclusion of the 96-hour etoposide infusion. If 5 or more 
high-dose cytarabine doses have been delivered, then give no more cytarabine. 


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7.1.5 
Supportive Care Measures: 
 
 
G-CSF 10 mcg/kg (actual body weight) SQ daily beginning day 14 and should be continued 
until the peripheral blood stem cell collection has been completed. Do not skip or dose 
reduce for bone pain. All G-CSF doses should be rounded up to a convenient dose based 
on vial sizes of 300 mcg and 480mcg. 
 
Fluoromethalone 0.1% ophthalmic solution (or equivalent medication) 2 drops qid to each 
eye Days 1-6. 
 
Voriconazole 4 mg/Kg (corrected weight) rounded to the nearest 50 mg will be administered 
PO Q12 hours beginning the day after completion of chemotherapy (Day 6). Dose may be 
modified or omitted due to toxicity and equivalent anti-fungal prophylaxis with fluconazole, 
itraconazole, posaconazole or Liposomal-based amphotericin (1mg/kg) may be used instead. 
 
Prophylaxis against bacterial infections should begin when the ANC is < 500/uL and continue 
until the ANC is > 1000/uL. Moxifloxacin 400 mg daily or an equivalent antibiotic is 
appropriate. 
 
Acyclovir 400 mg PO bid or valcyclovir 500 mg PO qd beginning day 6. Continuing antiviral 
prophylaxis following hospital discharge is recommended. Patients unable to take oral 
medication should receive acyclovir 2 mg/kg IV q12 h. 
 
Trimethoprim/Sulfamethoxazole DS PO bid (or IV equivalent dose) every Saturday and 
Sunday as Pneumocystis carinii prophylaxis. For sulfa allergy, substitute Dapsone 100mg PO 
once every Monday-Wednesday-Friday. If intolerant to dapsone, substitute aerosolized 
Pentamidine 300 mg Q month. 
 
Patients should be hospitalized in private rooms when possible. 
 
Showers are strongly encouraged twice a day during days 1 to 6 to minimize skin toxicity. 
 
Strict low bacteria diet should be used when ANC < 500 cells/uL. 
 
Recommended mouth care: salt and soda swish tid 
 
Transfusions: Institution standards should be followed for blood product support. In lieu of 
standards, packed RBCes should be given to maintain the hemoglobin >8.5 gm/dl or hematocrit 
>25%. Platelet should be transfused to keep the platelet count >10-20 x 109/l.  Blood should be 
filtered and irradiated (3000 cGy). 
 
7.2 PERIPHERAL BLOOD STEM CELL (PBSC) COLLECTION 
 
7.2.1 
Begin collections when the total white blood count exceeds 10,000/µl or when appropriate based 
on peripheral CD34+ cell counts (institutional standard) 
7.2.2 
Aim for a minimum CD34 cell dose of > 2 x 10 x 106/kg (actual body weight) and an optimal 
target CD34 cell dose of > 5 x 106/kg (actual body weight). 
7.2.3 
Stem Cell Collection: Process 18-20 L of whole blood over 3-4 hours according to institutional 
standards. 
7.2.4 
PBSC Processing: The buffy coat is concentrated by centrifugation. Cells are suspended in 
Normosol media with 5% autologous plasma and 10% DMSO to a final cell concentration of 2.5 x 
108/ml. Seventy ml aliquots are placed in polyolefin bags and frozen in a controlled rate freezer. 
Bags are labeled then stored in the liquid phase of a liquid nitrogen freezer. Institutional standard 
for PBSC processing should be followed. 
7.2.5 
Four 2 ml aliquots of PBSC will be frozen in liquid nitrogen for future analysis. 4 mL of PBSC will 
be used for MRD testing, if baseline test was informative. 
7.2.6 
Increased GCSF dosing or plerixafor (Mozobil) supplementation may be utilized after consultation 
with the principal investigator to augment CD34+ cell yield. Use of plerixafor constitutes a failure 
of mobilization with OVA. 
7.2.7 
Failure to Collect Peripheral Blood Stem Cells. Should the minimum number of CD34 cells not 
be reached, remobilization of peripheral blood stem cells or pelvic bone marrow harvest is 
permitted. The study PI needs to be consulted regarding re-mobilization or bone marrow harvest 
and the PI needs to grant permission for this to proceed. 


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7.3 High-Dose Therapy with Stem Cell Rescue (CBV) 
 
Drug administration and supportive care performed per institutional standard. 
 
7.4 Optional Radiotherapy 
Radiation therapy of a single site of residual disease or progression is allowed following OVA before or 
after transplant at the investigator’s discretion. 
 
 
8 Measurement of Effect 
8.1 Definition of Adequate Stem Cell Collection 
Acceptable stem cell collection is defined as a minimum CD34 cell dose of > 2 x 10 x 106/kg 
(actual body weight) and optimal stem cell collection as a CD34 cell dose of > 5 x 106/kg 
(actual body weight). Use of plerixafor or an autologous bone marrow harvest are considered 
mobilization failures. 
 
8.2 Definition of Engraftment 
Neutrophil engraftment is defined as the first day of 3 consecutive days with absolute neutrophil 
count of >500 cells/uL. Platelet engraftment will be defined as the first of three consecutive 
measurements for which the platelet count was > 20,000/uL, and must be at least 24 hours 
following the last platelet transfusion. 
 
8.3 Lymphoma response assessment (revised IWG criteria [12]) 
 
PET or PET/CT scans acquired prior to study entry will be utilized in evaluating the response to 
salvage therapy and the day 42 assessment. Semi-quantitative and qualitative PET analysis will 
be performed at our center using SUV, mediastinal blood pool, and liver uptake. We recommend 
that all PET scans be performed at the same instrument at our institution. 
 
CR: The designation of CR requires the following: 
 
1. Complete disappearance of all detectable clinical evidence of disease and disease-related 
symptoms if present before therapy. 
2. A post-treatment residual mass of any size is permitted as long as it is PET negative. 
3. The spleen and/or liver, if enlarged before therapy on the basis of the physical examination or 
CT scan, should not be palpable on physical examination and should be considered normal size 
by imaging studies, and nodules related to lymphoma should disappear. However, determination 
of splenic involvement is not always reliable because a spleen considered normal in size may still 
contain lymphoma, whereas an enlarged spleen may reflect variations in anatomy, blood volume, 
the use of hematopoietic growth factors, or causes other than lymphoma. 
4. If the bone marrow was involved by lymphoma before treatment, the infiltrate must have 
cleared on repeat bone marrow biopsy. The biopsy sample on which this determination is made 
must be adequate (with a goal of > 20 mm unilateral core). If the sample is indeterminate by 
morphology, it should be negative by immunohistochemistry. A sample that is negative by 
immunohistochemistry but that demonstrates a small population of clonal lymphocytes by flow 
cytometry will be considered a CR. 
 
PR: The designation of PR requires all of the following: 
 
1) 
The post-treatment PET should be positive in at least one previously involved site. 


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2) 
At least a 50% decrease in sum of the product of the diameters (SPD) of up to six of the 
largest dominant nodes or nodal masses. These nodes or masses should be selected according 
to all of the following: they should be clearly measurable in at least 2 perpendicular dimensions; if 
possible they should be from disparate regions of the body; and they should include mediastinal 
and retroperitoneal areas of disease whenever these sites are involved. 
3) 
No increase should be observed in the size of other nodes, liver, or spleen. 
4) 
Splenic and hepatic nodules must regress by ≥ 50% in their SPD or, for single nodules, in 
the greatest transverse diameter. 
5) 
With the exception of splenic and hepatic nodules, involvement of other organs is usually 
assessable and no measurable disease should be present. 
6) 
Bone marrow assessment is irrelevant for determination of a PR if the sample was 
positive before treatment. However, if positive, the cell type should be specified (eg, large-cell 
lymphoma or small neoplastic B cells). Patients who achieve a CR by the above criteria, but who 
have persistent morphologic bone marrow involvement will be considered partial responders. 
When the bone marrow was involved before therapy and a clinical CR was achieved, but with no 
bone marrow assessment after treatment, patients should be considered partial responders. 
7) 
No new sites of disease should be observed. 
 
Stable Disease: Stable disease (SD) is defined as the following: 
1) 
A patient is considered to have SD when he or she fails to attain the criteria needed for a 
CR or PR, but does not fulfill those for progressive disease (see Relapsed Disease [after 
CR]/Progressive Disease [after PR, SD]). 
2) 
The PET should be positive at prior sites of disease with no new areas of involvement on 
the post-treatment CT or PET. 
 
Relapsed Disease (after CR)/Progressive Disease (after PR, SD): 
Lymph nodes should be considered abnormal if the long axis is more than 1.5 cm regardless of 
the short axis. If a lymph node has a long axis of 1.1 to 1.5 cm, it should only be considered 
abnormal if its short axis is more than 1.0. Lymph nodes ≤ 1.0 x ≤ 1.0 cm will not be considered 
as abnormal for relapse or progressive disease. 
1) 
Appearance of any new lesion more than 1.5 cm in any axis during or at the end of 
therapy, even if other lesions are decreasing in size. Increased FDG uptake in a previously 
unaffected site should only be considered relapsed or progressive disease after confirmation with 
other modalities. 
2) 
At least a 50% increase from nadir in the SPD of any previously involved nodes, or in a 
single involved node, or the size of other lesions (eg, splenic or hepatic nodules). To be 
considered progressive disease, a lymph node with a diameter of the short axis of less than 1.0 
cm must increase by ≥ 50% and to a size of 1.5 x 1.5 cm or more than 1.5 cm in the long axis. 
3) 
At least a 50% increase in the longest diameter of any single previously identified node 
more than 1 cm in its short axis. 
4) 
Lesions should be PET positive unless the lesion is too small to be detected with current 
PET systems (< 1.5 cm in its long axis by CT). 
Measurable extranodal disease should be assessed in a manner similar to that for nodal disease. 
For these recommendations, the spleen is considered nodal disease. Disease that is only 
assessable (eg, pleural effusions, bone lesions) will be recorded as present or absent only, 
unless, while an abnormality is still noted by imaging studies or physical examination, it is found 
to be histologically negative. 
 
8.4 Survival-time parameters 
 
 
Overall Survival is defined as the time from day 0 until death as a result of any cause. 
Patients will be censored at the time of last followup. 


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 
PFS is defined as the time from day 0 until lymphoma progression, receipt of anti-lymphoma 
therapy (except for planned post-ASCT radiotherapy), or death as a result of any cause. 
Patients will be censored at the time of last followup. 
 
 
Time to Progression: Time to progression (TTP) is defined as the time from study entry until 
documented lymphoma progression or receipt of anti-lymphoma therapy (except for planned 
post-ASCT radiotherapy) or death due to lymphoma. Patients are to be censored at the time 
of last followup or death due to another cause. 
 
 
Event-Free Survival: Event-free survival (time to treatment failure) is measured from day 0 
to any treatment failure including disease progression, discontinuation of treatment for any 
reason, initiation of new therapy without documented progression, incidence of secondary 
AML or MDS, or death related to treatment. Patients are censored at the time of last followup 
or death unrelated to treatment or disease. 
 
 
9 Safety and Adverse Events 
9.1 Safety Definitions 
 
9.1.1 
Adverse Events: 
Any untoward medical occurrence in a subject or clinical investigation subject, temporally associated with 
the use of a medicinal product, whether or not considered related to the medicinal product. 
Events meeting the definition of an AE include: 
• 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other safety 
assessments e.g., ECGs, radiological scans, vital signs measurements), including those that worsen 
from baseline, and felt to be clinically significant in the medial and scientific judgment of the 
investigator 
• 
Exacerbation of a chronic or intermittent pre-existing condition including either an increase in 
frequency and/or intensity of the condition 
• 
New conditions detected or diagnosed after investigational product administration even though it 
may have been present prior to the start of the study 
• 
Signs, symptoms, or the clinical sequelae of a suspected interaction 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either investigational product 
or a concomitant medication (overdose per se will not be reported as an AE/SAE) 
“Lack of efficacy” or “failure of expected pharmacological action” per se will not be reported as an AE or 
SAE. However, the signs and symptoms and/or clinical sequelae resulting from lack of efficacy will be 
reported if they fulfill the definition of an AE or SAE. 
 
 
 
 
Events that do not meet the definition of an AE include: 
• 
Any clinically significant abnormal laboratory finding or other abnormal safety assessments that is 
associated with the underlying disease, unless judged by the investigator to be more severe than 
expected for the subject’s condition. 
• 
The disease/disorder being studied, or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the subject’s condition 
• 
Medical or surgical procedure (e.g., endoscopy, appendectomy); the condition that leads to the 
procedure is an AE 


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• 
Situations where an untoward medical occurrence did not occur (social and/or convenience 
admission to a hospital) 
• 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or detected at 
the start of the study that do not worsen 
• 
B cell depletion and hypogammaglobulinemia due to ofatumumab treatment 
 
9.1.2 
Grading: AEs and toxicities will be graded using the NCI Common Toxicity Grading Scale 
(Version 4.0; http://ctep.cancer.gov/reporting/ctc.html) included in Appendix 1. AEs that are not included 
in the NCI Common Toxicity Criteria will be graded as follows: 
 
1. Mild (Grade 1) – near the lowest intensity (or within the lower one-third) typically seen with the 
observed sign or symptom 
2. Moderate (Grade 2) – average intensity typically seen with the observed sign or symptom 
3. Severe (Grade 3) – near the highest intensity (or within the top third) typically seen with the observed 
sign or symptom 
4. Life-threatening (Grade 4) – any AE that places the patient, in the view of the investigator, at 
immediate risk of death from the reaction as it occurred. It does not refer to an event that hypothetically 
might have caused death if it were more severe. 
5. Fatal (Grade 5) 
 
 
9.1.3 
Causality: The association or relationship of the AEs to targeted busulfan will be defined 
according to the NCI Common Toxicity Criteria guidelines as follows: 
1. Definite – The AE is clearly related to the study product, e.g., an event that follows a reasonable 
temporal sequence from administration of the drug or in which the drug level has been established in 
body fluids or tissues, that follows a known or expected response pattern to the suspected drug, and that 
is confirmed by improvement on stopping or reducing the dosage of drug 
2. Probable – The AE is likely related to the study product, e.g., an event that follows a reasonable 
temporal sequence from administration of the drug, that follows a known or expected response pattern to 
the suspected drug, that is confirmed by stopping or reducing the dosage of the drug, and that could be 
reasonably explained by the known characteristics of the subject’s clinical state 
3. Possible – The AE may be related to the study product, e.g., an event that follows a reasonable 
temporal sequence from administration of the drug, that follows a known or expected response pattern to 
the suspected drug, but that could readily have been produced by a number of other factors 
4. Unlikely – The AE is doubtfully related to the study product 
5. Unrelated – The AE is clearly not related to the study product 
6. Not applicable – The AE occurred prior to administration of the study product 
7. Unknown – No evaluation for causality can be made 
 
9.1.4 Definition of a SAE 
A serious adverse event is any untoward medical occurrence that, at any dose: 
a. 
Results in death 
b. 
Is life-threatening 
NOTE: The term 'life-threatening' in the definition of 'serious' refers to an event in which the subject 
was at risk of death at the time of the event. It does not refer to an event, which hypothetically might 
have caused death, if it were more severe. 
c. 
Requires hospitalization or prolongation of existing hospitalization 
NOTE: In general, hospitalization signifies that the subject has been detained (usually involving at 
least an overnight stay) at the hospital or emergency ward for observation and/or treatment that 
would not have been appropriate in the physician’s office or out-patient setting. Complications that 
occur during hospitalization are AEs. If a complication prolongs hospitalization or fulfills any other 


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serious criteria, the event is serious. When in doubt as to whether “hospitalization” occurred or was 
necessary, the AE should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from baseline is 
not considered an AE. 
Hospitalizations or procedures performed for the routine purpose of chemotherapy administration will 
not be collected as adverse events and will not be reported as serious adverse events. This would 
include any elective hospitalization for the administration of radiation and/or chemotherapy, or 
hospitalization for the placement of central venous catheters to be used for chemotherapy 
administration. 
d. 
Results in disability/incapacity 
NOTE: The term disability means a substantial disruption of a person’s ability to conduct normal life 
functions. This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental 
trauma (e.g. sprained ankle) which may interfere or prevent everyday life functions but do not 
constitute a substantial disruption. 
e. 
Is a congenital anomaly/birth defect 
f. 
Medical or scientific judgment should be exercised in deciding whether reporting is appropriate in 
other situations, such as important medical events that may not be immediately life threatening or 
result in death or hospitalization but may jeopardize the subject or may require medical or surgical 
intervention to prevent one of the other outcomes listed in the above definition.  These should also 
be considered serious. Examples of such events are invasive or malignant cancers, intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency or drug abuse. 
 
 
9.1.5 
Laboratory and Other Safety Assessment Abnormalities Reported as AEs and SAEs 
• 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other safety 
assessments (e.g., ECGs, radiological scans, vital signs measurements), including those that 
worsen from baseline, and felt to be clinically significant in the medical and scientific judgment of 
the investigator are to be recorded as AEs or SAEs. 
 
• 
All events meeting liver stopping criteria must be recorded as an SAE. 
 
• 
However, any clinically significant safety assessments that are associated with the underlying 
disease, unless judged by the investigator to be more severe than expected for the subject’s 
condition, are not to be reported as AEs or SAEs. 
 
• 
B cell depletion, IgG below LLN, low CD19+ count, and hypogammaglobulinemia due to 
treatment with ofatumumab are not to be reported as AEs or SAEs. 
 
• 
Infusion related AEs may lead to a prolonged infusion time. Overnight stay at the hospital due to 
slow infusion rate is not to be reported as a SAE. 
 
 
9.1.6 
Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as SAEs 
An event which is part of the natural course of the disease under study (i.e., disease progression) does 
not need to be reported as an SAE. However, if the progression of the underlying disease is greater than 
that which would normally be expected for the subject, or if the investigator considers that there was a 
causal relationship between treatment with investigational product or protocol design/procedures and the 
disease progression, then this must be reported as an SAE. 


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9.2 Time Period and Frequency of Detecting and Reporting SAEs 
Once an investigator determines that an event meets the protocol definition of an SAE, the SAE will be 
reported to NOVARTIS within 24 hours of being notified of the event. All SAEs regardless of relationship 
to investigational product will be collected from the first dose of investigational product to after the last 
dose of investigational product (minimum of 6 months or until the end of the follow-up period which ever is 
longer). All SAEs regardless of causality will be collected until the end of the follow-up period. 
 
From the time a subject consents to participate in and completes the study all SAEs assessed as related 
to study participation (e.g., protocol-mandated procedures, invasive tests, or change in existing 
therapy) or related to NOVARTIS concomitant medication, will be reported promptly to NOVARTIS. 
 
Any SAE brought to the investigator’s attention after the subject has completed the study and considered 
by the investigator as possibly related to investigational product must be reported to NOVARTIS. 
 
You should report safety data to Novartis by fax to: 
• 
U.S. Drug Safety & Epidemiology 
 
o 
(Should the designated SAE Fax# be non-functional please send SAEs to the designated SAE 
mailbox: clinicalsafetyop.phuseh@novartis.com) 
• 
The attached Coversheets must be attached to all SAE submissions 
• 
SAE Submissions must reference your Novartis Study Code: COMB157DUS22T 
 
Reporting Process to UCSF IRB 
Serious and unexpected adverse events should be reported to the UCSF IRB within 10 working days of 
the occurrence. This includes any adverse experience which is fatal or life-threatening, permanently 
disabling, requires inpatient hospitalization or prolongs hospitalization, or has not been identified in 
nature, severity or frequency in the literature. Should a serious or unexpected toxicity occur please 
contact: 
 
Pregnancy 
Any pregnancy that occurs during study participation must be reported to NOVARTIS. To ensure subject 
safety, each pregnancy must be reported to NOVARTIS within 2 weeks of learning of its occurrence. The 
pregnancy must be followed up to determine outcome (including premature termination) and status of 
mother and child. Pregnancy complications and elective terminations for medical reasons must be 
reported as an AE or SAE. Spontaneous abortions must be reported as an SAE. 
Any SAE occurring in association with a pregnancy, brought to the investigator’s attention after the 
subject has completed the study and considered by the investigator as possibly related to the 
investigational product, must be promptly reported to NOVARTIS. 
In addition, the investigator must attempt to collect pregnancy information on any female partners of male 
study subjects who become pregnant while the subject is enrolled in the study. Pregnancy information 
must be reported to NOVARTIS as described above. 
 
9.3 Special Reporting Considerations 
 
9.3.1 
Intensive Consolidation and Stem Cell Mobilization with OVA 
The following adverse events are expected, based on experience with Etoposide and High-Dose 
Cytarabine in this patient population. They will be documented in the patient medical record but will 
ONLY be recorded in the Case Report Form if they are grade 3-5. 
Neutropenia: expect ANC < 500/µL for approximately 14 days with recovery to >500/µL by day 28. 
Thrombocytopenia: expect platelets <20,000/µL for 10-14 days with recovery to >25,000/µL without 
transfusion support by day 28. 
Anemia: Expect to transfuse approximately 6 units of packed RBC. 
Stomatitis: most patients do not need narcotic analgesia or TPN, but both are possible. 


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Diarrhea: enterocolitis is uncommonly seen. 
Skin: diffuse erythema is expected and common shortly after chemotherapy. Exfoliative dermatitis with 
blistering is uncommon. It would be unusual to need >7 days of narcotic analgesia for skin toxicity. 
Fatigue/Performance Status: patients require hospitalization for all or most of OVA and may be unable 
to fully care for themselves for 1-2 weeks following hospitalization. 
 
9.3.2 
High-Dose Therapy with CBV and Stem Cell Rescue 
The following adverse events are expected, based on experience with CBV in this patient population. 
They will be documented in the patient medical record but will ONLY be recorded in the Case Report 
Form if they are grade 3-5. 
Neutropenia: absolute neutropenia is expected for 7-10 days. Neutrophils begin to engraft around day +8 
to +10. Lack of neutrophil engraftment by day +21 IS REPORTABLE. 
Thrombocytopenia: Grade 4 thrombocytopenia is expected for 7-14 days. Platelet transfusion- 
independence usually occurs by day +9 to +12. Expect approximately 3 platelet transfusions. Reportable 
platelet recovery would be failure to reach transfusion independence by day +28. 
Anemia: expect to transfuse 4-6 units of packed RBC. 
Stomatitis: Grade 4 stomatitis can occur but is uncommon, usually between day +3 to +10. Some 
patients will require narcotic analgesia and possibly TPN (depending on institutional practices). 
Diarrhea: enterocolitis is uncommon, but may occur. It generally requires narcotic analgesia, anaerobic 
antibiotics, and TPN. 
Skin: exfoliative dermatitis requiring local skin care (including blistering and weeping wounds) may occur 
and may require narcotic analgesia; palms and soles and intertriginous areas are most common. Skin 
breakdown > 2 weeks would be considered distinctly unusual. 
Fatigue & Performance Status: patients will be hospitalized for most or all of this therapy. They are 
unlikely to be able to fully care for themselves for 1-2 weeks post-hospital discharge. 
 
 
10 Study Drug and Chemotherapeutic Agents 
10.1 Ofatumumab (Arzerra) 
Pharmaceutical Presentation 
Ofatumumab is formulated at two strengths, 20 mg/mL 
and 100 mg/mL, for IV and SC administration. 
 
Formulation Presentation 
20 mg/mL, acetate buffer 100 mg/vial (5 mL/vial) 
20 mg/mL acetate buffer 1000 mg/vial (50mL/vial) 
100 mg/mL, acetate buffer 500 mg/vial (5 mL/vial) 
100 mg/mL, acetate buffer 100 mg/vial (1 mL/vial) 
 
All drug product presentations are prepared aseptically and filled into clear glass, stoppered vials. The 
products are formulated without a preservative and are supplied as a single use vial. 
 
Physical, Chemical and Biological Properties of the Drug Substance 
Approved Name: INN: Ofatumumab 
Chemical  Name  (Chemical  Abstracts):  Immunoglobulin  G1,  anti-(human  CD20  (antigen))  (human 
monoclonal HuMax-CD20 heavy chain), disulfide with human monoclonal HuMax-CD20 κ-chain, dimer 
(CAS number: 679818-59-8) 
Other Names: Genmab Product code: HuMax-CD20 
Genmab Laboratory Code: 2F2 


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Biochemical and Structural Information: Ofatumumab is  a  fully human immunoglobulin G1 antibody 
(IgG1-kappa) against human CD20 molecule expressed on B cells. The antibody consists of two heavy 
IgG1 chains and two light kappa chains. The heavy chains are connected to each other by two interchain 
disulfide bonds and one light chain is attached to each heavy chain by a single interchain disulfide bond. 
The light chain has two intrachain disulfide bonds and the heavy chain has four intrachain disulfide bonds. 
The C-terminal lysine on the heavy chain is subject to partial post-translational cleavage, resulting in 
antibody populations which contain 0, 1, or 2 C-terminal lysine residues. The majority of the C-terminal 
heavy chains are clipped. There is a single N-linked glycosylation site on each heavy chain. The major 
glycans present are fucosylated biantennary structures with varying amounts of terminal galactose. 
Molecular Weight 149 kDa (including carbohydrate residues approximately 2%). 
Physical Form Clear, colourless liquid (at 20 mg/mL). 
Clear to hazy, colourless to pale yellow liquid (at 100 mg/mL). 
 
Summary of Manufacturing Process and Quality Assurance 
Ofatumumab Injection presentations were prepared according to current Good Manufacturing Practice 
(cGMP) and tested according to International Conference on Harmonization (ICH) and Food and Drug 
Administration (FDA) Guidelines for monoclonal antibodies and products derived from recombinant DNA 
technology.  The  cell  banks  used  to  manufacture  ofatumumab  have  been  extensively  tested  to 
demonstrate freedom from adventitious virus contamination. Ofatumumab is produced by a recombinant 
mammalian cell line, and no animal derived raw materials are used in the manufacture of Ofatumumab 
Injection. The antibody is purified by a multi-step sequential chromatography and filtration process, which 
has been validated to demonstrate removal and inactivation of a range of viruses in compliance with ICH 
guidelines. 
 
Storage and Handling 
The recommended storage conditions and expiration date, where required, are stated on the product 
label for Ofatumumab Injection 20 mg/mL and 100 mg/mL. 
 
Administration and Compatibility 
Ofatumumab Injection, 20 mg/mL and 100 mg/mL for intravenous administration must be diluted with 
0.9% w/v Sodium  Chloride for Injection.  Directions for administration are provided in section 6.1.1. 
Ofatumumab must be administered separately from other medications. 
 
Toxicity: Infusion reactions, neutropenia, pneumonia, pyrexia, cough, diarrhea, anemia, fatigue, dyspnea, 
rash, nausea, bronchitis, and upper respiratory tract infections. Detailed above. 
 
10.2 Etoposide (Vespid®; VP-16) 
Action: inhibition of Topoisomerase II results in metaphase arrest, predominantly G2. 
Availability: commercially available. 
Preparation: supplied as a liquid in mutli-dose vials (100 mg/5ml; 150 mg/7.5 ml; 500 mg/25 ml; 1,000 
mg/50 ml). 
Storage and Stability: unopened vials are stable for 24 months at room temperature. Vials opened and 
diluted to a concentration of 0.2-0.4 mg/ml are stable for 96 and 24 hours, respectively, at room 
temperature in glass or plastic containers. 
Administration: Can be administered undiluted intravenously over 4 hours with NS piggyback. 
Toxicity: 
fever, 
hypotension, 
bronchospasm, 
acidosis, 
and 
hypersensitivity 
reactions 
during 
administration, bone marrow suppression, stomatitis and enteritis, skin reactions, elevated liver tests, 
rarely paresthesias, nausea, vomiting, and alopecia. 
 
 
10.3 G-CSF (Filgrastim; Neupogen®) 
Action: stimulates the proliferation and differentiation of myeloid progenitor cells, stimulates their end-cell 
functional activation, and mobilizes hematopoietic stem cells into the peripheral circulation. 
Availability: G-CSF is commercially available. 


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Preparation: Supplied in 300 and 480 mcg vials containing 1.0 and 1.6 ml of sodium acetate, respectively. 
Storage and Stability: Vials should be stored at 2-8o C. Avoid freezing or shaking of vials. Vials are 
stable at room temperature for 6 hours. 
Administration: SQ or IV administration is permitted. 
Toxicity: mild to severe bone pain, leukocytosis, pain at injection site, anaphylaxis, Sweet’s syndrome, 
hypotension, splenomegaly, splenic pain. 
 
10.4 Cytarabine (Cytosar-U®; Ara-C; Cytosine arabinoside) 
Action: as a pyrimidine analog, cytarabine is incorporated into DNA and competitively inhibits DNA 
polymerase and thus inhibits DNA synthesis. 
Availability: commercially available. 
Preparation: supplied as 100, 500 mg, 1,000 mg, and 2,000 mg vials. 
Storage and Stability: diluted solutions are stable for at least 192 hours at room temperature. 
Administration: dilute with 0.9% benzyl alcohol (5 ml for 100-1,000 mg cytarabine; 20 ml for 2,000 mg 
cytarabine) plus 50-100 ml D5W or NS for 1-2 hour IV infusions or in 500-1,000 ml D5W or NS for longer 
IV infusions. May be given SQ (10-30 mg) in 1 ml NS. 
Toxicity: myelosuppression, central nervous system toxicity (doses ≥500 mg/m2, especially when 
creatinine clearance is <60 cc/min; see Sections 9.4.3 and 10.6.2), stomatitis, nausea, emesis, non- 
cardiogenic pulmonary edema, keratoconjunctivitis, cutaneous toxicity, alopecia, hepatic dysfunction. 
 
 
 
11 STATISTICAL CONSIDERATIONS 
 
This is a single-institution, single-arm, open-label Phase II study of Ofatumumab in combination with 
etoposide and high-dose cytarabine as an intensive consolidation and stem cell mobilization regimen in 
patients with relapsed/refractory diffuse large B-cell lymphoma. The primary efficacy endpoint of the 
study is the mobilization-adjusted complete response rate (maCR) which is defined as: the proportion of  
patients achieving complete response to the treatment upon successful stem cell mobilization, defined as  
at least 2 x10^6 CD34+cells/Kg of actual body weight. Secondary endpoints include time to neutrophil 
and platelet engraftment following ASCT, PFS in this high-risk patient population and other survival-time 
measures of clinical efficacy, i.e. OS, TTP, EFS, and CR/Pr proportion at day +90. Our study will also 
measure the FDG-PET conversion rate from PR to CR following OVA and correlate post-OVA PET 
results with PFS, TTP, and OS. We will examine potential relationships between Ofatumumab 
concentration at selected time points and PFS, TTP, OS. We will perform MRD testing at baseline, at the 
time of stem cell collection, and following ASCT, and will correlate the results to clinical endpoints. 
Finally, safety will be evaluated with regard to infusion-related reactions, B-cell number, 
hypogammaglobulinemia, and long-term hematologic toxicity. 
 
11.1 Sample Size 
Patients who have received a single infusion of study drug (day 0 of OVA) will be included in the 
statistical analyses. We are planning to accrue 24 subjects over the course of 2 years with an additional 
2-year follow-up. In terms of the composite primary endpoint, the historical CR rate after 2 cycles of 
salvage therapy among high risk, rituximab refractory patients is between 25% and 50% of the overal 
responses [i.e CR/(CR+PR].[8, 19, 20] Furthermore, the chance of a mobilization failure among complete 
and partial responders observed in the CORAL study is 15%.[9] We thus expect the null value of the 
composite endpoint of maCR to be 25% (~40% CR-15% mobilization failure). Given the excellent 
historical CR rates with intensive consolidation and the very low risk of mobilization failures, we expect 
the alternative maCR rate to be 50%. Based on the exact probability with type I error of 10% and 1-sided 
test, a sample size of N=24 in the single arm study will have > 80% power to detect the maCR rate for the 
following 
hypothesis: 
H0: 
p0<25% 
(40%CR/15%mobilization-failure) 
vs 
Ha: 
p1>50% 
(55%CR/5%mobilization-failure under OVA). The following table shows statistical power for the test of 
the null hypothesis under the assumed maCR of 25% and for various mobilization-adjusted complete 
response rates with 24 subjects (alpha=10% under 1-sided exact test): 


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maCR rate 
Statistical Power 
25% vs 40% 
51% 
25% vs 45% 
70% 
25% vs 50% 
84% 
25% vs 55% 
93% 
25% vs 60% 
97% 
 
An interim analysis for futility and safety will be performed when 12 subjects are enrolled. We will define 
the futility as >50% stem cell mobilization failure as excessive and unacceptable. If six or fewer (< 50%) 
subjects have adequate stem cell mobilization, the enrollment will not continue and the study will be 
closed for treatment futility. Otherwise we will enroll 12 additional patients to complete study for full maCR 
efficacy analysis. At the same time as the interim analysis for futility, we will also perform an interim 
evaluation for safety, which is defined as >30% SAE as too toxic and unacceptable. If 4 or more (>30%) 
of the first 12 patients treated are observed to have protocol-defined unacceptable toxicity, the study will 
be closed for lack of safety. If the stem cell collection success rate is less than 50%, the probability of 
early stopping due to futility is 61%. If the toxicity rate is greater than 30%, the probability of early  
stopping due to safety is 64%. 
 
11.2 Statistical Methods 
The results of this single-institution study will be evaluated and reported as follows. Proportions will be 
compared with the chi square test. Time-to-event variables will be analyzed with the Kaplan-Meier 
method and compared across subgroups with the log-rank test. 
 
Primary Analysis 
 
For primary efficacy analysis, the proportion of stem cell mobilization, the proportion of complete  
response and the proportion of mobilization-adjusted complete response will be analyzed and reported 
separately and collectively. Descriptive statistics with frequency and proportion with exact 95% 
confidence intervals will be reported for the study. The acceptable stem cell collection is defined as a 
minimum CD34 cell dose of > 2 x 10 x 106/kg (actual body weight) and optimal stem cell collection as a 
CD34 cell dose of > 5 x 106/kg (actual body weight). Subjects who require use of plerixafor or an 
autologous bone marrow harvest are considered mobilization failures and will be treated as non- 
responders, ie. they will be included in the denominator when calculating the percentage for the primary 
efficacy analysis. The CR rate will be calculated based on the PET/CT scan following 2 cycles of salvage 
therapy. 
 
Secondary Analyses 
 
Progression free survival (PFS), defined the time from day 0 until lymphoma progression, receipt of 
anti-lymphoma therapy (except for planned post-ASCT radiotherapy), or death as a result of any cause, 
will be summarized using Kaplan-Meier quartile estimates along with two-sided 95% confidence intervals. 
If a subject receives subsequent anti-lymphoma therapy prior to the date of documented progression or 
death, progression free-survival will be censored at the last adequate assessment prior to the initiation of 
that anti-cancer therapy. Otherwise, if the subject does not have a documented date of progression or 
death, progression-free survival will be censored at the date of the last adequate assessment. No formal 
hypothesis test will be performed for significance. 
 
Stem cell engraftment rate will be evaluated for neutrophil and platelet following successful mobilization. 
Failures of stem cell collection will be considered as non-responders. Neutrophil engraftment is defined as 
the first day of 3 consecutive days with absolute neutrophil count of >500 cells/uL. Platelet engraftment will 
be defined as the first of three consecutive measurements for which the platelet count was >      
20,000/uL, and must be at least 24 hours following the last platelet transfusion. Engraftment rate will be 
reported separately for neutrophil and platelet. Descriptive statistics with proportion and frequency will be 


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used and 95% confidence intervals will also be reported. No formal hypothesis test will be performed for 
significance. 
 
The Time to progression, defined as the time from study entry until documented lymphoma progression 
or receipt of anti-lymphoma therapy or death, will be summarized descriptively using Kaplan-Meier 
quartiles, along with two-sided 95% confidence intervals, for each of the cohorts. Only the subset of 
subjects who show a complete or partial tumour response will be included in this analysis. Censoring 
rules follow the rules for PFS. No formal hypothesis test will be performed for significance. 
 
Overall survival (OS): OS, defined as the time to death for any reason, will be summarized using 
Kaplan-Meier quartile estimates along with two-sided 95% confidence intervals. OS will be censored 
using the date of last known contact for those who are alive at the time of analysis. 
No formal 
hypothesis test will be performed for significance. 
 
Other secondary analyses will include the association between FDG-PET conversion, Ofatumumab 
concentration, the effect of OVA and the clinical outcomes such as PFS, OS and Time to progression 
(duration of response). 
 
11.3 Accrual and Estimated Duration of Study 
As a tertiary care referal BMT center in Northern Califronia, we perform approximately 15 such 
transplants in this patient population annually and we expect to enroll most of our patients on this study. 
There are no competing studies currently, in development, or planned. Thus the study should complete 
accrual within 24-30 months of initiation. 
 
11.4 DLBCL Subtyping 
 
Tumor tissue and peripheral blood stem and mononuclear cells will be collected for DLBCL subtyping. 
The best way to subtype DLBCL  is currently in evolution. For this study,  a combination  of gene 
expression profiling (GEP) and immunohistochemistry (IHC) will be utilized to distinguish different disease 
entities. 
 
11.5 Minimal Residual Disease Testing 
 
MRD assessments will take place in collaboration with Sequenta (South San Francisco, CA). For each 
patient the cancer-specific IgH rearrangement will be identified through the assessment of a diagnostic 
sample. The diagnostic sample will be the positive lymph node (frozen or archived FFPE) or bone marrow 
aspirate sample (whole aspirate, frozen cells, or clots) in patients with an involved marrow. All the IgH 
sequences are amplified from the diagnostic samples and the product is subjected to DNA sequencing. 
The cancer-specific sequence is expected to be present at high frequency (>10%) in contrast to most 
other sequences present at very low level (<0.1%). The cancer-specific sequence is then readily 
measured for each patient by determining the level of that sequence in a subsequent sample. This is 
done by amplifying all the IgH sequences from the relevant samples and subjecting the product to deep 
sequencing (1M reads or more). The level of the cancer-specific sequence can then be determined at 
very high sensitivity (due to the depth of sequencing) and specificity (due to the uniqueness of each IgH 
sequence). We will determine the feasibility of this methodology in our patient population. We will 
measure the MRD conversion rate following OVA and correlate this with clinical outcomes. Additionally, 
we will perform MRD surveillance following ASCT and correlate it with Ofatumumab pharmacokinetics 
and relapse. 
 
 
 
11.6 Data Safety Monitoring Plan: 


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The study data will be reviewed twice a month by the PI and study coordinator. Safety data and 
specifically SAEs and grade 3-5 AEs will be reviewed at the Hematology Site Committee twice a month. 
 
 
Monitoring and Reporting Guidelines 
Investigators will conduct continuous review of data and patient safety at weekly Transplant Meeting or 
Site Committee meetings where the results of each patient’s treatment are discussed. The discussion will 
include, the number of patients enrolled, significant toxicities, stem cell mobilization, and observed 
responses. The study coordinator will keep a log of subject(s) on study and grade 3-5 AE’s and SAE’s will 
be entered in the HDFCC Oncore database. 
 
Interim Analysis 
An interim analysis for futility and safety will be performed when 12 subjects are enrolled. We will define 
the futility as >50% stem cell mobilization failure as excessive and unacceptable. If six or fewer (< 50%) 
subjects have adequate stem cell mobilization, the enrollment will not continue and the study will be 
closed for treatment futility. Otherwise we will enroll 12 additional patients to complete study for full maCR 
efficacy analysis. At the same time as the interim analysis for futility, we will also perform an interim 
evaluation for safety, which is defined as >30% SAE as too toxic and unacceptable. If 4 or more (>30%) 
of the first 12 patients treated are observed to have protocol-defined unacceptable toxicity, the study will 
be closed for lack of safety. If the stem cell collection success rate is less than 50%, the probability of 
early stopping due to futility is 61%. If the toxicity rate is greater than 30%, the probability of early  
stopping due to safety is 64%. 
 
Serious Adverse Event Reporting 
Serious Adverse Event reporting will be in accordance with the UCSF-Committee on Human Research 
Regulations and Code of Federal Regulation Title 21 Volume 5 Part 312.32. In addition, SAEs will be 
entered into the Oncore database. 
 
UCSF 
CHR 
website 
for 
guidance 
in 
reporting 
serious 
adverse 
events  
http://www.research.ucsf.edu/chr/Guide/chrA_AE.asp 
 
FDA website for guidance in reporting serious adverse events  
http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=312.32 
 
MedWatch forms and information:  
http://www.fda.gov/medwatch/getforms.htm 
 
Serious Adverse events will be reported on the MedWatch form. A copy of the MedWatch report and CHR 
forms must be sent to CCC-DSMC at Box 1297. The date the SAE was sent to all required reporting 
agencies will be documented on Oncore; hard copies of the report will be maintained in the regulatory 
files. 
 
 
 
12 Data Management and Study Termination 
12.1 Data and Protocol Management 
 
1. Data Management: All patients enrolled on trial will be given a study-specific registration number. 
The registration number will be used to identify all patients on trial. 
2. Protocol Compliance: Patients and their medical records will be reviewed every other week until 
the first 30 days post-transplantation and otherwise monthly by the study investigators. Study 
endpoints will be reviewed and documented. Any questions regarding serious adverse events and 
toxicity should be discussed with the study chairman directly. 


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3. Case Report Forms: Clinical data  will be recorded on  case report forms.  CRF’s should be 
completed on a timely basis. The principal investigator will review all CRF’s. 
4. Accuracy of Data Collection: The UCSF Cancer Center DSMB, UCSF CHR, IBMTR or individual 
government board may review the data from this study for accuracy. The UCSF DSMB will be the 
final arbiter of eligibility, toxicity and other endpoints should a difference of opinion exist. 
 
12.2 Termination of Study 
 
UCSF retains the right to terminate the study at any time. 
 
UCSF retains the right to terminate an individual study patient’s participation in the study due to the 
following: 
1. Noncompliance with study procedures 
2. Concomitant use of any study drug or procedure without prior approval from the Principal 
Investigator 
3. Unanticipated adverse medical experiences in this or other studies indicating a potential health 
hazard caused by the study 
4. Study patient’s withdrawal from protocol 
 
 
13 Study Finances 
13.1 Funding Source 
This study is financed by NOVARTIS. 
 
13.2 Conflict of Interest 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, or financial gain 
greater than the minimum allowable by their institution, etc.) must have the conflict reviewed by a properly 
constituted Conflict of Interest Committee with a Committee-sanctioned conflict management plan that 
has been reviewed and approved by the study sponsor prior to participation in this study. Subject 
Stipends or Payments 


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14 References 
 
1. 
Coiffier, B., et al., CHOP chemotherapy plus rituximab compared with CHOP alone in elderly 
patients with diffuse large-B-cell lymphoma. N Engl J Med, 2002. 346(4): p. 235-42. 
2. 
Habermann, T.M., et al., Rituximab-CHOP versus CHOP alone or with maintenance rituximab in 
older patients with diffuse large B-cell lymphoma. J Clin Oncol, 2006. 24(19): p. 3121-7. 
3. 
Pfreundschuh, M., et al., CHOP-like chemotherapy plus rituximab versus CHOP-like 
chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: a 
randomised controlled trial by the MabThera International Trial (MInT) Group. Lancet Oncol, 
2006. 7(5): p. 379-91. 
4. 
Philip, T., et al., Autologous bone marrow transplantation as compared with  salvage 
chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin's lymphoma. N Engl J Med, 
1995. 333(23): p. 1540-5. 
5. 
Hahn, T., et al., The role of cytotoxic therapy with hematopoietic stem cell transplantation in the 
therapy of diffuse large cell B-cell non-Hodgkin's lymphoma: an evidence-based review. Biol 
Blood Marrow Transplant, 2001. 7(6): p. 308-31. 
6. 
Weaver, 
C.H., 
et 
al., 
High-dose 
fractionated 
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irradiation, 
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and 
cyclophosphamide followed by autologous stem-cell support in patients  with  malignant 
lymphoma. J Clin Oncol, 1994. 12(12): p. 2559-66. 
7. 
Guglielmi, C., et al., Time to relapse has prognostic value in patients with aggressive lymphoma 
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Hamlin, P.A., et al., Age-adjusted International Prognostic Index predicts autologous stem cell 
transplantation outcome for patients with relapsed or primary refractory diffuse large B-cell 
lymphoma. Blood, 2003. 102(6): p. 1989-96. 
9. 
Gisselbrecht, C., et al., Salvage Regimens With Autologous Transplantation for Relapsed Large 
B-Cell Lymphoma in the Rituximab Era. J Clin Oncol, 2010. 
10. 
Damon, L., et al., Impact of intensive PBSC mobilization therapy on outcomes following auto-SCT 
for non-Hodgkin's lymphoma. Bone Marrow Transplant, 2008. 42(10): p. 649-57. 
11. 
Juweid, M.E., et al., Response assessment of aggressive non-Hodgkin's lymphoma by integrated 
International 
Workshop 
Criteria 
and 
fluorine-18-fluorodeoxyglucose 
positron 
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tomography. J Clin Oncol, 2005. 23(21): p. 4652-61. 
12. 
Cheson, B.D., et al., Revised response criteria for malignant lymphoma. J Clin Oncol, 2007. 
25(5): p. 579-86. 
13. 
Derenzini, E., et al., Pretransplantation positron emission tomography scan is the main predictor 
of autologous stem cell transplantation outcome in aggressive B-cell non-Hodgkin lymphoma. 
Cancer, 2008. 113(9): p. 2496-503. 
14. 
Filmont, J.E., et al., Value of F-18 fluorodeoxyglucose positron emission tomography for 
predicting the clinical outcome of patients with aggressive lymphoma prior to and after autologous 
stem-cell transplantation. Chest, 2003. 124(2): p. 608-13. 
15. 
Cremerius, U., et al., Pre-transplant positron emission tomography (PET) using fluorine-18-fluoro- 
deoxyglucose (FDG) predicts outcome in patients treated with high-dose chemotherapy and 
autologous stem cell transplantation for non-Hodgkin's  lymphoma. Bone Marrow Transplant, 
2002. 30(2): p. 103-11. 
16. 
Svoboda, J., et al., Prognostic value of FDG-PET scan imaging in lymphoma patients undergoing 
autologous stem cell transplantation. Bone Marrow Transplant, 2006. 38(3): p. 211-6. 
17. 
Schot, B.W., et al., The role of serial pre-transplantation positron emission tomography in 
predicting progressive disease in relapsed lymphoma. Haematologica, 2006. 91(4): p. 490-5. 
18. 
Spaepen, K., et al., Prognostic value of pretransplantation positron emission tomography using 
fluorine 18-fluorodeoxyglucose in patients with aggressive lymphoma treated with high-dose 
chemotherapy and stem cell transplantation. Blood, 2003. 102(1): p. 53-9. 
19. 
Vellenga, E., et al., Rituximab improves the treatment results of DHAP-VIM-DHAP and ASCT in 
relapsed/progressive aggressive CD20+ NHL: a prospective randomized HOVON trial. Blood, 
2008. 111(2): p. 537-43. 


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20. 
Sud, R. and J.W. Friedberg,  Salvage therapy for relapsed or refractory diffuse large B-cell 
lymphoma: impact of prior rituximab. Haematologica, 2008. 93(12): p. 1776-80. 
21. 
Moskowitz, C.H., et al., High-dose chemo-radiotherapy for relapsed or refractory Hodgkin 
lymphoma and the significance of pre-transplant functional imaging. Br J Haematol, 2010. 148(6): 
p. 890-7. 
22. 
Teeling, J.L., et al., The biological activity of human CD20 monoclonal antibodies is linked to 
unique epitopes on CD20. J Immunol, 2006. 177(1): p. 362-71. 
23. 
Teeling, J.L., et al., Characterization of new human CD20 monoclonal antibodies with potent 
cytolytic activity against non-Hodgkin lymphomas. Blood, 2004. 104(6): p. 1793-800. 
24. 
Ofatumumab Investigator's Brochure, Version 4.0. 2011. 
25. 
Bleeker, W.K., et al., Estimation of dose requirements for sustained in vivo activity of a 
therapeutic human anti-CD20 antibody. Br J Haematol, 2008. 140(3): p. 303-12. 
26. 
Coiffier, B., et al., Ofatumumab monotherapy for treatment of patients with relapsed/progressive 
Diffuse Large B-Cell Lymphoma: Results of a mutlicenter phase II study. Blood, 2010. 116: p. 
abst 3955. 
27. 
Cilessen, S.A.G., W.J. Mackus, and K.C. Castricum, Chemotherapy-refractory diffuse large B-cell 
lymphomas are effectively killed by ofatumumab-induced complement-mediated cytotoxicity. 
Blood, 2007. 110: p. abstr 2346: 694a. 


OVA in High-Risk Relapsed/Refractory DLBCL 
Page 35 
 
 
 
 
 
15 Attachments 
15.1 Study Procedures 
 
Procedures 
Registration 
Salvage 
Assessment 
OVA 
Post ASCT Follow-up 
Long term follow-up 
Days: 
0 
1-4 
7 
14 
21 
42 
Days +30’, +60’ 
post ASCT 
Day +90’ 
post ASCT 
Month 6 
post ASCT 
Month 12 
post ASCT 
Month 24 
post ASCT13 
Informed Consent 
X 
Demography 
X 
Medical History 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Disease History 
X 
Therapy History 
X 
Efficacy Assessments 
Bone marrow biopsy 
X 
X1 
X1 
CT 
X 
X 
X 
X 
X 
X 
PET 
X 
X 
X 
X7 
LP2 
X 
Disease Status & survival 
X 
X 
X 
X 
X 
X 
Safety Assessments 
Physical Exam 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECOG 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
Weight 
X 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG 
X 
Echo or MUGA 
X 
PFTs with DLCO 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Therapy 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study Medication 
Ofatumumab 
X 
X 
X 
X 
Etoposide 
X 
Cytarabine 
X 
G-CSF 
X3 
X3 
X3 
 
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Dr. Charalambos Andreadis 


OVA in High-Risk Relapsed or Refractory DLBCL 
Page 36 
 
 
 
 
Procedures 
Registration 
Salvage 
Assessment 
OVA 
Post ASCT Follow-up 
Long term follow-up 
Days: 
0 
1-4 
7 
14 
21 
42 
Days +30’, +60’ 
post ASCT 
Day +90’ 
post ASCT 
Month 6 
post ASCT 
Month 12 
post ASCT 
Month 24 
post ASCT13 
Lab Assessments 
Hematology 
X 
X 
X 
X4 
X4 
X4 
X4 
X 
X 
X 
X 
X 
X 
Chemistry 
X 
X 
X 
X5 
X5 
X5 
X5 
X 
X 
X 
X 
X 
X 
Coags 
X 
X 
Serum Pregnancy Test 
X 
Hepatitis B&C antibodies6 
X 
HBV DNA PCR6 
X 
X 
X 
X 
X 
X 
X 
CD19+ B-Cells 
X 
X 
X 
X 
X 
X 
Quant Igs 
X 
X 
X 
X 
X 
X 
Ofa PK 
X8 
X 
X 
X 
X 
X 
Tumor Tissue Collection 
X9 
PBMC Aliquot 
X10 
MRD Testing on Blood 
X11 
X11 
X11 
X11 
X11 
X11 
X11 
MRD Testing on PBMC 
from apheresis 
X12 
1:BM performed on day 42 and +90’ If positive at salvage assessment 
2: LP performed only if previously positive or for suspected CNS involvement 
3: Starts day 14 and stops when stem cell collection complete 
4: Daily CBC with differential until leukapheresis completed. 
5: Daily: electrolytes, creatinine. Twice weekly: bilirubin, alkaline phosphatase, AST, ALT, LDH. Stop when leukapheresis completed 
6: Subjects who are HBcAb positive must undergo at least every 2 month HBV DNA PCR testing during the treatment course. Monitoring must also occur during the follow-up period for a 
minimum of 6 months after the last dose as long as the subject remains in the study at a minimum frequency of every 2 to 3 months. 
7: PET will be repeated at 6 months if positive at day +90’ evaluation 
8: Within 24 hours after end of infusion on day 21. 
9: 20 unstained slides or tissue block from the time of relapse (preferred) or initial diagnosis, if available. 
10: 4 cryovials with PBMC aliquot will be stored at time of first apheresis. Apheresis may occur on or after day 21. 
11: MRD determination will be performed on 10 mL of peripheral blood at the timepoints indicated. 
12. Some apheresis product (4cc) will be sent for MRD testing. 
13: Patients who do not progress in the first 24 months, will be followed for disease status and survival every 6 months, until 5 years.  See Section 6.0. 
 
 
 
 
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Dr. Charalambos Andreadis 


OVA in High-Risk Relapsed/Refractory DLBCL 
Page 37 
 
 
 
 
 
15.2 Calculation of sAAIPI 
This is calculated at the time of progression or relapse and prior to initiation of second-line (salvage) 
chemotherapy. 
 
-Serum LDH > upper limit of normal 
 
-ECOG PS ≥ 2 
 
-Stage ≥ III 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Version 01-17-2017 
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Dr. Charalambos Andreadis 


OVA in High-Risk Relapsed or Refractory DLBCL 
Page 38 
Version 01-17-2017 
Protocol #112525 
Dr. Charalambos Andreadis 
 
 
 
 
 
15.3 High Dose Therapy with Stem Cell Rescue (CBV) 
 
Carmustine 15 mg/kg IV (maximum dose, 550 mg/m2) on Day -6. 
 
a. 
Carmustine dose should be calculated based on corrected weight calculated as ideal weight plus 
25% of the difference between actual and ideal weight. Use actual weight if it is lower than ideal 
weight. 
b. Each Carmustine vial is reconstituted with 3 ml absolute ethanol and 27 mL sterile water. Total 
Carmustine dose is diluted in 1000 ml D5W or NS. 
c. 
Administer over 2-3 hours in a light-protected glass bottle or Excel bag. Maximum infusion rate is 180 
mg/m2/hour. 
d. Premedication with diphenhydramine 50 mg IV 30 minutes prior to Carmustine is recommended. 
 
Etoposide 60 mg/kg IV over 4 hours on Day -3. 
 
a. Etoposide dose should be calculated based on corrected weight calculated as ideal weight plus 25% 
of the difference between actual and ideal weight.  Use actual weight if it is lower than ideal weight. 
b. Etoposide should be given undiluted over 4 hours and piggybacked into NS at 1000 ml/hour. 
c. Premedication with hydrocortisone 100 mg IV to be repeated in 2 hours during the infusion, 
acetaminophen 650 mg PO, and cetirizine 10 mg PO is recommended. Meperidine 25 mg IV q1 hour 
prn for rigors may be administered up to 3 doses. 
d. Febrile reactions should be treated with hydrocortisone and diphenhydramine as is necessary. 
e. Hypotension may occur during the Etoposide administration. If this happens, first pause the infusion 
and restart when the blood pressure recovers. If hypotension persists or recurs, then give Dopamine 
IV to maintain the blood pressure in order to complete the Etoposide infusion. If hypotension persists, 
abort the Etoposide infusion. 
f. 
Etoposide Phosphate (Etopophos): may be substituted for etoposide for patients > 60 years old or 
for younger patients as clinically indicated. Etopophos 60 mg/kg IV over 3-4 hours. Mix in 250-500 
milliliters 0.9%NaCl for concentration > 0.1 mg/ml. Hydrocortisone 100 mg IV and cetirizine 10 mg 
PO will be given prior to infusion. Febrile reactions should be treated with additional hydrocortisone 
and diphenhydramine as is necessary. 
 
Cyclophosphamide 100 mg/kg IV over 2 hours day -2. 
 
a. Cyclophosphamide and Mesna dose should be calculated based on corrected weight calculated as 
ideal weight plus 25% of the difference between actual and ideal weight. Use actual weight if it is 
lower than ideal weight. 
b. One hour before cyclophosphamide begin IV NS plus KCl 20meq/L to run at 250 cc/hour to 
continuefor 20 hours after end of cyclophosphamide infusion, for a total of 24 hours. 
c. MESNA 120 mg/kg (corrected weight) in 1 liter D5W IV over 24 hours should begin one hour prior to 
cyclophosphamide infusion for a total of 24 hours. 
d. Cyclophosphamide should be infused over 3 hours in 500 mL D5W. 
e. Cyclophosphamide-related gross or microscopic hematuria correlates with the concentration of drug 
metabolites in the bladder. Adequately hydrate patients and ensure frequent voiding. If hemorrhagic 
cystitis occurs, consider adding bladder irrigation (500 cc/hour sterile urologic saline via a 3-way 
Foley catheter for 48 hours after cyclophosphamide administration). 
f. 
Furosemide may be used for volume management per institutional protocol. 
 
Autologous peripheral blood stem cell infusion will take place on Day 0. 
 
Peripheral blood stem cells should be thawed in a 37˚ water bath and immediately infused intravenously. 


OVA in High-Risk Relapsed or Refractory DLBCL 
Page 39 
Version 01-17-2017 
Protocol #112525 
Dr. Charalambos Andreadis 
 
 
 
 
Supportive Care 
 
 
G-CSF 5 mcg/kg SQ daily (actual body weight, rounded up to vial size) starting Day +6’. G- 
CSF should continue daily until the absolute neutrophil count exceeds 1500/µl for 2 consecutive days 
or > 5000/uL for one day. It should then be stopped but should be resumed if the ANC falls to < 
1000/µl. If G-CSF is resumed it should then be continued until the ANC > 5000/µl. 
 
Fluconazole 400 mg PO will be given daily starting from day +1’ and will continue until the 
neutrophils are at least > 500/uL. Equivalent anti-fungal prophylaxis with itraconazole or liposomal- 
based amphotericin product may be used. 
 
Prophylaxis 
against 
pneumocystis 
carinii 
will 
be 
used. 
The 
regimen 
of 
choice 
is 
trimethoprim/sulfamethoxosole (Septra) DS po bid 2 days/week starting after engraftment (ANC 
>1500/uL, and Platelets >30,000/uL). An alternative regimen is dapsone 100 mg po daily. Prophylaxis 
will continue until at least day +90’ after transplant. 
 
Prophylaxis against bacterial infections should begin when the ANC is < 500/uL and continue until the 
ANC is > 1000/uL. Moxifloxacin 400 mg daily or an equivalent antibiotic is appropriate. 
 
Prophylaxis against herpes simplex and herpes zoster with acyclovir 400 mg po bid from day –2 until 
1 year post-transplant or as per institutional standard. Patients unable to take oral medication should 
receive acyclovir 2 mg/kg IV q12 h. 
 
Patients should be hospitalized in private rooms with positive pressure ventilation and filtered air 
systems, when possible. 
 
Strict low bacteria diet should be used when ANC < 500/uL. 
 
Recommended mouth care: 
 
a. Salt and soda swish tid 
b. Gel clear is allowed 
 
 
Transfusions: Institution standards should be followed for blood product support. In lieu of standards, 
packed RBCes should be given to maintain the hemoglobin >8.5 gm/dl or hematocrit >25%. Platelet 
should be transfused to keep the platelet count >10-20 x 109/l as per institution standards. Blood should 
be filtered and irradiated (3000 cGy).