Conditions: Sarcoma, Kaposi
Keywords: Kaposi's Sarcoma HIV Doxil VEGF Bevacizumab
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 16
Healthy volunteers: no

Brief summary:
Background:

* The drug liposomal doxorubicin is approved by the U.S. Food and Drug Administration (FDA) for the treatment of Kaposi's sarcoma (KS). A second drug, bevacizumab, is a biologic agent (such as antibodies, interleukins, and vaccines) that stops abnormal blood supply to tumors. Bevacizumab is approved by the FDA, in combination with other drugs, for the treatment of breast cancer, colon cancer, and lung cancer.
* Researchers are now studying the combination of liposomal doxorubicin with bevacizumab as a novel approach to the treatment of advanced KS. Researches will be measuring KS tumor responses to this combination to determine whether the drugs might have anti-KS activity.

Objectives:

* To estimate the overall response rate (ORR) of six cycles of liposomal doxorubicin combined with bevacizumab in patients with advanced KS.
* To evaluate the safety of the regimen and to estimate the complete response rate after six cycles, the median number of cycles needed to obtain a partial response, and the 12-month progression-free survival.

Eligibility:

* Patients 18 years or older with relatively severe acquired immune deficiency syndrome (AIDS)-related KS or patients with KS unrelated to AIDS or human immunodeficiency virus (HIV) infection, whose KS that can be evaluated for potential response to therapy and meet a number of other criteria.
* Women who are pregnant or breastfeeding are not eligible.
* Other ineligibility criteria include surgery within 4 weeks, chemotherapy within 3 weeks, heart disease, hemoptysis (coughing up blood), or gastrointestinal bleeding.

Design:

* Researchers will conduct the following tests before the start of the study:
* Physical examination and a detailed medical history.
* A biopsy.
* Blood and urine tests.
* Treatment will include two phases, an induction phase and a maintenance phase:
* Induction phase dose: Intravenous (IV) bevacizumab 15 mg/kg once, followed 7 days later by liposomal doxorubicin mg/m2 and bevacizumab every 3 weeks for six cycles.

Maintenance phase dose: IV bevacizumab every 3 weeks for 11 cycles.

* Monitoring will include a review of side effects, physical exam (including blood pressure), and blood and urine samples; following the induction phase, the patient will receive a multi gated acquisition scan and electrocardiography (EKG) to record electrical activity in the heart.
* Research tests include blood and saliva samples, additional biopsies (optional), and noninvasive imaging.
* Treatment is stopped if any of the following occur: completion of 1 year of therapy, progressive KS, patient preference, or unacceptable toxicity.
* Post-treatment evaluations include clinic visits every 3 months or as needed up to 2 years, and blood and saliva samples (for research).

Detailed description:
Background:

* Standard treatment for advanced Kaposi's sarcoma (KS) is a liposomal anthracycline, plus antiretroviral therapy (HAART) in patients with human immunodeficiency virus (HIV).
* KS is not curable and relapses are common. Prolonged use of liposomal anthracyclines with cumulative dosing exceeding 550 mg/m(2) is frequently required.
* KS is notable for pathogenic autocrine and paracrine vascular endothelial growth factor (VEGF) signaling. The monoclonal antibody, bevacizumab is a rational agent for the treatment of KS.
* Preliminary results from our phase II study of bevacizumab monotherapy, 03-C0110, suggest that bevacizumab has promising activity in the treatment of KS.
* The combination of anti-angiogenic therapy with cytotoxic chemotherapy has been a successful strategy in KS as well as other solid tumors.
* This pilot study will evaluate the activity and safety of liposomal doxorubicin combined with bevacizumab followed by bevacizumab maintenance in patients with advanced KS. A goal of this combination strategy is to develop a tolerable and highly active regimen that would limit the need for prolonged anthracycline use.

Objectives:

* The primary objective is to estimate the overall response rate (ORR) of six cycles of liposomal doxorubicin combined with bevacizumab in patients with advanced KS.
* Secondary objectives include evaluation of the safety of the regimen, as well as estimation of the complete response rate after 6 cycles, the median number of cycles need to obtain a partial response, and 12-month progression-free survival.

Eligibility:

Inclusion criteria:

* Age greater than or equal to 18
* Biopsy proven KS
* Indication for chemotherapy
* Any HIV status
* Normal multigated acquisition scan (MUGA)
* Able to tolerate aspirin 81 mg
* systolic blood pressure (SBP) \<150, diastolic blood pressure (DBP) \<90
* Urine protein \<1+ or 500mg/24hrs

Exclusion Criteria:

* Surgery within 4 weeks
* Thrombo-embolic disease
* Chemotherapy within 3 weeks
* Hemoptysis or severe gastrointestinal bleeding, unless caused by KS
* Pregnancy or breast feeding

Design:

* This is an open label, single center pilot with 2 cohorts. Cohort 1: HIV negative, HIV infected with stable KS despite 1 year of HAART with HIV viremic control, or HIV infected with progressive KS despite 4 months of HAART with HIV viremic control. Cohort 2: All other patients with advanced AIDS-associated KS.
* Subjects will receive bevacizumab 15 mg/kg and liposomal doxorubicin 20 mg/m(2) every 3 weeks until complete response (CR) or a maximum of 6 cycles. Those with stable disease or better will continue on bevacizumab 15 mg/kg monotherapy every 3 weeks for 11 cycles. HIV infected subjects will receive HAART.
* ORR will be calculated with 80% CI for each cohort separately. If estimates in the two cohorts are similar (p\>0.30 by a Fisher s exact test), they may be combined to form a somewhat more precise estimate of ORR after 6 cycles of treatment.
* A total of 10 evaluable patients will be accrued in each cohort.

Arms:
arm 1: Kaposi's Sarcoma (KS) in patients who are Human immunodeficiency virus (HIV) Negative, HIV infected with stable disease for one year despite antiretroviral therapy or progressive disease despite 4 months of antiretroviral therapy. arm 2: All other patients with advanced acquired immune deficiency syndrome (AIDS)-associated KS

Interventions: intervention 1: Liposomal Doxorubicin intervention 2: Bevacizumab
Intervention descriptions: intervention 1: Induction phase dose: Intravenous (IV) bevacizumab 15 mg/kg once, followed 7 days later by liposomal doxorubicin mg/m\^2 and bevacizumab every 3 weeks for six cycles. intervention 2: Induction phase dose: Intravenous (IV) bevacizumab 15 mg/kg once, followed 7 days later by liposomal doxorubicin mg/m\^2 and bevacizumab every 3 weeks for six cycles. Maintenance phase dose: IV bevacizumab every 3 weeks for 11 cycles.

Protocol document:
ICF_001.pdf: 
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MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:  09-C-0130 
CONTINUATION: page 2 of 14 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
 
novel approach to the treatment of advanced KS. We will be measuring KS tumor responses to 
this combination, in an attempt to determine whether the drug might have anti-KS activity that 
should be explored in further research. 
 
Why are you being asked to take part in this study? 
Individuals may be eligible to participate in the research study if they have relatively severe 
AIDS-related Kaposi’s sarcoma, or if they have Kaposi’s sarcoma unrelated to AIDS or HIV 
infection. To be eligible for the trial, patient-volunteers must have KS that can be evaluated for 
potential response to therapy, and meet a number of other criteria.  If you meet these criteria, you 
are being asked to take part in this study so that we may evaluate this novel combination of 
liposomal doxorubicin with bevacizumab in people, like yourself, with advanced KS. 
 
How many people will take part in this study?  
We plan to enroll 20-26 patient-volunteers in this study. 
 
Description of Research Study 
If you consent to participate in this study, you will receive therapy through a vein (IV), starting 
with an initial dose, followed one week later by therapy every 3 weeks for one year.  We will 
continue to follow you for up to 2 additional years to make sure that your KS does not worsen 
once therapy is stopped.  If your KS worsens during the course of your participation in the study, 
you may be eligible for additional liposomal doxorubicin and/or bevacizumab within this study. 
 
The treatment for KS in this study will consist of two phases, an induction phase and a 
maintenance phase.  The goal of the induction phase is to rapidly reduce your KS.  During the 
induction phase, you will receive a single dose of bevacizumab followed by 6 cycles of the 
combination of liposomal doxorubicin and bevacizumab every 3 weeks.  The goal of the 
maintenance phase is to attain further tumor shrinkage and prevent recurrences of KS, while 
minimizing the amount of liposomal doxorubicin used.  In the maintenance phase, you will not 
receive liposomal doxorubicin, but will continue to receive bevacizumab every 3 weeks for a 
total of 1 year of therapy.  If, during the first phase, you have no evidence of KS after fewer than 
6 cycles, we will discontinue the liposomal doxorubicin, and proceed to the second phase of the 
study.  
 
During the study, we will also be collecting blood and saliva, performing non-invasive imaging 
studies of your KS for research purposes, and performing 1-3 biopsies both for routine purposes 
as well as special research into the biology of KS and the effect of the research medications on 
your body and on the KS tumors (biopsies for research alone are optional).  A description of 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:  09-C-0130 
CONTINUATION: page 3 of 14 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
 
what will happen if you take part in this study, as well as a list of potential risks and discomforts 
associated with participation in the study are listed below. 
 
Due to a shortage of liposomal doxorubicin (brand name Doxil) in the United States, you may 
receive an alternate imported brand of liposomal doxorubicin (Lipodox).  The FDA has approved 
the temporary use of Lipodox during the national shortage of Doxil. 
 
What will happen if you take part in this research study?   
Before you begin the study, you will be evaluated by a physician investigator, as well as other 
members of the research team for eligibility in the study.  We will discuss your medical history 
in detail and draw blood from a vein and collect a urine sample to determine your eligibility to 
participate in the study.  A biopsy is required for participation.  If you have already had a biopsy, 
we will work with you to have the biopsy sent to pathologists at the NCI for review.  If you have 
not have not had a biopsy, we will arrange for a biopsy to confirm the diagnosis of KS. You will 
also undergo special tests of your heart as well as a chest X-ray to make sure that you are eligible 
to participate and to document whether KS affects your lungs.  Additional studies may be 
required to document the extent of KS, depending on your symptoms. 
 
During the study, you will receive a single dose of bevacizumab followed one week later by both 
liposomal doxorubicin and bevacizumab every 3 weeks for 6 cycles.  Patients with HIV will be 
required to be taking combination antiretroviral medications.  All patients will be required to 
take a daily baby aspirin to prevent blood clots. During the first cycle, you will be evaluated by a 
physician prior to therapy, as well as one week later, to answer any questions you may have and 
to ensure that you are tolerating the therapy.  On subsequent cycles, a physician will evaluate you 
on the day you receive therapy.  After the first 6 cycles, you will receive bevacizumab alone.  
During each cycle, approximately 10 teaspoons of blood will be collected from a vein to be used 
for laboratory studies that are part of routine care for patients receiving therapy, as well as 
special research studies.  Saliva will be collected during the first cycle, then every 3 cycles 
afterwards.  We will also collect a urine sample every cycle to make sure that the therapy is not 
damaging your kidneys.   If your KS completely disappears, you will be asked to repeat any 
abnormal tests that you had when you entered the study, including a biopsy. Optional tests will 
include an additional biopsy for special studies evaluating the effect of therapy on your KS 
tumor.  Part of the evaluation will include measurement of your blood pressure.  If your blood 
pressure is greater than 140/90 on two consecutive visits, you will be started on oral medications 
to control your blood pressure.  After completing the 6 cycles of the combination of liposomal 
doxorubicin and bevacizumab, you will have a repeat evaluation of your heart. 
 
 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:  09-C-0130 
CONTINUATION: page 4 of 14 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
 
On this protocol, you will have periodic conventional photographs made of your lesions. 
Additionally, three experimental imaging methods will be performed. The three methods are 
called: 1) laser Doppler imaging, 2) multi-spectral imaging and, 3) infrared thermal imaging. 
Laser Doppler imaging takes about 3 minutes to perform on each lesion.  It uses a low power 
laser beam that scans across the skin lesion being measured.  The instrument does not touch your 
skin. You may be asked to have a blood pressure cuff put on your arm and have laser Doppler 
imaging performed before and after the cuff is inflated for a short time (generally less than thirty 
seconds). We do not believe that this instrument will harm your skin: in standard practice a 
similar machine is used to measure how deeply severe burns affect the skin.  If you stare at a 
laser light it could harm your eyes, but precautions will be taken so that you will not stare at it.  It 
is also used to assess allergic responses in the skin.  However, its use in Kaposi’s sarcoma is 
experimental.  The purpose of this experimental use is to attempt to measure the amount of blood 
flow through the blood vessels in the Kaposi’s sarcoma lesions.  It will not have a therapeutic 
effect on the lesions.  The multi-spectral imaging exam should take about 2 minutes to perform 
on each lesion. It uses principles of the way hemoglobin absorbs light.  Hemoglobin is a protein 
in the blood that carries oxygen to your tissues.  The light on the multi-spectral imaging 
instrument is absorbed differently depending on whether the hemoglobin has oxygen attached to 
it or not.  This will allow an estimate to be made regarding the total blood volume, and how 
much of it is carrying oxygen or not.  We do not believe that the instrument will harm you.  The 
technique will not make your Kaposi’s sarcoma improve.  The thermal imaging takes about a 
minute to perform on each lesion. It uses a special camera to take digital infrared pictures of your 
skin. This enables us to form a picture of the temperature of your KS lesions and thus assess the 
blood flow in the Kaposi’s sarcoma lesions. We do not believe that the camera and lights will 
harm you.  These experimental imaging studies will be performed twice during the first cycle 
then repeated after the sixth cycle and after the last cycle of therapy. 
 
When you are finished taking the drugs, we will continue to follow you in clinic every 3 months 
for up to 2 years to make sure that your KS does not return or get worse.  If the KS should get 
worse during the observation, a second course of therapy may be possible within the study, and 
we would discuss further treatment options with you.  


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:  09-C-0130 
CONTINUATION: page 5 of 14 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
 
The following Study Chart outlines what will happen if you choose to participate. 
 
 
 
 
 
 
↓ 
 
 
 
 
 
 
 
 
 
 
 
↓ 
 
 
 
 
 
Screening for Eligibility 
• Medical History and Physical Exam 
• Review of Biopsy 
• Blood and Urine Studies 
• Cardiac MUGA and EKG 
• Chest X-Ray 
Treatment 
Induction Phase:  
IV Bevacizumab once, followed 7 days later by Liposomal 
Doxorubicin and Bevacizumab every 3 weeks for 6 cycles 
Maintenance Phase:  IV Bevacizumab every 3 weeks for 11 cycles 
Monitoring:  
Review of side effects 
Physical Exam, including blood pressure 
Blood and Urine Samples 
Cardiac MUGA and EKG after completing induction phase 
Research: 
Blood and saliva samples 
Additional biopsy (optional) 
Non-invasive imaging  
Stop treatment: 
Completion of one year of therapy 
Progressive KS 
 
Patient preference 
Unacceptable toxicity 
After treatment 
• Clinic visit every three months or as needed for up to 2 
years 
• Research blood and saliva samples 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:  09-C-0130 
CONTINUATION: page 6 of 14 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
 
Standard of Care Treatment: 
Treatments required for those participating in the study may include standard medications.  For 
example, patient-volunteers who are HIV positive must agree to take combination antiretroviral 
therapy. Those who develop hypertension while participating in this study will be prescribed 
blood pressure medications based on national guidelines for the management of hypertension. 
These treatments will not be experimental. Your doctors will describe your treatment plan to you 
in detail before asking you to sign this consent form.  Furthermore, participation in the study may 
include additional procedures to document the extent of KS in your case.  In such a case, you 
may be asked to sign a separate consent form for any additional treatment procedures not 
outlined in this consent. 
Birth Control 
If you are a woman who is breast feeding or pregnant, you may not take part in the study because 
we don’t know how this medicine would affect your baby or your unborn child. If you are a 
woman who can become pregnant, or are the partner of a woman who can become pregnant, you 
will need to practice an effective form of birth control before starting study treatment, during 
study treatment, and for 3 months after you finish study treatment.  If you think that you or your 
partner is pregnant, you should tell your study doctor or nurse at once.   
Effective forms of birth control include: 
  
• Abstinence  
• Intrauterine device (IUD) 
• Hormonal [birth control pills, injections, or implants] 
• Tubal ligation 
• Vasectomy 
• Barrier Methods [condoms] 
 
Alternative Approaches or Treatments 
 
People with advanced KS have several FDA approved therapy options for the management of 
advanced KS.  These include liposomal daunorubicin, liposomal doxorubicin, or paclitaxel.  
Those who are HIV positive should be taking combination antiretroviral therapy.  For patients 
with AIDS-associated KS who are not taking combination antiretroviral therapy at the time of 
diagnosis, additional therapy may be deferred to see if the KS improves with the treatment of 
HIV.  However, this approach generally takes longer than approaches that incorporate 
chemotherapy, and may not be appropriate for people with advanced AIDS-associated KS.  
Patients with limited or mild KS may be treated with radiation therapy, interferon-α, injection of 
chemotherapy into the KS tumor, or topical treatments. 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:  09-C-0130 
CONTINUATION: page 7 of 14 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
 
What other choices do I have if I do not take part in this study?  
 
Instead of being in this study, you have these options: 
 
• Getting treatment or care for your cancer without being in a study 
• Taking part in another study 
• Getting comfort care, also called palliative care.  This type of care helps reduce pain, 
tiredness, appetite problems and other problems caused by the cancer.  It does not treat 
the cancer directly.  Instead, it tries to improve how you feel.  Comfort care tries to keep 
you as active and comfortable as possible. 
Please talk to your doctor about these and other options. 
 
Risks or Discomforts of Participation 
What side effects or risks can I expect from being in this study?  
Likely (10% or greater incidence) 
• Weakness 
• Fever 
• Hypertension 
• Protein or blood in urine 
• Mouth sores 
• Nausea 
• Nose bleed  
• Low platelet counts (increased risk for bleeding) 
• Low white blood cells (increased risk for infection) 
• Anemia (low red blood cell counts, increased fatigue and mild shortness of breath) 
• Infections 
• Pain  
• Discomfort from blood draws, catheter placement or biopsies 
Less Likely (less than 10% incidence) 
• Diarrhea 
• Vomiting 
• Dehydration 
• Constipation 
• Difficulty swallowing 
• Weight loss 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:  09-C-0130 
CONTINUATION: page 8 of 14 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
 
• Asymptomatic abnormalities in liver tests 
• Gastrointestinal ulcers (esophagus, stomach, intestine, rectum or anus) 
• Gum bleeding 
• Bleeding hemorrhoids 
• Blood clots (thrombosis) in veins or arteries 
• Abdominal swelling 
• Leg swelling 
• Pleural effusion (fluid collection between ribs and lungs) 
• Dizziness  
 
Less Likely (less than 10% Incidence), continued 
 
• Anxiety, depression or panic attack 
• Cough 
• Herpes outbreak 
• Hoarseness  
• Kidney dysfunction 
• Hair loss 
• Rash 
• Wound healing complications 
• Hand and foot redness (hand-foot syndrome) 
• Abnormalities in blood levels of sodium, calcium, potassium, and magnesium or glucose 
• Muscle or joints aches 
• Cataracts 
• Increased tearing 
• Elevation in the level of bilirubin (a waste product of the liver), may lead to jaundice or 
discolored urine 
Rare but Serious 
• Gastrointestinal perforation 
• Fistula formation (abnormal hole or connection between organs) 
• Peritonitis (inflammation or infection of the abdominal cavity) 
• Hernias at sites of surgery 
• Bleeding from lungs, gastrointestinal tract, bladder or vagina 
• Bleeding after surgical procedures 
• Pancreatitis 
• Liver Failure 
• Bone marrow failure – Severely decreased red blood cells, white blood cells and platelets 
• Severe hypertension with headaches, confusion or other neurological symptoms 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:  09-C-0130 
CONTINUATION: page 9 of 14 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
 
• Stroke 
• Chest Pain / Heart Attack / Myocardial Infarction 
• Pulmonary Embolism 
• Abnormalities in heart rhythm 
• Acute pulmonary edema (shortness of breath due to fluid in the lungs) 
• Heart failure 
• Seizures, confusion, blindness (Reversible posterior leukoencephalopathy syndrome) 
• Severe kidney dysfunction 
• Acute infusion reaction (pain, low blood pressure, difficulty breathing) 
• Death 
 
Potential Benefits of Participation 
Are there benefits to taking part in this study?  
The aim of this study is to see if this experimental combination of liposomal doxorubicin with 
bevacizumab followed by bevacizumab alone will cause your KS to shrink.  We hope that you 
will get personal medical benefit from taking part in this study, but we cannot be certain. 
Because this study includes an effective FDA drug approved for KS, we expect that most 
participants will have some degree of tumor shrinkage while participating in this study. 
However, we do not know if the combination of liposomal doxorubicin with bevacizumab will 
be as good as or better than liposomal doxorubicin alone.  We cannot predict whether you will 
benefit directly from taking part in this study, although the knowledge gained from this study 
may help others in the future who have cancer.  Potential benefits could include shrinking of 
your KS or lessening of your symptoms, such as pain and swelling, which are caused by the 
cancer.  Additionally, you may require less liposomal doxorubicin than usually needed through 
participation in this study. 
Research Subject’s Rights 
What are the costs of taking part in this study?  
If you choose to take part in the study, the following will apply, in keeping with the NIH policy: 
• 
You will receive study treatment at no charge to you. This may include 
surgery, medicines, laboratory testing, x-rays or scans done at the 
Clinical Center, National Institutes of Health (NIH), or arranged for you 
by the research team to be done outside the Clinical Center, NIH if the 
study related treatment is not available at the NIH.  
• 
There are limited funds available to cover the cost of some tests and 
procedures performed outside the Clinical Center, NIH.  You may have 
to pay for these costs if they are not covered by your insurance company. 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:  09-C-0130 
CONTINUATION: page 10 of 14 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
 
• 
Medicines that are not part of the study treatment will not be provided or 
paid for by the Clinical Center, NIH. 
• 
Once you have completed taking part in the study, medical care will no 
longer be provided by the Clinical Center, NIH. 
Will your medical information be kept private?  
We will do our best to make sure that the personal information in your medical record will be 
kept private.  However, we cannot guarantee total privacy.  Organizations that may look at 
and/or copy your medical records for research, quality assurance, and data analysis include: 
 
• The National Cancer Institute (NCI) and other government agencies, like the Food and 
Drug Administration (FDA), which are involved in keeping research safe for people. 
• National Cancer Institute Institutional Review Board 
• Qualified representatives from Genentech, the pharmaceutical company who produces 
Bevacizumab. 
 
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.  
 
Stopping Therapy  
Your doctor may decide to stop your therapy for the following reasons: 
• if he/she believes that it is in your best interest 
• if your disease comes back during treatment 
• if you have side effects from the treatment that your doctor thinks are too severe 
• if new information shows that another treatment would be better for you 
 
In this case, you will be informed of the reason therapy is being stopped. 
 
You can stop taking part in the study at any time. However, if you decide to stop taking part in 
the study, we would like you to talk to the study doctor and your regular doctor first. 
 
If you decide at any time to withdraw your consent to participate in the trial, we will not collect 
any additional medical information about you. However, according to FDA guidelines, 
information collected on you up to that point may still be provided to Genentech or designated 
representatives. If you withdraw your consent and leave the trial, any samples of yours that have 
been obtained for the study and stored at the NCI can be destroyed upon request. However, any 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:  09-C-0130 
CONTINUATION: page 11 of 14 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
 
samples and data generated from the samples that have already been distributed to other 
researchers or placed in the research databases cannot be recalled and destroyed. 
 
Conflict of Interest 
 
The National Institutes of Health (NIH) reviews NIH staff researchers at least yearly for conflicts 
of interest.  The following link contains details on this process 
http://ethics.od.nih.gov/procedures/COI-Protocol-Review-Guide.pdf.  You may ask your 
research team for a copy of the Protocol Review Guide or for more information.  Members of the 
research team who do not work for NIH are expected to follow these guidelines but they do not 
need to report their personal finances to the NIH. 
 
Members of the research team working on this study may have up to $15,000 of stock in the 
companies that make products used in this study.  This is allowed under federal rules and is not a 
conflict of interest.  
 
The National Institutes of Health and the research team for this study are using bevacizumab, a 
drug developed by Genentech, through a joint study with your researchers and the company.  
This means it is possible that the results of this study could lead to payments to NIH scientists 
and to the NIH.  By law, government scientists are required to receive such payments for their 
inventions.  You will not receive any money from the development of bevacizumab.  
Optional Biopsy  
A punch skin biopsy will be performed.  Prior to the biopsy, you will receive local anesthesia 
through a small injection into the area of skin surrounding the biopsy site.  One or two half-
centimeter samples of KS will be removed with a needle during the skin biopsy.  You may 
require a stitch after the biopsy.  Risks of the biopsy include local oozing of blood or discomfort.  
Infection is a rare complication of skin biopsies.  The biopsy to be performed is exclusively for 
research purposes and will not benefit you.  It might help other people in the future.  Even if you 
sign "yes" to have the biopsy you can change your mind at any time.  Please read each sentence 
below and think about your choice. After reading each sentence, circle and initial the answer that 
is right for you. The decision to participate in this part of the research is optional, and no matter 
what you decide to do, it will not affect your care.  
 
I agree to have the tumor biopsy for the research tests in this study.  
 
 
Yes              No               Initials_________ 
 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:  09-C-0130 
CONTINUATION: page 12 of 14 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
 
Optional Studies  
We would like to keep some of the specimens and data that are collected for future research.  
These specimens and data will be identified by a number and not your name.  The use of your 
specimens and data will be for research purposes only and will not benefit you.  It is also 
possible that the stored specimens and data may never be used.  Results of research done on your 
specimens and data will not be available to you or your doctor.  It might help people who have 
cancer and other diseases in the future.   
 
If you decide now that your specimens and data can be kept for research, you can change your 
mind at any time. Just contact us and let us know that you do not want us to use your specimens 
and/or data.  Then any specimens that remain will be destroyed and your data will not be used 
for future research.  
 
Please read each sentence below and think about your choice. After reading each sentence, circle 
and initial the answer that is right for you.  No matter what you decide to do, it will not affect 
your care. 
1. My specimens and data may be kept for use in research to learn about, prevent, or treat cancer.  
 
Yes              No               Initials_________ 
2. My specimens and data may be kept for use in research to learn about, prevent or treat other 
health problems (for example: diabetes, Alzheimer's disease, or heart disease).  
 
Yes              No               Initials_________ 
 
3. My specimens and data may be used to evaluate genetic changes in genes called VEGF and 
VEGF-R.  These genes may be involved in one’s risk for KS, as well as the way the drug 
bevacizumab works.  NIH researchers are interested in studying these genes, in a preliminary 
way, in patient-volunteers with KS who are receiving bevacizumab.  
 
Yes              No               Initials_________ 
 
4. Someone may contact me in the future to ask permission to use my specimens and/or data in 
new research not included in this consent.  
 
Yes              No               Initials_________ 
 


MEDICAL RECORD 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
STUDY NUMBER:  09-C-0130 
CONTINUATION: page 13 of 14 pages 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH 
STUDY (Continuation Sheet) 
• 
Adult Patient or 
• Parent, for Minor Patient 
NIH-2514-1 (07-09) 
P.A.:  09-25-0099 
 
File in Section 4:  Protocol Consent 
 
 
 
OTHER PERTINENT INFORMATION 
1. 
Confidentiality.  When results of an NIH research study are reported in medical journals 
or at scientific meetings, the people who take part are not named and identified.  In most cases, 
the NIH will not release any information about your research involvement without your written 
permission.  However, if you sign a release of information form, for example, for an insurance 
company, the NIH will give the insurance company information from your medical record.  This 
information might affect (either favorably or unfavorably) the willingness of the insurance 
company to sell you insurance. 
The Federal Privacy Act protects the confidentiality of your NIH medical records.  However, you 
should know that the Act allows release of some information from your medical record without 
your permission, for example, if it is required by the Food and Drug Administration (FDA), 
members of Congress, law enforcement officials, or authorized hospital accreditation 
organizations. 
2. 
Policy Regarding Research-Related Injuries.  The Clinical Center will provide short-
term medical care for any injury resulting from your participation in research here.  In general, 
no long-term medical care or financial compensation for research-related injuries will be 
provided by the National Institutes of Health, the Clinical Center, or the Federal Government.  
However, you have the right to pursue legal remedy if you believe that your injury justifies such 
action. 
3. 
Payments.  The amount of payment to research volunteers is guided by the National 
Institutes of Health policies.  In general, patients are not paid for taking part in research studies at 
the National Institutes of Health.  Reimbursement of travel and subsistence will be offered 
consistent with NIH guidelines. 
4. 
Problems or Questions.  If you have any problems or questions about this study, or 
about your rights as a research participant, or about any research-related injury, contact the 
Principal Investigator, Robert Yarchoan, M.D., Building 10, Room 6N106, Telephone:  301-496-
0328. You may also want to contact the lead research nurse, Ms. Kathleen Wyvill at 301-496-
8959.  If you have any questions about the use of your specimens or data for future research 
studies, you may also contact the Office of the Clinical Director, Telephone:  301-496-4251.  
You may also call the Clinical Center Patient Representative at 301-496-2626. 
5. 
Consent Document.  Please keep a copy of this document in case you want to read it 
again. 


MEDICAL RECORD 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
STUDY NUMBER:  09-C-0130 
CONTINUATION: page 14 of 14 pages 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH 
STUDY (Continuation Sheet) 
• 
Adult Patient or 
• Parent, for Minor Patient 
NIH-2514-1 (07-09) 
P.A.:  09-25-0099 
 
File in Section 4:  Protocol Consent 
 
 
 
 
 
COMPLETE APPROPRIATE ITEM(S) BELOW: 
A. Adult Patient’s Consent 
B. Parent’s Permission for Minor Patient. 
I have read the explanation about this study 
and have been given the opportunity to discuss 
it and to ask questions.  I hereby consent to 
take part in this study. 
I have read the explanation about this study 
and have been given the opportunity to discuss 
it and to ask questions.  I hereby give 
permission for my child to take part in this 
study.   
(Attach NIH 2514-2, Minor’s Assent, if 
applicable.) 
 
  
  
 
 
 
Signature of Adult Patient/ 
Legal Representative 
Date 
Signature of Parent(s)/ Guardian Date 
 
 
Print Name 
 
 
Print Name 
C. Child’s Verbal Assent (If Applicable) 
The information in the above consent was described to my child and my child agrees to 
participate in the study. 
 
  
  
 
Signature of Parent(s)/Guardian 
Date 
Print Name 
THIS CONSENT DOCUMENT HAS BEEN APPROVED FOR USE  
FROM MARCH 13, 2017 THROUGH MARCH 12, 2018.  
 
 
 
 
 
 
 
 
Signature of Investigator 
Date 
Signature of Witness 
Date 
 
 
Print Name 
 
 
Print Name 
 

Prot_000.pdf: 
Amendment
Protocol Number:
09C0130-H
Principal Investigator: Robert Yarchoan 
NCI 
HAMB 
301.496.0328 
robert.yarchoan@nih.gov
(NIH Employee Name, Institute/Branch, Telephone and e-mail)
Reference Number:
378575
Protocol Title:
Pilot Study of Liposomal Doxorubicin Combined with Bevacizumab Followed by Bevacizumab Monotherapy in Adults with Advanced 
Kaposi's Sarcoma
SIGNATURES
Principal Investigator (*): 
Robert Yarchoan - applied signature on 03/07/2018 2:06 PM EST
Accountable Investigator:
PI is the Accountable Investigator
Branch Chief/CC Department Head (**):
Robert Yarchoan - applied signature on 03/07/2018 2:07 PM EST
Medical Advisory Investigator (if applicable):
N/A
Lead Associate Investigator signature:
Ramya Ramaswami - applied signature on 03/07/2018 2:17 PM EST
Referral Contact signatures:
Anaida Widell - applied signature on 03/07/2018 3:29 PM EST
Associate Investigators signatures:
Kathryn Lurain - applied signature on 03/07/2018 3:24 PM EST 
Matt Lindsley - applied signature on 03/12/2018 9:44 AM EDT 
Anaida Widell - applied signature on 03/07/2018 3:29 PM EST
For Institute/Center Scientific Review Committee:
N/A
Other IC Clinical Director signatures:
N/A
APPROVALS
IRB Chair:
Michael Hamilton - applied signature on 03/14/2018 3:01 PM EDT
Clinical Director:
N/A
CONCURRENCE
OPS Protocol Specialist:
Signature
Print Name
Date
* Signature signifies that investigators on this protocol have been informed that the collection and use of personally identifiable information at
the NIH are maintained in a system of record governed under provisions of the Privacy Act of 1974. The information provided is mandatory for 
employees of the NIH to perform their assigned duties as related to the administration and reporting of intramural research protocols and 
used solely for those purposes.  Questions may be addressed to the Protrak System Owner. 
** I have reviewed this research project and considered the NIH Policy for Inclusion of Women and Minorities in Clinical Research. Taking into 
account the overall impact that the project could have on the research field involved, I feel the current plans adequately includes both sex/
gender, minorities, children, and special populations, as appropriate. The current enrollment is in line with the planned enrollment report for 
inclusion of individuals on the basis of their sex/gender, race, and ethnicity and is appropriate and of scientific and technical merit. 
Tonica Johnson
AM H
03/19/18


Abbreviated Title: Doxil/Bevacizumab in KS 
Version Date: 01/16/2018 
 
1 
Abbreviated Title: 
 
Doxil/Bevacizumab in KS 
 
CC Protocol Number:  
09-C-0130 H 
Version Date: 
 
01/16/2018 
NCT#:  
 
 
NCT00923936 
Title:  Pilot Study of Liposomal Doxorubicin Combined with Bevacizumab Followed by 
Bevacizumab Monotherapy in Adults with Advanced Kaposi’s Sarcoma 
 
NCI Principal Investigator:  
Robert Yarchoan, MD A-F 
 
 
 
 
 
HIV and AIDS Malignancy Branch 
 
 
 
 
 
Center for Cancer Research 
 
 
 
 
 
National Cancer Institute 
 
 
 
 
 
10 Center Drive, 6N-106  
Bethesda, MD 20892-1868  
240-760-6075  
robert.yarchoan@nih.gov  
 
 
Commercial Agents:  
Bevacizumab and Liposomal Doxorubicin  


Abbreviated Title: Doxil/Bevacizumab in KS 
Version Date: 01/16/2018 
 
2 
 
PRÉCIS 
Background: 
• Standard treatment for advanced Kaposi’s sarcoma (KS) is a liposomal anthracycline, 
plus antiretroviral therapy (HAART) in patients with HIV. 
• KS is not curable and relapses are common. Prolonged use of liposomal anthracyclines 
with cumulative dosing exceeding 550 mg/m2 is frequently required.  
• KS is notable for pathogenic autocrine and paracrine VEGF signaling. The monoclonal 
antibody, bevacizumab is a rational agent for the treatment of KS.  
• Preliminary results from our phase II study of bevacizumab monotherapy, 03-C0110, 
suggest that bevacizumab has promising activity in the treatment of KS. 
• The combination of anti-angiogenic therapy with cytotoxic chemotherapy has been a 
successful strategy in KS as well as other solid tumors. 
• This pilot study will evaluate the activity and safety of liposomal doxorubicin combined 
with bevacizumab followed by bevacizumab maintenance in patients with advanced KS.  
A goal of this combination strategy is to develop a tolerable and highly active regimen 
that would limit the need for prolonged anthracycline use. 
Objectives: 
• The primary objective is to estimate the overall response rate (ORR) of six cycles of 
liposomal doxorubicin combined with bevacizumab in patients with advanced KS. 
Eligibility: 
Inclusion criteria: 
• Age ≥18 
• Biopsy proven KS 
• Indication for chemotherapy 
• Any HIV status 
• Normal MUGA  
• Able to tolerate aspirin 81 mg  
• SBP <150, DBP <90 
• Urine protein <1+ or 
500mg/24hrs 
Exclusion Criteria: 
• Surgery within 4 weeks  
• Thrombo-embolic disease  
• Chemotherapy within 3 weeks 
• Hemoptysis or severe 
gastrointestinal bleeding, unless 
caused by KS 
• Pregnancy or breast feeding 
Design: 
• This is an open label, single center pilot with 2 cohorts. Cohort 1: HIV negative, HIV 
infected with stable KS despite 1 year of HAART with HIV viremic control, or HIV 
infected with progressive KS despite 4 months of HAART with HIV viremic control. 
Cohort 2: All other patients with advanced AIDS-associated KS. 


Abbreviated Title: Doxil/Bevacizumab in KS 
Version Date: 01/16/2018 
 
3 
• Subjects will receive bevacizumab 15 mg/kg and liposomal doxorubicin 20 mg/m2 
every 3 weeks until complete response (CR) or a maximum of 6 cycles. Those with 
stable disease or better will continue on bevacizumab 15 mg/kg monotherapy every 3 
weeks for 11 cycles. HIV infected subjects will receive HAART. 
• ORR will be calculated with 80% CI for each cohort separately. If estimates in the two 
cohorts are similar (p>0.30 by a Fisher’s exact test), they may be combined to form a 
somewhat more precise estimate of ORR after 6 cycles of treatment. 
• A total of 10 evaluable patients will be accrued in each cohort. 


Abbreviated Title: Doxil/Bevacizumab in KS 
Version Date: 01/16/2018 
 
4 
TABLE OF CONTENTS 
PRÉCIS .......................................................................................................................................... 2 
TABLE OF CONTENTS ............................................................................................................. 4 
1. 
INTRODUCTION................................................................................................................. 6 
1.1 
STUDY OBJECTIVES ..................................................................................................... 6 
1.2 
BACKGROUND AND RATIONALE................................................................................... 6 
2. 
ELIGIBILITY ASSESSMENT AND ENROLLMENT .................................................. 14 
2.1 
ELIGIBILITY CRITERIA ............................................................................................... 14 
2.2 
RESEARCH ELIGIBILITY EVALUATION ........................................................................ 17 
2.3 
REGISTRATION PROCEDURES ..................................................................................... 18 
3. 
STUDY IMPLEMENTATION .......................................................................................... 18 
3.1 
STUDY DESIGN .......................................................................................................... 18 
3.2 
DRUG ADMINISTRATION ............................................................................................ 19 
3.3 
TREATMENT MODIFICATIONS .................................................................................... 20 
3.4 
PHARMACOKINETIC STUDIES ..................................................................................... 25 
3.5 
PROTOCOL EVALUATION ........................................................................................... 25 
3.6 
CONCURRENT THERAPIES .......................................................................................... 31 
3.7 
SURGICAL GUIDELINES .............................................................................................. 33 
3.8 
RADIATION THERAPY GUIDELINES ............................................................................ 33 
3.9 
OFF TREATMENT AND OFF STUDY CRITERIA ............................................................. 33 
3.10 
OFF-STUDY PROCEDURE ............................................................................................ 34 
3.11 
POST TREATMENT EVALUATION (FOLLOW-UP) ......................................................... 34 
4. 
SUPPORTIVE CARE ........................................................................................................ 35 
4.1 
GENERAL KS AND HIV RELATED .............................................................................. 35 
4.2 
OPPORTUNISTIC INFECTIONS ...................................................................................... 36 
4.3 
ANEMIA ..................................................................................................................... 36 
4.4 
THROMBOCYTOPENIA ................................................................................................ 36 
4.5 
FEBRILE NEUTROPENIA .............................................................................................. 36 
4.6 
HYPERTENSION .......................................................................................................... 36 
5. 
DATA COLLECTION AND EVALUATION ................................................................. 36 
5.1 
DATA COLLECTION .................................................................................................... 36 
5.2 
RESPONSE CRITERIA .................................................................................................. 37 
5.3 
TOXICITY CRITERIA ................................................................................................... 39 


Abbreviated Title: Doxil/Bevacizumab in KS 
Version Date: 01/16/2018 
 
5 
5.4 
STATISTICAL CONSIDERATIONS ................................................................................. 40 
5.5 
MULTI-INSTITUTIONAL GUIDELINES .......................................................................... 43 
5.6 
DATA AND SAFETY MONITORING PLAN ..................................................................... 43 
6. 
HUMAN SUBJECTS PROTECTIONS ............................................................................ 43 
6.1 
RATIONALE FOR SUBJECT SELECTION ........................................................................ 43 
6.2 
PARTICIPATION OF CHILDREN .................................................................................... 44 
6.3 
EVALUATION OF BENEFITS AND RISKS/DISCOMFORTS ............................................... 44 
6.4 
RISK/BENEFITS ANALYSIS ......................................................................................... 44 
6.5 
SPECIMEN HANDLING GUIDELINES ............................................................................ 44 
6.6 
CONSENT AND ASSENT PROCESS AND DOCUMENTATION ........................................... 46 
7. 
SAFETY REPORTING REQUIREMENTS/ DATA AND SAFETY MONITORING 
PLAN ............................................................................................................................................ 47 
7.1 
DEFINITIONS .............................................................................................................. 47 
7.2 
NCI-IRB AND CLINICAL DIRECTOR REPORTING ....................................................... 48 
7.3 
DATA AND SAFETY MONITORING PLAN ..................................................................... 49 
8. 
PHARMACEUTICAL AND INVESTIGATIONAL DEVICE INFORMATION ....... 49 
8.1 
BEVACIZUMAB ........................................................................................................... 49 
8.2 
LIPOSOMAL DOXORUBICIN ......................................................................................... 53 
9. 
REFERENCES .................................................................................................................... 55 
10. 
APPENDICES ................................................................................................................. 60 
10.1 
APPENDIX 1: SCHEDULE OF EVALUATION .............................................................. 60 
10.2 
APPENDIX 2: ECOG PERFORMANCE CRITERIA ....................................................... 62 
10.3 
APPENDIX 3: DESCRIPTION OF NON-INVASIVE IMAGING DEVICES ......................... 63 
 
 
 
 


Abbreviated Title: Doxil/Bevacizumab in KS 
Version Date: 01/16/2018 
 
6 
1. INTRODUCTION 
1.1 
STUDY OBJECTIVES 
1.1.1 Primary 
1.1.1.1 
Estimate the overall response rate of liposomal doxorubicin combined with 
bevacizumab after six 3-week cycles in patients with advanced KS. 
1.1.2 Secondary 
1.1.2.1 
Assess the safety and toxicities of liposomal doxorubicin combined with 
bevacizumab in patients with advanced KS 
1.1.2.2 
Estimate the complete response rate of liposomal doxorubicin combined with 
bevacizumab after six 3-week cycles in evaluable patients with advanced KS  
1.1.2.3 
Estimate the median number of cycles of liposomal doxorubicin combined with 
bevacizumab followed by bevacizumab alone required to achieve a partial response 
in evaluable patients with advanced KS 
1.1.2.4 
Estimate 12-month progression-free survival in evaluable patients with advanced 
KS treated with liposomal doxorubicin combined with bevacizumab followed by 11 
cycles of bevacizumab 
1.1.2.5 
Evaluate the impact of liposomal doxorubicin combined with bevacizumab on CD4 
counts 
1.1.2.6 
Evaluate the impact of liposomal doxorubicin combined with bevacizumab, 
followed by 11 cycles of bevacizumab maintenance, on peripheral blood 
mononuclear cell (PBMC) and saliva KSHV viral load 
1.1.2.7 
Explore the short-term effects of bevacizumab and intermediate and long term 
effects of the combination of bevacizumab and liposomal doxorubicin on blood 
flow to cutaneous KS lesions using non-invasive imaging techniques 
1.2 
BACKGROUND AND RATIONALE 
Kaposi’s Sarcoma (KS) is a multifocal angioproliferative malignancy histologically consisting of 
proliferative endothelial cells with enhanced vascular permeability, an inflammatory component, 
and a proliferation KSHV infected spindle cells. The γ-herpes virus, Kaposi’s sarcoma-
associated herpes virus (KSHV), also known as human herpesvirus-8 (HHV-8), is a necessary 
but insufficient cause of KS, while HIV is an important co-factor, which markedly increases the 
risk for the development of KS. 
1.2.1 Background on Liposomal Doxorubicin for the Treatment of KS  
First line therapy for HIV-associated KS is combination anti-retroviral therapy (HAART). The 
effectiveness of HAART in the management of KS is likely due to control of HIV viremia and 
improved KSHV specific cellular immunity 1, 2.  Regression of KS lesions has been reported with 
HAART.  However, in patients with advanced or symptomatic disease, chemotherapy is 
indicated.  Cytotoxic agents with modest efficacy in KS include bleomycin, vincristine, 
vinblastine, doxorubicin, and etoposide, whereas paclitaxel3, 4 and liposomal anthracyclines5, 6 
have been demonstrated to have improved response rates over older agents.  Liposomal 
preparation of doxorubicin may improve delivery of doxorubicin to the vascular lesions of KS7, 


Abbreviated Title: Doxil/Bevacizumab in KS 
Version Date: 01/16/2018 
 
7 
and the addition of liposomal doxorubicin has been demonstrated to be effective in leading to 
biopsy demonstrated regression of KS spindle-cells8. Currently, liposomal anthracyclines are the 
standard-of-care first line cytotoxic agent based on phase III studies (conducted prior to 
widespread availability of HAART) demonstrating overall response rates (ORR) of 46-59%, 
which were superior to combination chemotherapy. Liposomal anthracyclines also offer reduced 
toxicity 5, 6  and improved quality-of-life compared to doxorubicin, bleomycin and vincristine 
(ABV)9.  Studies of liposomal doxorubicin conducted after the introduction of HAART have 
demonstrated an ORR of 55-76% 10-12, and liposomal doxorubicin has retained its high 
therapeutic index in long term follow-up of patients treated in the HAART era.  However, KS is 
not curable, and one-year progression-free survival with either liposomal doxorubicin until best 
response (median number of cycles = 9) or 6 cycles of liposomal doxorubicin plus IL12 followed 
by IL-12 maintenance is approximately 70% 11, 13. Long-term administration of chemotherapy is 
often required.  An approach to advanced KS that employs combination bio-chemotherapy 
followed by biologic therapy alone was established in our phase II study of liposomal 
doxorubicin combined with IL12 followed by IL12 alone.  In this study, the median number of 
cycles required to obtain a partial response was 2 cycles, and seven of the nine complete 
responses observed in this study occurred while subjects were receiving IL12 monotherapy13.  
Overall survival of patients with KS has improved dramatically since the introduction of 
HAART in 199614. While death from KS is rare in HIV-infected individuals in North America 
and Europe15, patients with advanced KS, especially HIV-associated KS, are a population at risk 
for second malignancies or death.  Based on SEER data from 1980-200, patients with HIV-
associated KS have are 9 times more likely to develop a second cancer than the general 
population, and 75 times more likely to develop non-Hodgkin’s lymphoma16.  Estimates of death 
due to KS in the HAART era are available from recent KS treatment studies as well as from the 
Mortalité 2000 Study Group, which performed a national survey of causes of death among 
people with HIV performed in France in 200017.  For patients that require chemotherapy, 
approximately 3-8% of patients will die of KS within 12 months, despite liposomal doxorubicin 
based therapy.11, 13.  Furthermore, an additional 9% died of second malignancies during phase IV 
evaluation of liposomal doxorubicin.11  In the Mortalité 2000 Study of 964 deaths among people 
with HIV in France in 2000, 28% of all  deaths were related to malignancy, and 15% of 
malignant deaths were due to KS, 39% were due to NHL, 1% was due to cervical cancer, and 
45% were due to non-AIDS defining malignancies17. 
Given the dramatically improved survival of patients with HIV after the introduction of HAART 
and the tendency for KS to recur, long-term toxicities must be considered.  While cardiotoxicity 
associated with liposomal doxorubicin is less frequent than that with doxorubicin, long-term 
treatment with liposomal doxorubicin (at 20mg/m2 per cycle) in the management of KS often 
leads to cumulative dosing greater than 550 mg/m2 11.  The long-term cardiac toxicity of 
prolonged exposure to liposomal doxorubicin in this population is unknown.  Symptomatic heart 
failure occurred in less than 1% of 754 patients with KS treated on clinical trials. (Doxil 
prescribing information).  However changes in echocardiograph findings have been noted in 
11% of women with breast cancer treated with 50 mg/m2 of liposomal doxorubicin to a 
cumulative dose of > 450 mg/m2, which has lead to a Black Box Warning for cumulative 
liposomal doxorubicin doses approaching 550mg/m2.  (Doxil prescribing information).  
Additionally, endomyocardial biopsies performed on patients who had received cumulative 
doses > 400 mg/m2 of liposomal doxorubicin for the treatment of KS demonstrated early 


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(Billingham scale Grade 1) myocyte damage in 3 of 10 patients.  Novel anthracycline sparing 
approaches are therefore needed. 
1.2.2 Background on Targeting Angiogenesis in KS 
Rational approaches to the targeted treatment of KS exploit pro-angiogenic signaling pathways 
that are central to the molecular pathogenesis of KSHV related malignancies. Multiple 
preclinical models and evaluation of KS biopsy samples have demonstrated that KS depends on 
autocrine and paracrine signaling through multiple pathways.  Early work demonstrated that 
various KS cell lines expressed bFGF mRNA levels 6-8 times that of HUVEC cells. Cultured 
media from KS cell lines was able to stimulate both HUVEC and KS cell growth, while anti-
bFGF Ab inhibited this paracrine signaling18. Shortly thereafter, it was noted that KS3 and KS4 
cell lines, derived from pleural effusions, also expressed elevated levels VEGF121 and VEGF165, 
two isoforms of VEGF-A derived from alternative splicing19. Using in-situ radiolabeled mRNA 
probes in biopsy samples from AIDS-KS cases, VEGF165 mRNA was increased in spindle 
shaped cells (compared to granulation tissue) but not in tumor endothelial cells. 
Immunohistochemistry for VEGF165, on the other hand, demonstrated high levels on the 
endothelial cells20.  As the case with bFGF, cultured media of AIDS-KS cell lines also has high 
levels of VEGF-A, and anti-VEGF antibodies inhibit the HUVEC proliferation that occurs in the 
presence of AIDS-KS cell line cultured media. Furthermore, anti-bFGF Ab and anti-VEGF-A 
antibodies are synergistic in inhibiting paracrine signaling21.  Evaluation of VEGFR-1 and 
VEGFR-2, the receptors for VEGF-A, in KS preclinical models and KS biopsies support the role 
of VEGF-A autocrine and paracrine signaling in the pathogenesis of KS. In 
immunohistochemical stains of KS biopsies, stromal vessels stain strongly for VEGFR-1 and 
VEGFR-2 while spindle cells had strong expression of VEGFR-222. KS cell lines express 
elevated levels of VEGF-A mRNA, and both cell lines and KS tumor samples express increased 
VEGFR-1 and VEGFR-2 mRNA compared to normal skin biopsies23. In addition to up-
regulation of VEGFR-2 in KS cell lines, the cultured media from KSHV infected BMEC lead to 
upregulation of VEGFR-2 in uninfected HUVEC24. VEGF-A siRNA inhibits KS cell 
proliferation23. Evaluation of various PEL cell lines confirms up-regulation of VEGF-A, 
VEGFR-1 and VEGFR-2 mRNA, and anti-VEGF-A antibodies inhibit the formation of PEL in a 
nude mouse xenograph model25. Antibodies against VEGFR-2, VEGF-A siRNA or VEGFR-2 
siRNA inhibit cell proliferation, again supporting the importance of autocrine signaling26. 
Together, this data demonstrates the importance of paracrine and autocrine VEGF-A signaling, 
and provides evidence of upregulation of VEGF-A, VEGFR-1 and VEGFR-2 in both the spindle 
cell and endothelial cell compartments of KS lesions. 
Additionally, VEGFR-3, a receptor whose expression is generally limited to lymphoid 
endothelial cells, has been evaluated in KS59 and KS35 cell lines.  Immunohistochemistry and 
Western blot demonstrates robust VEGFR-3 expression in these cell lines27, 28.  
Immunohistochemical and radiolabeled staining of KS biopsy samples confirmed VEGFR-3 
expression on spindle cells but not endothelial cells.28-30. When KSHV infected HUVEC cell 
cultures are compared to uninfected HUVEC cultures, increases in mRNA by RT-PCR for 
VEGF A, B, C, and D as well as VEGFR-1, VEGFR-2, and VEGFR-3 are noted, and IHC 
confirmed the strong expression of all three receptors in the KSHV infected HUVEC cells26.  For 
the spindle cells in KS, additional proliferative pathways through VEGFR-3 appear to also be 
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Evaluation of KSHV lytic and latent genes suggests that the virus has developed redundant 
mechanisms for up-regulation of cellular VEGF.  Evaluation of several viral genes, including v-
GPCR, v-IL-6, LANA, and K1 offer some insight into the signaling pathways involved.  The v-
GPCR, encoded by ORF74, is a constitutively activated lytic gene most closely related to the 
chemokine receptor CXCR2. Transfection of NIH3T3 cells or a PEL cell line (BC3) with v-
GPCR leads to cells that produce VEGF-A 31, 32.  Cultured media from these transfected cells 
support HUVEC cell cultures, while anti-VEGF-A antibodies inhibit proliferation. Furthermore, 
inoculation of these transfected cells in nude mice leads to the formation of vascular tumors with 
histological features of KS. Evaluation of intracellular signaling cascades using kinase assays 
demonstrate that v-GPCR induces JNK and p38 but not MAPK31. A VEGF-A luciferase reporter 
in this model demonstrates that the upregulation of VEGF depends on a hypoxia response 
element (HRE) in the VEGF promoter. v-GPCR stimulated upregulation of VEGF is associated 
with p38 phosporylation and stabilization of HIF-133. HUVEC cell lines transfected with v-
GPCR also maintain high mRNA expression of VEGFR-2, and these cells undergo apoptosis 
when exposed PTK787, a small molecule tyrosine kinase inhibitor that inhibits all VEGF 
receptors34.  
v-IL6 is a second lytic gene product with 25% amino acid homology to human IL-6. 
Transfection of v-IL6 into NIH 3T3 also leads to 6-8 fold increases in VEGF-A mRNA. 
Subcutaneous injection of v-IL6 transfected NIH3T3 cells in nude mice also leads to spindle 
shaped tumors35. 
The K1 gene of KSHV encodes a transmembrane glycoprotein related to the immunoglobin 
receptor family with a constitutively active signaling through an intracellular immunoreceptor 
tyrosine-based activation motif (ITAM). K1 transgenic mice develop plasmacytoid and 
sarcomatoid tumors36, and the lymph nodes from the K1 transgenic mouse show high levels of 
VEGF-A by immunohistochemistry.  A lymphoma cell line derived from tumors from the K1 
transgenic mouse, KVL-1, produce high levels of VEGF in cultured supernatants. Transfection 
of K1 into various B-cell lymphoma cell lines also lead to increased VEGF compared to the 
same cell lines transfected with a K1-mutant that lacked the ITAM sequence37. In an endothelial 
cell model, K1 transduction into HUVECs leads to immortalized cell that produce high levels of 
VEGF-A through increased transcriptional activity. As in the KLV-1 model, increases in 
supernatant VEGF are only seen with transfection with wild-type K1 and not K1 mutation 
expression plasmids38. Co-immunoprecipitation and western blot studies suggest that K1 
transfected endothelial cells activate VEGFR-2, with downstream signaling occurring through 
the PI3K/Akt pathway. KS tissue array from the AIDS and Cancer Specimen Resource was 
stained with polyclonal anti-K1 antibody. While some tumors only expressed LANA, others 
expressed both LANA and K139, supporting the potential role of K1 in the pathogenesis of 
AIDS-associated KS. 
LANA, which is a latent KSHV gene may also have an effect on VEGF transcription. 293T cells 
transduced with LANA have a dose dependent increase VEGF-A transcription and increased 
VEGF-A in cell culture supernatant40. The ability of LANA to affect VEGF-A expression may 
be due to effects on HIF-1.  Co-immunoprecipitation assays demonstrate that LANA interacts 
with HIF-1α in transduced 293T cells, and immunoflouresence studies show that LANA and 
HIF-1 co-localize in the nucleus of the PEL cell line, BCBL-1.  In 293T cells transfected with 
LANA, HIF-1 promoter luciferase assays and RT-PCR demonstrate enhanced transcription of 


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HIF-1α over vector alone 293T cells. These studies suggest that LANA is a regulator of HIF-1α, 
and may enhance HIF-1α transcriptional activating activity in the setting of hypoxia41.  
Evaluation of these molecular pathways offer insight into the redundant mechanisms by which 
KSHV infection may lead to angiogenic and proliferative signaling through VEGF-A in KS, and 
provides rational for targeting VEGF-A in the treatment of KS.   
Anti-angiogenic approaches to the treatment of KS are also supported through early phase 
clinical studies conducted by the HIV and AIDS Malignancy Branch (HAMB).  Phase I and II 
studies conducted by HAMB have evaluated monotherapy with thalidomide42 and IL-1243, 
agents with pleiotropic effects that include potential anti-angiogenic mechanisms of action. In 
these studies, we demonstrated ORRs of 40-70%.  More recently, we have been evaluating 
approaches employing anti-VEGF monoclonal antibodies in a Phase II study of bevacizumab 
(03-C-0110) in patients with classical or AIDS-associated KS that was stable or progressing on 
HAART.  Bevacizumab (rhuMAb VEGF) is a recombinant humanized anti-VEGF monoclonal 
antibody composed of human IgG1 framework regions and antigen-binding 
complementarity-determining regions from a murine monoclonal antibody 
(muMAb VEGF A.4.6.1) that blocks binding of human VEGF-A to its receptors.  Approximately 
93% of the amino acid sequence, including most of the antibody framework, is derived from 
human IgG1, and ~7% of the sequence is derived from the murine antibody.  In vitro binding 
studies have shown it to consistently and potently neutralize the biologic activities of human 
VEGF-A, including the endothelial cell mitogenic activity, the vascular permeability-enhancing 
activity, and the angiogenic properties in the chick chorioallantoic membrane44.  This antibody 
has been shown to recognize all isoforms of VEGF-A, with a Kd of ~8 × 10–10 M. muMAb 
VEGF A.4.6.1 is specific for VEGF-A; it fails to recognize other peptide growth factors tested 
(fibroblast growth factor, epidermal growth factor, hepatocyte growth factor, platelet-derived 
growth factor, and nerve growth factor).   
1.2.3 Rationale for Combination of Liposomal Doxorubicin with Bevacizumab in Patients with 
Advanced KS 
Based on the rationale of targeting VEGF in the treatment of KS, we have been conducting a 
phase II study of the humanized anti-VEGF monoclonal antibody, bevacizumab, in patients with 
KS.  Study subjects are administered bevacizumab 15 mg/kg every 3 weeks.  Interim review of 
our phase II study of single agent bevacizumab, which has enrolled 17 patients, demonstrates a 
somewhat promising ORR, preliminarily estimated at 22%, with 1-year progression free survival 
estimated at 40% (Unpublished data).  As shown in Table 1, bevacizumab was reasonably well 
tolerated in this setting. While the response rate of bevacizumab monotherapy in KS is modest 
compared to cytotoxic therapy, this level of activity is comparable to that seem in other solid 
malignancies when used as monotherapy. Phase II studies that have evaluated bevacizumab 
monotherapy have demonstrated ORR of 16-21% in platinum resistant ovarian cancer45, 46, 10% 
in patients with renal cell carcinoma that progressed after IL-247, and 7% in previously treated 
breast cancer48.  
 
 
 
 


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Table 1. Selected Toxicities of bevacizumab monotherapy in patients with Kaposi’s sarcoma 
Toxicity 
Grade 1    Grade 2 Grade 3 
Grade 4 
HTN 
6% 
33% 
Proteinuria 
56% 
39% 
Epistaxis 
44% 
Hematuria 
67% 
Neutropenia 
50% 
33% 
Neutropenia +Infection
11% 
≥ 1 Other * 
56% 
11% 
(Yarchoan, et. al., Unpublished) 
* Additional Grade 3 and 4 toxicities included: dizziness, CPK elevations, headache, rash, 
alkaline phosphatase elevations, hypophosphatemia, and hyperglycemia. One patient had 
multiple grade 4 toxicities related to a prolonged hospitalization for necrotizing fasciitis.  
Despite the modest response rates when bevacizumab is used as monotherapy, the clinical 
benefit of bevacizumab when combined with cytotoxic agents, has been demonstrated in several 
other solid tumors. Bevacizumab increases progression-free survival when used alone or in 
combination with interferon-α in patients with renal cell carcinoma47, 49 or in combination with 
paclitaxel (but not capecitabine50) in patients with previously treated breast cancer51. 
Furthermore, the addition of bevacizumab to standard cytotoxic regimens in both lung and colo-
rectal cancer has lead to improvements in progression-free and overall survival when compared 
to cytotoxic therapy alone 52-55.  Our previous phase II study of liposomal doxorubicin with IL-12 
13 demonstrated an ORR of 83%, further supporting the rationale of combination anti-angiogenic 
and cytotoxic chemotherapy in advanced KS.  Given a strong preclinical rationale, and the 
promising activity of bevacizumab as monotherapy in patients with KS that was stable or 
progressing on HAART, we hypothesize that a combination of liposomal doxorubicin, which has 
demonstrated efficacy in causing tumor regression, with bevacizumab that targets VEGF 
signaling, will provide a platform that may lead to improved overall response rates, time to 
response and progression free survival in patients. This combination could potentially offer an 
important therapeutic option for patients with advanced and difficult to control KS. 
We further hypothesize that in addition to being a highly active combination, that liposomal 
doxorubicin combined with bevacizumab, at the dosing schedule used in our phase II study, will 
be safe and tolerable, and may potentially to decrease anthracycline requirements in the 
management of patients with advanced KS. 
 


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Several phase II studies have evaluated the combination of doxorubicin with bevacizumab in 
other tumors. Ganjoo et. al. reported 13 patients with diffuse large B-cell lymphoma treated with 
bevacizumab 15mg/kg combined with the R-CHOP regimen (rituximab, cyclophosphamide, 
vincristine, doxorubicin and prednisone). Two of the 13 patients developed grade 3 hypertension, 
and 2 of 13 developed deep vein thromboses.  No grade 3 or grade 4 proteinuria, heart failure or 
hemorrhage was observed with this regimen56.  Wedham et. al treated 21 women with newly 
diagnosed inflammatory and local advanced breast cancer with neo-adjuvant bevacizumab 15 
mg/kg in combination with doxorubicin 50 mg/m2 and docetaxel 75 mg/m2. Grade 3 
hypertension was observed in 8 patients, and 5 patients had surgical wound healing 
complications.  Other toxicities were acceptable.  Two patients had an asymptomatic decrease in 
left ventricular ejection fraction after a cumulative doxorubicin dose 300 mg/m2.  Of the 2 
patients, one had normalization of her ejection fraction 3 weeks after completing therapy, while 
the other had normalization in 6 months after discontinuing therapy and starting an angiotensin 
converting enzyme inhibitor57. Lastly, D’Amato et. al. evaluated the combination of 
bevacizumab 15 mg/kg combined with bolus doxorubicin 75 mg/m2 as second-line therapy in 17 
patients with metastatic sarcoma.  Patients were evaluated by echocardiogram every 2 cycles, 
and 4 patients were removed from study due to asymptomatic Grade 2 decreases in ejection 
fraction, while 1 patient developed grade III congestive heart failure after 11 cycles and 1 patient 
grade IV congestive heart failure after 8 cycles of the combination. In 5 of these 6 patients, the 
ejection fraction improved after cessation of therapy.  Overall, this data suggests that the 
combination may be associated with reversible asymptomatic decreases in ejection fraction at 
lower cumulative doses of anthracycline.  Cardiac toxicity associated with cumulative dosing of 
bolus anthracyclines > 450 mg/m2 and delayed wound healing must be considered in the 
evaluation of the combination of liposomal doxorubicin with bevacizumab. However, these 
phase II combination studies suggest an acceptable toxicity profile. Further combination 
regimens that include liposomal doxorubicin with bevacizumab are currently being evaluated in 
breast cancer (NCT00635050 and NCT00608972), and are planned for platinum sensitive 
ovarian cancer (NCT00698451). 
1.2.4 Bleeding and Thrombotic risk with bevacizumab in Relation to Patients with Kaposi 
Sarcoma and/or HIV 
Bevacizumab has been associated with both bleeding and thrombosis in clinical studies. The risk 
of these appears to depend in part on tumor type and location, and the optimal strategy to 
mitigate these risks, including the possible role of thromboprophylaxis, remains unclear. 
Overall, grade 3 and 4 events associated with bleeding or hemorrhage were observed in 4.0% of 
1,132 patients treated with bevacizumab in a pooled database from eight phase 1, 2, and 3 
clinical trials in multiple tumor types.  The hemorrhagic events that have been observed in 
bevacizumab clinical studies were predominantly tumor-associated hemorrhage and minor 
mucocutaneous hemorrhage. Major or massive pulmonary hemorrhage/hemoptysis has been 
observed primarily in patients with squamous cell NSCLC, and the majority of these occurred in 
patients with additional bleeding risk factors such as tumor cavitation and/or necrosis53. Serious 
tumor associated bleedings have also been observed in patients with pancreatic cancer, gastric 
cancer, central nervous system (CNS) metastases, hepatoma, or varices treated with 
bevacizumab. GI hemorrhages, including rectal bleeding and melena have similarly been 
reported in patients with colorectal cancer52.  


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Across all bevacizumab clinical trials, mucocutaneous hemorrhage has been seen in 20%-40% of 
patients treated.  These were most commonly NCI-CTC Grade 1 epistaxis that lasted less than 5 
minutes, resolved without medical intervention, and did not require any changes in bevacizumab 
treatment regimen. There have also been less common events of minor mucocutaneous 
hemorrhage in other locations, such as gingival bleeding and vaginal bleeding. 
The risk of arterial thromboembolic events (ATE) is increased with bevacizumab therapy; such 
events included cerebral infarction, transient ischemic attack (TIA), myocardial infarction (MI), 
and other peripheral or visceral arterial thrombosis60.  A pooled analysis of five randomized 
studies showed a two-fold increase in these events (3.8% vs. 1.7%)60.  ATE led to a fatal 
outcome in 0.8% patients with bevacizumab (vs. 0.5% without bevacizumab).  The rate of 
cerebrovascular accidents (including TIA) was 2.3% vs. 0.5%, and the rates of MI 1.7% vs. 
0.7%.  Certain baseline characteristics, such as age and prior arterial ischemic events, appear to 
confer additional risk.  In patients >65 years treated with bevacizumab and chemotherapy, the 
rate of ATE was approximately 8.5%. Aspirin is a standard therapy for primary and secondary 
prophylaxis of ATE in patients at high risk of such events, and the use of aspirin ≤325 mg daily 
was allowed in randomized studies of bevacizumab, though safety analyses specifically 
regarding aspirin use were not preplanned.  Due to the relatively small numbers of aspirin users 
and ATE events, retrospective analyses of the ability of aspirin to affect the risk of ATE were 
inconclusive.  Further analyses of the effects of concomitant use of bevacizumab and aspirin are 
ongoing. 
In the phase 3 trial in metastatic colorectal cancer, there was also a slightly higher rate of venous 
thromboembolic events (VTE), including deep venous thrombosis, pulmonary embolism, and 
thrombophlebitis), in patients treated with chemotherapy plus bevacizumab compared with 
chemotherapy alone (19% vs. 16%)52.  The incidence of NCI-CTC Grade≥3 VTEs in one 
NSCLC trial (E4599) was higher in the bevacizumab-containing arm compared to the 
chemotherapy control arm (5.6% vs. 3.2%). In clinical trials across all indications, the overall 
incidence of VTEs ranged from 2.8% to 17.3% in the bevacizumab-containing arms compared to 
3.2% to 15.6% in the chemotherapy control arms. The use of bevacizumab with chemotherapy 
does not substantially increase the risk of VTE compared with chemotherapy alone. However, 
patients with metastatic colorectal cancer who receive bevacizumab and experienced VTE may 
be at higher risk for recurrence of VTE. 
The baseline risks of bleeding and/or thrombosis associated with KS and HIV play an important 
part in estimating the potential risk of bleeding and/or thrombosis with bevacizumab therapy, but 
for KS these risks are not well established. HIV infection is established as a thrombotic risk 
factor (particularly when poorly controlled or associated with comorbidities), and an elevated 
risk of bleeding has not been reported in patients with HIV61-62. In KS, in our clinical practice 
mild bleeding from involved sites has been observed in patients with GI and/or pulmonary KS 
(Yarchoan, personal communication), but bleeding rates have not been estimated. Such bleeding 
is commonly asymptomatic (i.e. noted by stool guaic only), and usually responds promptly with 
institution of KS-directed therapy. Evidence regarding thrombotic risk in KS is mixed. One case 
series in the pre-HAART era, of patients with relatively severe KS, reported an increased 
incidence of thrombosis in limbs affected by KS63. This has not been confirmed, and in more 
recent studies of thrombotic risk in patients with HIV, KS has not emerged as an independent 
risk factor 61,62,64 (also, Musselwhite and Sereti, personal communication). One case-control study 
in post-transplant KS showed an increased occurrence of DVT in KS cases, but the small number 


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14 
of cases and long time elapsed between KS and DVT (over 2 years) raise the possibility that this 
finding was coincidental65. Nonetheless, it would not be unexpected that the peripheral venous 
stasis and endothelial damage that may been seen in patients with extensive KS, combined with 
effects of HIV in those with HIV-associated disease, could elevate thrombotic risk. One 
superficial vein thrombosis was seen over 202 cycles of therapy in the HAMB phase 2 study of 
bevacizumab in KS (04-C-0110)., Bleeding in that study included epistaxis (5%) and heavy 
menses (1 patient). Given the generally mild nature of observed bleeding, possible elevated 
thrombotic risk with HIV and KS, and potential severity of thrombotic complications, we will 
employ thromboprophylaxis with aspirin for all study subjects.  This practice is common in 
current bevacizumab studies. Patients with recent bleeding not directly related to KS and/or a 
history of bleeding diastheses will not be eligible, nor will patients with known procoagulant 
disorders. 
2. ELIGIBILITY ASSESSMENT AND ENROLLMENT 
2.1 
ELIGIBILITY CRITERIA 
2.1.1 Inclusion Criteria 
2.1.1.1 
Age ≥ 18 years 
2.1.1.2 
Kaposi’s sarcoma pathologically confirmed by CCR pathology 
2.1.1.3 
Evaluable KS involving the skin and/or viscera, including at least one of the 
following: 
2.1.1.3.1 
KS of the skin with ≥ 5 KS lesions that are evaluable by non-invasive methods 
that have not been treated with local therapeutic modalities 
2.1.1.3.2 
Pulmonary KS evaluable by CT scan 
2.1.1.3.3 
Gastrointestinal KS evaluable by direct visualization or fiberoptic 
instrumentation 
2.1.1.3.4 
Biopsy proven lymph node involvement measurable by CT scan 
2.1.1.4 
ECOG performance status ≤ 2 
2.1.1.5 
Life expectancy > 6 months 
2.1.1.6 
At least one of the following indications for therapy:  
2.1.1.6.1 
Pulmonary involvement 
2.1.1.6.2 
Visceral involvement 
2.1.1.6.3 
Pain 
2.1.1.6.4 
Edema 
2.1.1.6.5 
Substantial lymph node involvement 
2.1.1.6.6 
Ulcerating lesions 
2.1.1.6.7 
Decreased range of joint motion due to KS 
2.1.1.6.8 
Multiple lesions not amenable to local therapy 
2.1.1.6.9 
Significant psychological impact leading to social withdrawal 


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2.1.1.7 
Patients with HIV infection must be willing to comply with a regimen of highly 
active antiretroviral therapy (HAART).  
2.1.1.8 
Patients may have received any number of prior therapies, including monotherapy 
with liposomal doxorubicin or bevacizumab 
2.1.1.9 
Blood pressure 
2.1.1.9.1 
SBP < 150 mm/Hg 
2.1.1.9.2 
DBP < 90 mm/Hg 
2.1.1.9.3 
Patients receiving anti-hypertensive medicines must be on a stable regimen for 
at least 1 month 
2.1.1.10 EF > 50% by MUGA 
2.1.1.11 The following hematologic parameters: 
2.1.1.11.1 Hemoglobin > 9 g/dl 
2.1.1.11.2 WBC > 1000/mm3 
2.1.1.11.3 ANC > 750/mm3 
2.1.1.11.4 Platelets > 75,000/mm3 
2.1.1.11.5 PT and PTT ≤ 120% of control, unless patient has the presence of a lupus 
anticoagulant 
2.1.1.12 The following hepatic parameters: 
2.1.1.12.1 Bilirubin ≤ 1.5 X ULN unless the patient is receiving protease inhibitor therapy  
(i.e. indinavir, ritonavir, nelfinavir, and atazanavir) known to be associated with 
increased bilirubin: in this case total bilirubin ≤7.5 mg/dl and the direct fraction 
is ≤ 0.7 mg/dl.   
2.1.1.12.2 AST/GOT ≤ 2.5 times the upper limit of normal 
2.1.1.13 Either serum creatinine ≤ 1.5 mg/dL or measured creatinine clearance ≥ 60 mL/min 
2.1.1.14 Either urine protein <1+ or measured 24 hour urine protein < 500 milligram 
2.1.1.15 Able to take aspirin 81mg daily. 
2.1.1.16 Study participant must use birth control measure prior to study entry (during 
screening), during study participation, and for 12 weeks after bevacizumab is 
discontinued. 
2.1.1.17 Inclusion of women and minorities: Both men and women and members of all races 
and ethnic groups are eligible for this trial. 
2.1.2 Exclusion Criteria 
2.1.2.1 
Inability to provide informed consent 
2.1.2.2 
KS therapy other than HAART within 3 weeks 
2.1.2.3 
History of cumulative doxorubicin or liposomal doxorubicin dose > 430 mg/m2 


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2.1.2.4 
Supraphysiologic doses of corticosteroids within 3 weeks 
2.1.2.5 
Major surgical procedure (including periodontal) within 4 weeks  
2.1.2.6 
Surgical or other non-healing wounds, other than KS ulcers 
2.1.2.7 
Pregnancy (because of unknown potential for fetal malformation) 
2.1.2.8 
Breast feeding (because of unknown potential for adverse infant developmental 
consequences) 
2.1.2.9 
Has an uncontrolled illness including, but not limited to, ongoing or active infection 
requiring IV antibiotics, symptomatic congestive heart failure, unstable angina 
pectoris, cardiac arrhythmia, cirrhosis, or psychiatric illness/social situations that 
would limit adherence to study requirements 
2.1.2.10 Past or present history of malignant tumors other than KS unless: a) in a complete 
remission for ≥ 1 year from the time a response was first documented; b) 
completely resected basal cell carcinoma; or c) in situ squamous cell carcinoma of 
the cervix or anus 
2.1.2.11 Severe or life-threatening infection within 2 weeks of entry onto the study  
2.1.2.12 History of deep venous or arterial thrombotic diasease(including but not limited to, 
acute myocardial infarction due to coronary thrombosis, ischemic stroke, and 
peripheral arterial disease), unless: 
2.1.2.12.1 Line-related thrombosis without embolus  
2.1.2.12.2 Occurring ≥1 year prior to screening 
2.1.2.13 Known procoagulant disorder including prothrombin gene mutation 20210, 
antithrombin III deficiency, protein C deficiency, protein S deficiency and 
antiphospholipid syndrome but not including heterozygosity for the Factor V 
Leiden mutation or the presence of a lupus anticoagulant in the absence of other 
criteria for the antiphospholipid syndrome. 
2.1.2.14 Known bleeding diathesis 
2.1.2.15 History of severe gastrointestinal bleeding within 6 months. Patients with 
gastrointestinal blood loss due to KS may be included. (see 2.1.1.3.3.) 
2.1.2.16 Hemoptysis within 4 weeks 
2.1.2.17 Substantial CNS disease including 
2.1.2.17.1 History of CNS bleeding 
2.1.2.17.2 Mass lesions in the brain 
2.1.2.17.3 Uncontrolled seizure disorder 
2.1.2.17.4 Recent history of CVA (e.g. within the past 6 months) 
2.1.2.18 Proteinuria > 500 mg/24hrs 
2.1.2.19 Patients with any other abnormality that would be scored as a grade 3 or greater 
toxicity, except: 


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2.1.2.19.1 Lymphopenia 
2.1.2.19.2 Direct manifestations of KS 
2.1.2.19.3 Direct manifestation of HIV 
2.1.2.19.4 Direct manifestation of HIV therapy (i.e. Hyperbilirubinemia associated with 
protease inhibitors) 
2.1.2.19.5 Asymptomatic hyperuricemia 
2.1.2.19.6 Hypophosphatemia 
2.1.2.20 Previous bevacizumab within 6 weeks prior to enrollment 
2.1.2.21 Known hypersensitivity to bevacizumab, Chinese hamster ovary cell products, or 
other recombinant human or humanized antibodies 
2.1.2.22 Any condition, including the presence of laboratory abnormalities, which in the 
opinion of the Principal Investigator or Lead Associate Investigator places the 
subject at unacceptable risk if they were to participate in the study or confounds the 
ability to interpret data from the study.  
2.2 
RESEARCH ELIGIBILITY EVALUATION 
Potential subjects will be evaluated by a HAMB physician-investigator for protocol eligibility.  
Baseline pretreatment evaluation will include a complete medical history, review of systems, and 
physical examination with documentation of extent of KS and determination of target lesions.  
Screening is performed to determine eligibility and obtain certain baseline data. Screening 
studies, except for KS biopsy, HIV serology and cardiac studies (see section 3.5.1.4.) must be 
completed within 2 weeks of starting study. 
2.2.1 Clinical Evaluation 
2.2.1.1 
Complete medical history 
2.2.1.2 
Comprehensive physical examination  
2.2.2 Pathology  
Biopsy demonstrating Kaposi’s sarcoma, reviewed by NCI pathologists (See section 3.5.1.6. for 
punch biopsy sample collection instructions.) 
2.2.3 Laboratory Data 
2.2.3.1 
Acute care panel (Sodium, Potassium, Chloride, CO2, Creatinine, Glucose, and 
Urea Nitrogen) 
2.2.3.2 
Mineral panel (Phosphorus, Magnesium, Albumin, and Calcium) 
2.2.3.3 
Hepatic panel (Alkaline Phosphatase, ALT, AST, Total Bilirubin, and Direct 
Bilirubin) 
2.2.3.4 
Total protein, LDH, creatine kinase, uric Acid 
2.2.3.5 
C-reactive protein 
2.2.3.6 
APTT, PT, thrombin time (TT), fibrinogen, D-dimer 


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2.2.3.7 
Hepatitis B S Ag, Hepatitis B S Ab, Hepatitis B core Ab. 
2.2.3.8 
Hepatitis C antibody 
2.2.3.9 
CBC, diff (automated lymphocyte count), reticulocyte count 
2.2.3.10 HIV Western blot 
2.2.3.11 HIV viral load if HIV seropositive by Western Blot 
2.2.3.12 Lymphocyte phenotype TBNK.  Simultaneous CBC and automated differential 
must be drawn. 
2.2.3.13 Urinalysis  
2.2.3.14 24-hour urine for protein if ≥1+proteinuria on dipstick  
2.2.3.14.1 Urine β-hCG (women) 
2.2.4 Cardiovascular Studies 
2.2.4.1 
EKG 
2.2.4.2 
Cardiac Multiple Uptake Gated Acquisition Scan (MUGA) 
2.2.5 Imaging 
2.2.5.1 
Chest x-ray 
2.2.5.2 
Chest CT to assess abnormal chest x-ray, if indicated. 
2.2.5.3 
Other studies when indicated to evaluate and measure internal tumor 
2.3 
REGISTRATION PROCEDURES 
Each potential subject will be discussed with the Principal Investigator or a physician Associate 
Investigator.  Informed consent will be documented from eligible participating subjects using the 
NCI Institutional Review Board (IRB) approved Informed Consent form. Authorized staff must 
register an eligible candidate with NCI Central Registration Office (CRO) within 24 hours of 
signing consent. A registration Eligibility Checklist from the web site 
(http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) must be completed and faxed to 301-
480-0757. After confirmation of eligibility at Central Registration Office, CRO staff will call 
pharmacy to advise them of the acceptance of the patient on the protocol prior to the release of 
any investigational agents. Verification of Registration will be forwarded electronically via e-
mail.  
3. STUDY IMPLEMENTATION 
3.1 
STUDY DESIGN 
This is an open label, single center pilot study that will enroll two cohorts of subjects. 
3.1.1 Cohort 1: Patients who are either: 
3.1.1.1 
HIV negative  
3.1.1.2 
HIV infected with stable KS despite one year of HAART with HIV viremic control 
3.1.1.3 
HIV infected with progressive KS despite four months of HAART with HIV 
viremic control 


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3.1.2 Cohort 2: All other patients with advanced AIDS-associated KS 
The primary objective is to estimate the ORR of the combination of liposomal doxorubicin and 
bevacizumab after 6 cycles in subjects with advanced KS in each of these two cohorts.  KS 
response in Cohort 1 subjects would not be considered as being influenced by the recent 
initiation of HAART, while KS response in Cohort 2 subjects may include a component of 
HAART effect. Subjects will be treated with bevacizumab combined with liposomal doxorubicin 
every three weeks until complete response or a maximum of 6 cycles. Subjects with a partial 
response or complete response will continue on bevacizumab monotherapy every 3 weeks for an 
additional 11 cycles. Information regarding efficacy and toxicity of the combination will be 
obtained.  Duration of response will be assessed over 3-year follow-up. 
3.2 
DRUG ADMINISTRATION 
Induction phase will consist of a loading dose of bevacizumab followed one week later by the 
combination of bevacizumab with liposomal doxorubicin administered every three weeks until 
complete response or a maximum of six cycles.  Subjects with stable disease, partial response or 
complete response after the induction phase will be continued on maintenance bevacizumab for 
11 cycles. See Figure 1 for a schema of the dosing schedule. 
3.2.1 Induction Phase 
3.2.1.1 
Bevacizumab 15 mg/kg will be infused over 90 minutes as a loading dose on Day 1 
of Cycle 1, one week prior to initiation of the combination of bevacizumab and 
liposomal doxorubicin 
3.2.1.2 
On Day 8 of Cycle 1, bevacizumab 15 mg/kg will be infused over 60 minutes (as 
long as no adverse reactions incurred during the first infusion) prior to liposomal 
doxorubicin. See section 8.1.4. for dilution and mixing instructions. 
3.2.1.3 
On Day 1 of Cycles 2-6, bevacizumab 15 mg/kg will be infused over 30 minutes (as 
long as no adverse reactions incurred during the first two infusions) every 3 weeks 
prior to liposomal doxorubicin. See section 8.1.4. for dilution and mixing 
instructions. 
3.2.1.4 
Prior to each dose, blood pressure measurements should be obtained in the 
outpatient clinic and should not be repeated in the chemotherapy suite immediately 
prior to drug administration to avoid “white coat hypertension” that could be 
induced if measurements are taken in the chemotherapy administration suites 
immediately prior to drug administration.  For SBP > 160 or DBP > 100 delay 
administration and repeat blood pressure measurement no sooner than 30 minutes 
later.  If parameters remain elevated above these levels, bevacizumab will not be 
administered, and the responsible physician Investigator(s) will be notified. 
3.2.1.5 
Prior to each dose, urine dipstick for protein must be obtained.  If ≥ 2+, a 24-hour 
urine for protein must be obtained prior to dose administration. 
3.2.1.6 
Liposomal doxorubicin 20 mg/m2 will be administered by intravenous bolus over 
30 minutes every 3 weeks. See section 8.2.4. for dilution and mixing instructions. 
3.2.1.7 
Prior to liposomal doxorubicin administration, a CBC with differential should be 
obtained.  Liposomal doxorubicin and bevacizumab should be held for an absolute 
neutrophil count (ANC) < 750 /µL or a platelet count less than 75,000 /µL. 


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3.2.2 Maintenance phase 
Bevacizumab 15 mg/kg will be infused over 30 minutes every 3 weeks for a total of 11 cycles.  
3.2.2.1 
Prior to each dose, blood pressure measurements should be obtained in the 
outpatient clinic and should not be repeated in the chemotherapy suite immediately 
prior to drug administration to avoid “white coat hypertension” that could be 
induced if measurements are taken in the chemotherapy administration suites 
immediately prior to drug administration.  For SBP > 160 or DBP > 100 delay 
administration and repeat blood pressure measurement no sooner than 30 minutes 
later.  If parameters remain elevated above these levels, bevacizumab will not be 
administered, and the responsible physician Investigator(s) will be notified. 
3.2.2.2 
Prior to each dose, urine dipstick for protein must be obtained.  If ≥ 2+, a 24-hour 
urine for protein must be obtained prior to dose administration. 
Figure 1. Dosing Schedule 
CYCLE 
1 
1  
2   3   
4   
5   
6    7  
8  
9  
10  
11  
12  
13   14  
15  
16  
17 
WEEK 
1 
2   5   8     11  14 
17  20  23  26   29   32 
35 
38 
41  
44 
47 
50 
BEVACIZUMAB   ⇓ 
⇓ 
⇓ 
⇓ 
⇓ 
⇓ 
⇓ 
⇓ 
⇓ 
⇓ 
⇓ 
⇓ 
⇓ 
⇓ 
⇓ 
⇓ 
⇓ 
⇓ 
LIPOSOMAL 
DOX 
 
⇓ 
⇓ 
⇓ 
⇓ 
⇓ 
⇓ 
 
 
 
 
 
 
 
 
 
 
 
3.3 
TREATMENT MODIFICATIONS 
During the induction period, if there is an indication to hold bevacizumab, liposomal doxorubicin 
may be continued.  If the bevacizumab is held for 1 week or less, the liposomal doxorubicin may 
be delayed until the bevacizumab is given.  If there is indication to hold bevacizumab for more 
than one week, liposomal doxorubicin may be continued as monotherapy. Bevacizumab will be 
resumed on subsequent cycles if criteria for administration of bevacizumab are met.   
If there is an indication to hold liposomal doxorubicin, both liposomal doxorubicin and 
bevacizumab will be held. Patients will be evaluated weekly until resolution of toxicities allow 
for continued administration of the combination of liposomal doxorubicin and bevacizumab. 
In the event of unforeseen circumstances (e.g., travel difficulties) or Federal holidays, treatment 
may be rescheduled to the closest subsequent day possible, to a maximum of 1 week late, 
without constituting a protocol violation 
Indications for treatment modification for each agent are outlined.  
3.3.1 Bevacizumab 
3.3.1.1 
Hypertension 
3.3.1.1.1 
Bevacizumab will not be administered unless SBP< 160 and DBP < 100.  
Management of hypertension is outlined below. 
3.3.1.1.2 
Mild/Moderate Hypertension 


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For SBP > 140 and < 210 mm Hg or DBP > 90 and < 120 mm Hg that is 
sustained over at least a two week period, initiate or adjust anti-hypertensive 
therapy.  Bevacizumab must be delayed until the blood SBP< 160 and DBP < 
100.   
3.3.1.1.3 
Severe Hypertension 
For SBP ≥ 210 mm Hg or DBP ≥ 120 mm Hg but without end organ damage, 
begin anti-hypertensive therapy.  Bevacizumab must be delayed until blood 
SBP< 150 and DBP < 90.   
3.3.1.1.4 
Hypertensive Urgency or Emergency 
Bevacizumab therapy will be permanently discontinued in the presence of 
hypertensive urgency (DBP >120 with evidence of optic disc edema or 
progressive end-organ complications) or hypertensive emergency (SBP > 210 
and DBP > 120 presenting with headaches, blurred vision, or focal neurological 
symptoms, or papilledema).  Only grade 4 hypertension will require expedited 
reporting to the NCI-IRB.   
3.3.1.2 
Thrombotic Events 
3.3.1.2.1 
Deep Vein Thrombosis 
3.3.1.2.2 
Bevacizumab will not be administered in the presence of deep vein thrombosis 
or in the presence of therapeutic anticoagulation.  
3.3.1.2.3 
Arterial Thromboembolic Events 
3.3.1.2.4 
Bevacizumab will not be administered in the presence of new arterial 
thrombotic disease, including but not limited to, myocardial infarct due to 
coronary thrombosis and ischemic stroke. 
3.3.1.3 
Thrombocytopenia 
Bevacizumab and thromboprophylaxis (aspirin 81 mg) will not be administered during the 
maintenance phase unless the platelets are ≥ 50,000 / µL. 
3.3.1.4 
Neutropenia 
Bevacizumab will be held if the absolute neutrophil count (ANC) is less than 750 
cells/µL until ANC is again above 750 cells/µL.  Filgrastim or pegfilgrastim may be 
scheduled to individual patient requirement in order to maintain a neutrophil count 
targeted to meet or exceed 750 cells/µL.   
Subjects that develop neutropenic fever while receiving the combination of 
liposomal doxorubicin and bevacizumab will receive either filgrastim 5µg/kg 
(rounded to the nearest vial size of 300 µg or 480 µg) daily for 5 days or 
pegfilgrastim 6 mg once starting on day 2 of subsequent cycles that include 
liposomal doxorubicin.   
Subjects that develop neutropenic fever while on bevacizumab monotherapy will 
receive either filgrastim 5µg/kg (rounded to the nearest vial size of 300 µg or 480 
µg) daily for 5 days or pegfilgrastim 6 mg once, starting on day 2 of subsequent 
cycles. 


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3.3.1.5 
Hemorrhage 
3.3.1.5.1 
Life Threatening 
In the case of hemoptysis, hematemesis, hematochezia, intracranial hemorrhage or any 
significant blood loss, bevacizumab will not be administered.  
3.3.1.5.2 
Cutaneous KS 
In the case of cutaneous bleeding at tumor site(s), bevacizumab may be delayed.  If the 
bleeding is minor and appears to be due to tumor necrosis, bevacizumab may be 
administered without schedule or dose modification at the discretion of the Principal 
Investigator.  Bevacizumab will be held for grade 3 tumor bleeding. 
 
 
3.3.1.6 
Proteinuria 
If urine dipstick indicates ≥2+ proteinuria, bevacizumab administration will be 
delayed pending the results of a 24-hour urine collection for protein.  If the 24-hour 
urine protein is ≥2 grams, bevacizumab will be delayed for up to 6 weeks, until the 
proteinuria is <2+ or the 24-hour urine protein is < 1 grams/24 hr. 
3.3.1.7 
Liver Function Abnormalities 
Bevacizumab should be withheld in the event of ≥ Grade 3 LFT elevations and 
should not resume until the abnormalities have recovered to ≤ Grade 1 (with the 
exception of hyperbilirubinemia attributable to protease inhibitor therapy, in which 
case the total bilirubin must recover to ≤ 7.5 mg/dL and the direct fraction ≤ 0.7 
mg/dl.)  If LFT elevations recur with re-treatment, bevacizumab should be 
permanently discontinued.  Liver function tests included are the transaminases 
alanine aminotransferase (ALT, SGPT), aspartate aminotransferase (AST, SGOT), 
alkaline phosphatase, and bilirubin.  Elevated bilirubin due to protease inhibitor 
therapy will not require treatment modification.  
3.3.1.8 
Allergic Reaction 
In case of flushing, shortness of breath, facial edema, headache, chills, back pain, 
tightness of the chest and throat, and/or hypotension, fever or rash, the infusion 
should be suspended until the patient is assessed until the events have subsided.  For 
grade 3 or 4 allergic reactions, bevacizumab will be permanently discontinued. 
3.3.1.9 
Surgical or periodontal procedures 
If there is need for an elective major surgical or periodontal procedure, 
bevacizumab should be held beginning at least 6 weeks prior to the procedure and 
must not be resumed before 4 weeks after the surgical procedure.  For urgent or 
emergent surgery or endoscopic procedures, bevacizumab will be held for 4 weeks 
after the procedure. Longer delays may be necessary, if clinically indicated, in order 
to ensure that adequate healing has taken place prior to bevacizumab resumption.  
For KS skin biopsies and other minor procedures (i.e. interventional radiology 


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diagnostic procedures), bevacizumab will be held only if there is evidence that 
healing is compromised.  
3.3.1.10 Reversible Posterior Leukoencephalopathy Syndrome (RPLS) 
Bevacizumab should not be administered to patients with signs or symptoms of 
RPLS.  Evaluation should include neurologic evaluation, ocular examination, head 
MRI, and blood pressure assessment.  If these clinical criteria are consistent with 
the diagnosis of RPLS, bevacizumab will be permanently discontinued. 
3.3.1.11 Fistula Formation 
Bevacizumab will be discontinued in the event of formation of a fistula. 
3.3.1.12 Other Grade 3 or 4 Toxicities 
Bevacizumab will be held for any other Grade 3 or 4 toxicity thought to be at least 
possibly related to bevacizumab.  Lymphopenia and other toxicities clearly related 
to HIV or its therapy or to the Kaposi’s sarcoma itself will not require dose 
modification.  Grade 3 or higher asymptomatic hyperuricemia, hypophosphatemia, 
elevated creatinine phosphokinase levels will not result in dose delay. 
3.3.1.13 Option of Deferring Bevacizumab Loading Dose 
If deferral of cytotoxic chemotherapy for one week is deemed to be unsafe by the 
Principal Investigator or Lead Associate Investigator, the loading dose (Day 1) of 
bevacizumab may be omitted. 
3.3.1.14 Option of Additional Bevacizumab 
For patients showing evidence of progressive improvement on bevacizumab after 
one year, therapy may be continued for up to an additional 12 months, for a 
maximum of up to 24 months of therapy from the date of enrollment on protocol.  
In addition, patients who receive additional liposomal doxorubicin after the initial 6 
cycles (see Section 3.3.2.6.) may receive up to 12 months of bevacizumab, starting 
at the time of the re-initiation of the liposomal doxorubicin. Depending on when 
they start receiving their additional liposomal doxorubicin, such patients could thus 
receive up to 24 months total of therapy, starting from the date of enrollment on 
protocol. Subjects receiving bevacizumab beyond 12 months will be followed on-
study for safety endpoints during therapy and 4 weeks after the last dose of therapy 
(see Section 3.10.1.1).  Toxicity evaluation for patients receiving additional 
bevacizumab will follow the schedule outlined in Section 3.5.2. For patients 
receiving additional liposomal doxorubicin, repeat cardiac evaluation will occur 3 
weeks (+/- 1 week) after the final dose of liposomal doxorubicin as outlined in 
Section 3.5.2.6.  Patients will be followed on study for up to 2 years on study after 
their final dose of therapy (see Section 3.10.1.2.). 
3.3.2 Liposomal Doxorubicin 
3.3.2.1 
Infusion Related Events 
In case of flushing, shortness of breath, facial edema, headache, chills, back pain, 
tightness of the chest and throat, and/or hypotension, the infusion should be 
suspended until the patient is assessed and the events have subsided.  Unless 


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discontinuance of the drug is clinically indicated (due to repeated severe reactions 
and discussed with the Principal Investigator), the infusion rate should be resumed 
at one-half the previous rate.  
3.3.2.2 
Hematologic Toxicities 
3.3.2.2.1 
Neutropenia 
Liposomal doxorubicin will be held if the absolute neutrophil count (ANC) is 
less than 750 cells/µL on Day 1 of a cycle until ANC is again above 750 
cells/µL. Liposomal doxorubicin will not be administered within 14 days 
following pegfilgrastim administration. 
Filgrastim or pegfilgrastim may be scheduled to individual patient requirement 
in order to maintain a neutrophil count targeted to meet or exceed 750 cells//µL.  
Patients that develop neutropenic fever will receive either filgrastim 5µg/kg 
(rounded to the nearest vial size of 300 µg or 480 µg) daily for 5 days or 
pegfilgrastim 6 mg once, starting on day two of subsequent cycles that include 
liposomal doxorubicin. 
3.3.2.2.2 
Thrombocytopenia 
Liposomal doxorubicin will be held for up to 4 weeks if the platelet count is 
<75, 000 / µL. Aspirin will also be held if the platelet count is <50,000 / µL. 
Liposomal doxorubicin dose will be reduced by 25% in subsequent cycles if the 
platelet count nadir is <25,000, or if there is > 1week delay due to 
thrombocytopenia or if dose delays due to thrombocytopenia occur in > 1 cycle. 
3.3.2.3 
Palmer-Planter Erythrodysethesia 
3.3.2.3.1 
Grade 1: Delay up to 2 weeks until substantial resolution.  
3.3.2.3.2 
Grade 2: Delay liposomal doxorubicin cycles up to two weeks until toxicity 
substantially resolves.  If patient has experienced Grade 2 or higher hand-foot 
skin reaction, decrease dose by 25%.   
3.3.2.3.3 
Grade 3 or 4: Discontinue liposomal doxorubicin and begin maintenance phase 
of protocol after toxicity decreases to grade I or lower, provided this occurs 
within 4 weeks.  
3.3.2.4 
Stomatitis 
3.3.2.4.1 
Grade ≥ 2: Delay up to two weeks. 
3.3.2.4.2 
Grade ≥ 3: Delay up to two weeks and reduce dose by 25%. 
3.3.2.5 
Congestive Heart Failure 
For CTCAEv3.0 Grade 2 or greater congestive heart failure and at least 10% 
decrease from baseline, discontinue liposomal doxorubicin and bevacizumab 
(including bevacizumab monotherapy). 
3.3.2.6 
Option of Additional Liposomal Doxorubicin 
Up to 6 cycles of additional liposomal doxorubicin combined with bevacizumab 
may be prescribed for patients who demonstrate clinical improvement with 


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liposomal doxorubicin combined with bevacizumab, but later have progressive 
disease or disease requiring chemotherapy (as outlined in section 2.1.1.6) while 
receiving bevacizumab alone.  Subjects requiring additional liposomal doxorubicin 
will be counted as progressive disease, but will continued to be followed for the 
safety and tolerability of the combination.  There is no limit for maximum 
cumulative dose of liposomal doxorubicin.  
3.4 
PHARMACOKINETIC STUDIES 
No pharmacokinetic studies are planned for this protocol. 
3.5 
PROTOCOL EVALUATION 
The schedule for protocol evaluations, including baseline studies, on-treatment studies, and post-
treatment studies are outlined below. Tests may be rescheduled to the closest day possible 
without constituting a protocol violation (e.g. for Federal holidays or unforeseen circumstances 
such as travel difficulties.) 
3.5.1 Baseline Studies  
If the patient begins treatment within 48 hours of screening, the screening evaluations in section 
2.2 do not need to be repeated. 
3.5.1.1 
Clinical Evaluation 
3.5.1.1.1 
Complete Medical History, Vital Signs and Physical Exam 
3.5.1.1.2 
ECOG Performance Status 
3.5.1.1.3 
Review of symptoms, documenting baseline symptoms using CTCAE v3.0 
3.5.1.2 
Clinical Kaposi’s Sarcoma Evaluation 
3.5.1.2.1 
Documentation of Extent of Disease 
Baseline whole body photographs will be obtained upon entry into the study.  At this 
time, 5 lesions (hereafter called marker lesions), representative of the patient’s 
disease and, if possible, located on separate areas of the body will be selected.  These 
marker lesions should be lesions that have never been treated with local therapies 
such as radiation therapy or intralesional injections.  Detailed photographs of these 
lesions will be obtained with a metric rule beside them.  The size, color and 
nodularity of these lesions will be recorded on Day 1 of each cycle.  Documentation 
will depend on the number of lesions. 
3.5.1.2.1.1 
50 or More Lesions 
For patients with 50 or more lesions at entry, between 1 and 3 representative 
areas will be selected at baseline and these will be used for each subsequent 
evaluation.  Representative areas are sections of the body (e.g. the back, a leg, an 
arm, etc.), which contain at least 20 KS lesions.  The total number of lesions in 
these representative areas will be counted and a record made of whether they are 
flat or raised.  If, in the course of treatment, a single lesion breaks up into 2 or 
more smaller lesions (whose area does not extend beyond the boundary of the 
initial lesion), these lesions will still be counted as single lesions for the purpose 
of assessing total numbers in defining a response to therapy.  An attempt will be 


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made to distribute the “marker” lesions between the representative areas and the 
rest of the body.   
3.5.1.2.1.2 
Less than 50 Lesions 
For patients with less than 50 lesions at entry, the total number of lesions will be 
counted and a record made of whether they are flat or raised. 
3.5.1.2.2 
Additional Studies for Visceral Disease 
Additional studies, including but not limited to, gastrointestinal endoscopy, 
bronchoscopy, and CT scans, will be performed at entry where clinically indicated, 
based on clinical evaluation of the patient.  
3.5.1.3 
Laboratory Evaluation 
3.5.1.3.1 
Acute care panel (Sodium, Potassium, Chloride, CO2, Creatinine, Glucose, and 
Urea Nitrogen) 
3.5.1.3.2 
Mineral panel (Phosphorus, Magnesium, Albumin, and Calcium) 
3.5.1.3.3 
Hepatic panel (Alkaline Phosphatase, ALT, AST, Total Bilirubin, and Direct 
Bilirubin) 
3.5.1.3.4 
C-reactive protein 
3.5.1.3.5 
Total protein, LDH, creatine kinase, uric Acid 
3.5.1.3.6 
CBC, diff (automated lymphocyte count), reticulocyte count 
3.5.1.3.7 
APTT, PT, fibrinogen, D-dimer 
3.5.1.3.8 
Hepatitis A IgG 
3.5.1.3.9 
VDRL 
3.5.1.3.10 Thyroid function tests (TSH, Free T4) 
3.5.1.3.11 Urinalysis, urine protein, urine creatinine 
3.5.1.3.12 Pregnancy test (if female) 
3.5.1.3.13 Lymphocyte phenotype TBNK.  A simultaneous CBC and automated 
differential must be drawn. 
3.5.1.3.14 HIV Viral load 
3.5.1.3.15 Four 10cc red-topped tubes (send to SAIC, Frederick) for storage 
3.5.1.3.15.1 Assays to include IL-6, viral IL-6, and CD105 
3.5.1.3.15.2 One red top for KSHV Elisa of IFA (send to SAIC, Frederick) for storage 
3.5.1.3.16 Up to 30 cc may be drawn for virologic testing, establishment of cell lines, 
evaluation of hematologic parameters, or other studies that become clinically 
important during conduct of the trial.  If the investigators are interested in 
studying germline genotypic information other than VEGF or VEGF-R 
polymorphisms or HLA typing, they will return to the IRB with an amendment 
to the protocol in order to conduct this research.  


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3.5.1.3.17 Quantitative immunoglobulin levels, including IgE  
3.5.1.3.18 Four yellow top tubes for storage for plasma and PBMC KSHV viral load levels 
(send to SAIC, Frederick) 
3.5.1.3.19 Saliva for KSHV viral load to Dr. Denise Whitby (send to SAIC-Frederick 
Building 535, Room 428A) 
3.5.1.4 
Cardiology Evaluation 
3.5.1.4.1 
EKG (must have EKG from within 6 weeks of starting therapy) 
3.5.1.4.2 
MUGA (must have MUGA from within 6 weeks of starting therapy) 
3.5.1.5 
Radiology Evaluation 
3.5.1.5.1 
CXR (must have within 2 weeks of starting therapy) 
3.5.1.5.2 
Other imaging as clinically indicated (See section 3.5.1.2.2) 
3.5.1.5.3 
Evaluation of the vascularity in KS will be performed using 3 non-invasive 
modalities: laser Doppler imaging, multi-spectral imaging, and infared thermal 
imaging.  Imaging will use the modalities explored in 01-C-0158. A target 
lesion of KS as well as normal skin will be identified and recorded for follow-
up studies. Imaging should occur on Day 1, Cycle 1, prior to the loading dose of 
bevacizumab, or up to one 1 week prior to starting therapy.  Use of these non-
invasive modalities will be subject to technician and machine availability. 
Inability to schedule non-invasive imaging should not alter planned therapy, and 
will not result in a protocol violation. 
3.5.1.6 
Pathologic Kaposi’s Sarcoma Evaluation 
If adequate research tissue was obtained during screening, do not repeat baseline 
pathology evaluation.  Otherwise, obtain one to two 4-6 mm cutaneous KS “punch” 
biopsies for the following studies.  Divide the tissue into approximately equal 3mm 
pieces.  If only limited tissue is available, the priority for laboratories is to submit 
the material in the order listed below: 
3.5.1.6.1 
CCR Pathology for histology and LANA IHC 
3.5.1.6.2 
If adequate tissue is available, a sample will be sent to the lab of Dr. Giovanna 
Tosato for IHC of Dll4, PDGF-C, G-CSF and other potential markers of 
resistance to bevacizumab (Building 37, Room 4134B) 
3.5.1.6.3 
Molecular pathology: if there is sufficient tissue, an aliquot will be sent to the 
laboratory of Dr. Robert Yarchoan (Building 10, Room 5A25) for storage for 
molecular pathology studies (dry, transported in a tube placed on ice). 
3.5.2 Evaluation During Treatment Phase 
3.5.2.1 
Evaluation Schedule 
3.5.2.1.1 
Cycle 1: Subjects will be evaluated on Day 1, Day 8 and Day 15 
3.5.2.1.2 
Cycle 2 – 17: Subjects will be evaluated on Day 1 
3.5.2.2 
General Clinical Evaluation 


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3.5.2.2.1 
Vital signs and focused physical exam, with documentation of pertinent positive 
and negative findings.  
The Principal Investigator or an Associate Investigator will be notified if the 
SBP >140 or DBP >90  (See section 3.3.1.1).  
3.5.2.2.2 
ECOG Performance Status 
3.5.2.2.3 
Evaluation of subjective symptoms, documenting symptoms using CTCAE v3.0 
3.5.2.3 
Laboratory Studies 
3.5.2.3.1 
Tests Obtained on Day 1 of Every Cycle 
3.5.2.3.1.1 
CBC with differential, reticulocyte count, ESR 
3.5.2.3.1.2 
Acute care panel (Sodium, Potassium, Chloride, CO2, Creatinine, Glucose, 
and Urea Nitrogen) 
3.5.2.3.1.3 
Mineral panel (Phosphorus, Magnesium, Albumin, and Calcium) 
3.5.2.3.1.4 
Hepatic panel (Alkaline Phosphatase, ALT, AST, Total Bilirubin, and Direct 
Bilirubin)  
3.5.2.3.1.5 
Total protein, LDH, creatine kinase, uric Acid 
3.5.2.3.1.6 
APTT, PT,  
3.5.2.3.1.7 
Urinalysis  
3.5.2.3.1.8 
Two Red top tubes to storage (send to SAIC, Frederick), assays to include 
IL6, viral IL-6, and CD105 
3.5.2.3.1.9 
Up to 30 cc of blood may optionally be drawn for virologic testing, 
establishment of cell lines, evaluation of hematologic parameters, or other 
studies that become clinically important during conduct of the trial. For 
patients co-enrolled in 01-C-0038, this will routinely include 2 green top 
tubes and 2 ACD yellow top tubes for storage of plasma and cells for future 
studies. If the investigators are interested in studying patient germline 
genotypic information other than VEGF or VEGF-R polymorphisms or HLA 
typing, they will return to the IRB with an amendment to the protocol in 
order to conduct this research. 
3.5.2.3.2 
Tests Obtained on (Day 21 +/- 1 week) of Every 3rd Cycle  
3.5.2.3.2.1 
HIV viral load if subject was HIV infected at entry 
3.5.2.3.2.2 
Lymphocyte phenotype TBNK.  A simultaneous CBC and automated 
differential must be drawn 
3.5.2.3.2.3 
4 yellow top tubes for storage for plasma and PBMC KSHV viral loads 
3.5.2.3.2.4 
Saliva for KSHV viral Load to Dr. Denise Whitby (send to SAIC-Frederick 
Building 535, Room 428A) 
3.5.2.4 
Evaluation of Extent of Kaposi’s Sarcoma 
3.5.2.4.1 
Day 1 of Every Cycle 


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The marker lesions will be measured, and a record made of their size, color, and 
nodularity, and the total number of lesions (if the patient, at baseline, had less 
than 50 lesions) or the lesions within previously defined representative areas (if 
the patient had more than 50 lesions) will be counted at the completion of each 
cycle as described in Section 3.5.1.4.1. 
3.5.2.4.2 
Day 21 (+/- 7 days) of Cycle 6 and Cycle 17  
Whole body and marker lesion photographs will be obtained. 
3.5.2.5 
Pathologic Kaposi’s Sarcoma Evaluation 
3.5.2.5.1 
Scheduled Biopsies 
One to two 4-6 mm cutaneous KS “Punch” Biopsies will be performed to 
confirm clinical complete response, or to document progressive disease if there 
is clinical uncertainty about new lesions. Divide the tissue into approximately 
equal 3mm pieces.  If only limited tissue is available, the priority for 
laboratories is to submit the material in the order listed below: 
3.5.2.5.1.1 
CCR Pathology histology and LANA IHC 
3.5.2.5.1.2 
If adequate tissue is available, a sample will be sent to the lab of Dr. 
Giovanna Tosato for IHC of Dll4, PDGF-C, G-CSF and other potential 
markers of resistance to bevacizumab (Building 37, Room 4134B)  
3.5.2.5.1.3 
Molecular pathology: if there is sufficient tissue, an aliquot will be sent to the 
laboratory of Dr. Robert Yarchoan (Building 10, Room 5A25) for storage for 
molecular pathology studies (dry, transported in a tube placed on ice). 
3.5.2.5.2 
Research Biopsies 
Paired tissue biopsies may be obtained (including one sample at baseline) for 
correlative biomarker studies evaluating the effects of therapy on Kaposi’s 
sarcoma. If the investigators are interested in studying germline genotypic 
information other than VEGF or VEGF-R polymorphisms or HLA typing, they 
will return to the IRB with an amendment to the protocol in order to conduct 
this research. Research biopsies are not required for participation in this study. 
3.5.2.6 
Cardiology Evaluation 
3.5.2.6.1 
Repeat MUGA will be performed on cycle 7 day 1 (+/- 7 days), after the 
completion of the combination of liposomal doxorubicin and bevacizumab. 
3.5.2.6.2 
If additional liposomal doxorubicin is given, MUGA will be repeated on day 21 
(+/- 7 days) after the 6th or last dose of additional liposomal doxorubicin. 
3.5.2.6.3 
Patients with an ejection fraction less than <50% (≥CTCAEv3.0 Grade 2 
toxicity) and at least 10% decrease from baseline on follow-up will have a 
repeat MUGA 3 months (+/- 7days) after the abnormal evaluation. 
3.5.2.6.4 
Patients with a continued ejection fraction less than <50% (≥CTCAEv3.0 Grade 
2 toxicity) and at least 10% decrease from baseline on 3-month follow-up will 
have a repeat MUGA at the end of the follow-up period. 


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3.5.2.6.5 
Additional diagnostic cardiology evaluations will be performed only as 
clinically indicated 
3.5.2.7 
Radiology evaluation 
3.5.2.7.1 
Abnormal non-invasive imaging from baseline studies should be repeated Day 
21 (+/-7 days) of every 3rd cycle until complete response. 
3.5.2.7.2 
Abnormal imaging from invasive studies should be repeated once a subject 
achieves a clinical complete response. 
3.5.2.7.3 
Evaluation of the vascularity in KS will be performed using 3 non-invasive 
modalities: laser Doppler imaging, multi-spectral imaging, and infrared thermal 
imaging.  Imaging will use the modalities explored in 01-C-0158. The target 
lesion and target normal skin established at baseline will be used as the imaged 
site. Use of these non-invasive modalities will be subject to technician and 
machine availability. Inability to schedule non-invasive imaging should not alter 
planned therapy, and will not result in a protocol violation. Follow-up imaging 
will be repeated as follows: 
3.5.2.7.3.1 
Day 8, cycle 1, prior to the administration of the combination of 
bevacizumab with liposomal doxorubicin.   
3.5.2.7.3.2 
Day 1, cycle 7 (+/- 7 days), after completing 6 cycles of the combination of 
liposomal doxorubicin with bevacizumab. 
3.5.2.7.3.3 
Day 21 cycle 17 (+/- 7 days), after completing bevacizumab monotherapy (if 
there are persistent lesions). 
3.5.3 Off-Study Evaluation 
3.5.3.1 
General Evaluation 
General evaluation will consist of history with review of symptoms and physical 
with vital signs. Adverse events reported during a review of systems will be 
evaluated using CTCAEv3. 
3.5.3.2 
Laboratory Studies 
3.5.3.2.1 
CBC with differential, reticulocyte count 
3.5.3.2.2 
Acute care panel (Sodium, Potassium, Chloride, CO2, Creatinine, Glucose, and 
Urea Nitrogen) 
3.5.3.2.3 
Mineral panel (Phosphorus, Magnesium, Albumin, and Calcium) 
3.5.3.2.4 
Hepatic panel (Alkaline Phosphatase, ALT, AST, Total Bilirubin, and Direct 
Bilirubin)  
3.5.3.2.5 
C-reactive protein 
3.5.3.2.6 
Total protein, creatine kinase, uric acid, LDH 
3.5.3.2.7 
APTT, PT, thrombin time (TT), fibrinogen, D-dimer Urinalysis, urine protein, 
urine creatinine 


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3.5.3.2.8 
Four Red top tubes to storage (send to SAIC, Frederick), assays to include IL6  
CD105, and possibly KSHV viral IL-6. 
3.5.3.2.9 
HIV viral load if subject was HIV infected at entry 
3.5.3.2.10 FACS: including CD4 and CD8 T-cells.  A simultaneous CBC and automated 
differential must be drawn 
3.5.3.2.11 4 yellow to tubes for storage for plasma and PBMC KSHV viral loads 
3.5.3.2.12 Saliva for KSHV viral Load to Dr. Denise Whitby (send to SAIC-Frederick 
Building 535, Room 428A) 
3.5.3.2.13 Up to 30 cc of blood may optionally be drawn for virologic testing, 
establishment of cell lines, evaluation of hematologic parameters, or other 
studies that become clinically important during conduct of the trial.  If the 
investigators are interested in studying patient germline genotypic information, 
they will return to the IRB with an amendment to the protocol in order to 
conduct this research. 
3.6 
CONCURRENT THERAPIES 
3.6.1 Anti-retroviral Therapy 
Patients will receive antiretroviral therapy if it is indicated.  Combination therapy will be 
generally based on Department of Health and Human Services Guidelines for treatment of HIV 
infection, available at http://www.aidsinfo.nih.gov/guidelines/.  However, patients may have 
extenuating circumstances requiring deviation from these guidelines.  Whenever possible, 
changing antiretroviral therapy should be avoided unless needed for optimal patient care.  
Additionally, referring physicians may manage this component of patient care.   
3.6.2 Pneumocystis jiroveci Prophylaxis 
For HIV-infected patients with history of PCP or with CD4 cells ≤ 200/mm3 should receive 
Bactrim DS PO 3x/week.  Alternatives include but are not limited Bactrim DS PO daily, 
Dapsone 100 mg PO qd, and monthly aerosolized pentamidine. 
3.6.3 MAC Prophylaxis 
Consider for all HIV-infected patients with a historic CD4 nadir less than 75 cells/mm3, or for 
patients whose CD4 cells fall below this level while on study. Recommend azithromycin 1200 
mg once weekly, but other agents are acceptable. 
3.6.4 Antihypertensive Therapy 
Blood pressure will be monitored at baseline and throughout follow-up.  Blood pressure 
diagnosis and management will follow the general principals of the Seventh Report of the Joint 
Committee on the Prevention, Detection, Evaluation, and Treatment of high Blood pressure 
(JNC-7)58.  All patients who are diagnosed with hypertension during screening or follow-up will 
be treated for hypertension. 
3.6.4.1 
Blood Pressure Definitions 


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3.6.4.1.1 
Blood pressure will be measured with the subject sitting in a supine position for 
5 minutes, with the arm supported at heart level, using a bladder cuff that covers 
at least 80% of the subjects upper arm 
3.6.4.1.2 
Pre-Hypertension: Systolic Blood Pressure (SBP) 120-139 or Diastolic Blood 
Pressure 80-89 
3.6.4.1.3 
Stage 1 Hypertension: SBP 140-159 or DBP 90-99 
3.6.4.1.4 
Stage 2 Hypertension: SBP ≥ 160 or DBP ≥ 100 
3.6.4.1.5 
Goal Blood pressure for patients receiving anti-hypertensive agents <140/90 or 
<130/85 if subject has diabetes or chronic renal insufficiency 
3.6.4.2 
Other Cardiovascular Risk Factors 
Subjects noted to have hypertension at baseline will be evaluated through medical 
history for other cardiovascular risk factors, including age (>55 in men or >65 in 
women), family history of premature cardiovascular disease in first degree relatives 
(< 55 in men or < 65 in women), smoking history, obesity, diabetes, chronic renal 
insufficiency and dyslipidemia.  Patients with >2 cardiovascular risk factors should 
be evaluated and monitored by either the subject’s primary internist or a 
cardiologist. 
3.6.4.3 
Treatment of Hypertension 
3.6.4.3.1 
Initiation of Anti-hypertensive therapy 
Antihypertensive therapy will be started for all subjects who are diagnosed with ≥ 
Stage 1 (see Section 3.6.4.1.3.) hypertension on two separate days. 
3.6.4.3.2 
Antihypertensive Agents 
Patient treatment will be individualized using standard anti-hypertensive therapy, 
including but not limited to the following classes of drugs: thiazide diuretics, beta-
blockers, angiotensin converting enzyme inhibitors, angiotensin receptor blockers, 
and calcium channel blockers.  Priority will be given to angiotensin receptor 
blockade when feasible59, due to potential protection against proteinuria. 
3.6.5 Thromboprophylaxis 
3.6.5.1 
Subjects will receive thromboprophylaxis with aspirin 81mg orally once daily for 
the duration of study therapy, ceasing 3 months following the last cycle of therapy 
if continued aspirin is not otherwise indicated. 
3.6.5.2 
Aspirin will not be administered when platelet count is ≤ 50,000/µL. 
3.6.6 Contraindicated Therapies 
3.6.6.1 
It is important to avoid systemic glucocorticoid steroid administration if at all 
possible, as glucocorticoids may exacerbate KS.  Short courses of corticosteroids 
(<10 days) are not strictly contraindicated. 
3.6.6.2 
Specific therapy for KS (e.g. cytotoxic chemotherapy agents, radiation therapy, 
topical anti-KS medications) is not allowed during the treatment phase of the 
protocol. 


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3.6.6.3 
Patients will not receive any immunomodulatory agents or, as stated above, 
therapies for their KS.  Patients may receive erythropoietin or filgrastim (G-CSF) as 
per standard medical practice.  The use of other cytokines will not be allowed.   
3.6.6.4 
Intravenous antibiotics may not be administered concurrently with bevacizumab 
and/or liposomal doxorubicin.  In the setting of infections requiring IV antibiotics, 
the guidelines for treatment modifications (Section 3.3.) and off study criteria 
(Section 3.9.) will be followed.  
3.7 
SURGICAL GUIDELINES 
Elective surgery is contraindicated in patients receiving bevacizumab due to potential wound 
healing complications. If there is need for an elective major surgical or periodontal procedure, 
bevacizumab should be held beginning at least 6 weeks prior to the procedure and must not be 
resumed before 4 weeks after the surgical procedure.  For urgent or emergent surgery or 
endoscopic procedures, bevacizumab will be held for 4 weeks after the procedure. Longer delays 
may be necessary, if clinically indicated, in order to ensure that adequate healing has taken place 
prior to bevacizumab resumption.  For KS skin biopsies and other minor procedures (i.e. 
interventional radiology diagnostic procedures), bevacizumab will be held only if there is 
evidence that healing is compromised. For eligibility criteria for enrollment after surgery, see 
sections 2.1.2.4. and 2.1.2.5.  
3.8 
RADIATION THERAPY GUIDELINES 
Radiation therapy is contraindicated for patients receiving therapy on protocol, as the effects of 
radiation therapy in combination with bevacizumab in patients with KS are unknown.   
3.9 
OFF TREATMENT AND OFF STUDY CRITERIA 
Subjects will be monitored each cycle for toxicity, co-morbidities and evidence of disease 
progression on physical exam.  Treatment will be discontinued for any of the reasons listed 
below.  Subjects removed from treatment for criteria 3.9.1 through 3.9.7 will be followed on–
study in post-treatment evaluation as outlined in section 3.10.  Patients will be taken off-study 
based on criteria 3.9.8 through 3.9.12. 
3.9.1 Grade 3 or 4 allergy attributed to bevacizumab. 
3.9.2 Grade 3 or 4 toxicity possibly, likely or definitely attributable to liposomal doxorubicin 
combined with bevacizumab or bevacizumab alone that does not resolve to grade 1 or 
baseline (whichever is higher) within 6 weeks, with the following exceptions (consistent 
with Section 2.1.2.19): 
3.9.2.1 
Lymphopenia 
3.9.2.2 
Asymptomatic hyperuricemia 
3.9.2.3 
Asymptomatic hyperbilirubinemia 
3.9.2.4 
Hypophosphatemia 
3.9.2.5 
Hypermagnesemia or hypomagnesemia 
3.9.2.6 
Asymptomatic elevations in creatine phosphokinase (CPK) 
3.9.2.7 
Direct manifestations of KS, HIV, or HIV therapy 


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3.9.3 Development of venous or arterial thrombosis 
3.9.4 Proteinuria >2 gram/24 hours that does not resolve to ≤ 1.5 grams within 4 weeks. 
3.9.5 Severe illness lasting > 6 weeks that precludes administration of liposomal doxorubicin 
in combination with bevacizumab or bevacizumab alone. 
3.9.6 Pregnancy 
3.9.7 Institution of a non-protocol treatment for KS 
3.9.8 Disease progression as compared to baseline and lasting at least 6 weeks (see section 5.2 
for definitions of response criteria) not attributed to immune reconstitution syndrome.  
As KS may wax and wane, and improvements may be seen despite an initial period of 
progression, physician investigators may continue therapy through the first 6 cycles, 
despite meeting formal criteria for progressive disease, as long as disease progression is 
not clinically significant or life threatening.  Such cases must be discussed with the 
Principal Investigator and study subject.  Furthermore, patients may be eligible for 
additional liposomal doxorubicin and/or bevacizumab, as outlined in Sections 3.3.1.13 
and 3.3.2.6. 
3.9.9 Subject requests to discontinue treatment and/or continued evaluation. 
3.9.10 Subjects may be taken off-study for lack of adherence to protocol therapies (including 
HAART) and the assessment that continuing on the study would compromise subject 
safety and interfere with protocol integrity.  Additionally, the Principal Investigator may 
take a subject off-study for adverse events deemed sufficiently serious to warrant 
discontinuation of therapy. 
Subjects may be taken off study at the discretion of the Principal Investigator 
3.10 OFF-STUDY PROCEDURE  
Authorized staff must notify Central Registration Office (CRO) when a patient is taken off-
study. An off-study form from the web site 
(http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) main page must be completed and 
faxed to 301-480-0757. 
3.10.1 Unacceptable toxicities that have not resolved at time of “off treatment” or “off study” 
must be followed until stabilization or resolution. 
3.11 POST TREATMENT EVALUATION (FOLLOW-UP) 
3.11.1 Clinical 
3.11.1.1 Subjects will be evaluated for short-term toxicity at a follow up appointment 
scheduled 4 weeks (+/- 1 week) after completion of treatment.  If any drug toxicity 
remains at the follow-up evaluation, patients will be followed as medically 
indicated until the toxicity stabilizes. 
3.11.1.1.1 Review of symptoms will be performed, and toxicity will be graded using the 
NCI – CTCAE v3.0. 
3.11.1.1.2 Objective signs will include a complete physical examination (with recording of 
abnormalities), blood pressure weight changes, and fever. Temperatures and 
weights will be evaluated at each clinic visit. 


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3.11.1.2 Subjects will be evaluated in clinic every 3 months or as clinically indicated for up 
to 2 years after completion of therapy to evaluate for disease progression.  This 
follow up will end when patients meet criteria for disease progression. 
3.11.2 Laboratory studies 
The following laboratory studies will be drawn 4 weeks (+/- 1 week) after completion of therapy. 
3.11.2.1 CBC with differential, ESR, reticulocyte count 
3.11.2.2 APTT, PT, fibrinogen 
3.11.2.3 Acute panel, hepatic panel, mineral panel 
3.11.2.4 Thyroid function tests (TSH, Free T4) 
3.11.2.5 Creatine kinase, total protein, amylase, LDH, uric acid 
3.11.2.6 Urinalysis,  
3.11.2.7 Four Red top tubes to storage (send to SAIC, Frederick), assays to include IL6, viral 
IL-6 and CD105 
3.11.2.8 Lymphocyte phenotype TBNK. A simultaneous CBC and automated differential 
must be drawn 
3.11.2.9 HIV viral load (if HIV positive at entry) 
3.11.2.10 Up to 30 cc of blood may optionally be drawn for virologic testing, establishment of 
cell lines, evaluation of hematologic parameters, or other studies that become 
clinically important during conduct of the trial. 
3.11.2.11 Four yellow top tubes for storage for plasma and PBMC KSHV viral load (send to 
SAIC, Frederick) 
3.11.3 Extent of Kaposi’s Sarcoma 
3.11.3.1 The marker lesions will be measured, and a record made of their size, color, and 
nodularity, and the total number of lesions (if the patient, at baseline, had less than 
50 lesions) or the lesions within previously defined representative areas (if the 
patient had more than 50 lesions) will be counted at the completion of each cycle as 
described in Section 3.5.2.4.1.  
3.11.3.2 Whole body and marker lesion photographs will be obtained. 
3.11.4 Pathologic Kaposi’s Sarcoma Evaluation 
One to two 4-6 mm cutaneous KS “Punch” Biopsies will be performed, if indicated, to confirm 
clinical complete response, or to document progressive disease if there is clinical uncertainty 
about new lesions.  Tissue handling is outlined in Section 3.5.2.5. 
4. SUPPORTIVE CARE 
4.1 
GENERAL KS AND HIV RELATED 
Medications may be administered as clinically indicated, or at the discretion of the Principal 
Investigator, with the following exceptions: 
4.1.1 Other specific therapies for KS 


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4.1.2 Any medications noted in the exclusion criteria or Section 3.6.5. with the exception of 
short-term courses of corticosteroids. 
4.2 
OPPORTUNISTIC INFECTIONS 
Subjects who develop opportunistic infections, including but not limited to pneumocystis jiroveci 
pneumonia, mycobacterial diseases, cytomegalovirus (CMV), and fungal infections will be 
treated using standard regimens.  All opportunistic infections will be discussed with the Principal 
Investigator. Consultation with the Infectious Disease Service is mandatory for subjects 
diagnosed with mycobacterium tuberculosis. 
4.3 
ANEMIA 
If subject develops symptomatic anemia, or if the hemoglobin falls below 8 mg/dl erythropoietin 
may be considered. Appropriate evaluation for etiology of the anemia should be initiated. 
4.4 
THROMBOCYTOPENIA 
Thrombocytopenia should be treated conservatively.  In the absence of bleeding or a planned 
invasive procedure, platelet transfusions should be given for a platelet count below 10,000.  If 
invasive procedures are planned or the patient develops bleeding, platelet transfusions should be 
administered in accordance with standard of practice, usually maintaining a platelet count > 
50,000/mm3.  Liposomal doxorubicin in combination with bevacizumab will not be administered 
unless the platelets are ≥ 75, 000/mm3, and bevacizumab monotherapy will not be administered 
unless the platelets are ≥ 50, 000/mm3. 
4.5 
FEBRILE NEUTROPENIA 
Patients who develop febrile neutropenia will be hospitalized and treated with intravenous 
antibiotics. See sections 3.3.1.4. and 3.3.2.2.1 for Treatment Modifications and filgrastim use 
pertaining to neutropenia.  The use of filgrastim will be based on based on whether the 
development of neutropenia or neutropenic fever develops while the patient is receiving the 
combination of liposomal doxorubicin with bevacizumab or bevacizumab monotherapy. 
4.6 
HYPERTENSION 
Blood pressure will be monitored at baseline and throughout treatment and follow-up.  
Antihypertensive medications will be introduced early in subjects that develop hypertension.  
The procedures for monitoring blood pressure and treating hypertension are fully outlined in 
Section 3.6.4.  
5. DATA COLLECTION AND EVALUATION 
5.1 
DATA COLLECTION 
Members of the HIV and AIDS Malignancy Branch clinical research team will collect data on 
study subjects according to the Schedule of Evaluations outlined in Appendix 1.  Complete 
records must be maintained on each patient including supplementary information obtained from 
outside laboratories, radiology reports, or physician’s records. These records will serve as the 
primary source material that forms the basis for the research record. The primary source 
documentation will assure the following:  
5.1.1 The patient satisfied each eligibility criterion.  
5.1.2 Signed informed consent was obtained prior to registration and treatment.  


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5.1.3 Treatment was given according to protocol or any protocol deviations or non-compliance 
is documented and justified.   
5.1.4 Toxicity and response were assessed according to protocol. 
5.1.5 Drug accountability records were kept on each patient.  
Clinical data will be coded for database entry. Data will be stored in the CCR C3D clinical trials 
database.  Dr. Robert Yarchoan, the Principal Investigator, will be responsible for the protocol.   
All adverse events, including clinically significant abnormal findings on laboratory evaluations, 
regardless of severity, will be followed until return to baseline or stabilization of event. Patients 
will be followed for adverse events for 4 weeks after removal from study treatment or until off-
study, whichever comes first. 
An abnormal laboratory value will be recorded in the database as an AE only if the laboratory 
abnormality is characterized by any of the following: 
• 
Results in discontinuation from the study 
• 
Is associated with clinical signs or symptoms  
• 
Requires treatment or any other therapeutic intervention 
• 
Is associated with death or another serious adverse event, including hospitalization.  
• 
Is judged by the Investigator to be of significant clinical impact 
• 
If any abnormal laboratory result is considered clinically significant, the investigator will 
provide details about the action taken with respect to the test drug and about the patient’s 
outcome. 
End of study procedures: Data will be stored according to HHS, FDA regulations, and NIH 
Intramural Records Retention Schedule as applicable.  
Loss or destruction of data: Should we become aware that a major breach in our plan to protect 
subject confidentiality and trial data has occurred, the IRB will be notified.  
 
5.2 
RESPONSE CRITERIA 
The evaluation of the response of KS to an agent or regimen is difficult to grade by means of 
commonly used oncologic definitions.  However, in an effort to standardize the evaluation of 
therapy against KS, the AIDS Clinical Trial Group Oncology Committee has devised a set of 
staging and response definitions for KS.  We will use a modification of these criteria to assess 
responses, which is consistent with the criteria used in our previous KS studies.  It should be 
noted that there is some observer variability in the evaluation of the number, size, nodularity, and 
color of lesions, and this must be taken into account when measurements are interpreted. 
For evaluation of less than complete responses in patients with more than 50 lesions at entry, 
only the previously selected 1 - 3 representative areas that contain at least 20 lesions will be 
considered.  However, complete responses still require the absence of any detectable disease 
over the entire body (i.e. not confined to the representative areas). 
5.2.1 Complete Response 


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5.2.1.1 
The absence of any detectable residual disease, including tumor-associated edema, 
persisting for at least 4 weeks.   
5.2.1.2 
In patients in whom pigmented macular skin lesions persist after apparent CR, 
biopsy of at least one representative lesion is required to document the absence of 
malignant cells.   
5.2.1.3 
In patients known to have had visceral disease, an attempt at restaging with 
appropriate endoscopic or radiographic procedures should be made.  If such 
procedures are medically contraindicated, the patient may be classified as having a 
clinical CR. 
5.2.2 Clinical Complete Response 
5.2.2.1 
The absence of any detectable residual disease, including tumor associated edema, 
persisting for at least 4 weeks.   
5.2.2.2 
For patients with pigmented macular skin lesions persisting after apparent complete 
response, a representative lesion has not been biopsied.   
5.2.2.3 
For patients with visceral disease, the diagnostic radiologic or endoscopic study 
should be repeated if not medically contraindicated and found to be negative for 
evidence of disease. If such procedures are medically contraindicated but the patient 
has no clinical evidence of visceral disease, the patient may be classified as having 
a clinical CR. 
5.2.3 Partial Response 
 
No progressive disease (see below and noting, that single lesions which split up into 2 or more 
smaller lesions during the course of treatment will still be counted as one); no new lesions 
occurring in previously uninvolved areas of the body; no new visceral sites of involvement or the 
appearance or worsening of tumor-associated edema or effusions and: 
5.2.3.1 
A 50% or greater decrease in the number and/or size of previously existing lesions 
lasting for at least 4 weeks or 
5.2.3.2 
Complete flattening of at least 50% of all previously raised lesions (i.e., 50% of all 
previously nodular or plaque-like lesions become macular) lasting for at least 4 
weeks or 
5.2.3.3 
A 50% decrease in the sum of the products of the largest perpendicular diameters of 
the marker lesions lasting for at least 4 weeks or 
5.2.3.4 
A 50% decrease in radiologically measurable visceral lesions sustained without 
evidence of re-growth for at least 4 weeks or 
5.2.3.5 
Patients who otherwise meet the criteria for a CR but still have residual tumor-
associated edema or effusions will be classified as having a PR. 
5.2.4 Progressive Disease 
5.2.4.1 
For those criteria that involve measurement of lesions in the clinic, the designation 
of progression should be made, when feasible, only when the criteria below have 
been met in two measurements spaced at least 1 week apart. For the assignment of 


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progressive disease for the primary outcome analysis, progression will be defined in 
comparison to baseline measurements. 
5.2.4.2 
An increase of 25% or more over baseline in the number of lesions and/or the size 
(sum of the products of the largest perpendicular diameters) of the marker lesions 
or 
5.2.4.3 
A change in character from macular to plaque-like or nodular of at least 25% of the 
lesions or 
5.2.4.4 
New visceral sites of involvement or progression of visceral disease or 
5.2.4.5 
The development of new or increasing tumor-associated edema or effusion that lasts 
at least 1 week and interferes with the patient’s normal activities. 
5.2.5 Stable Disease 
Any tumor measurement not meeting the criteria for Complete Response, Partial Response, or 
Progressive Disease. 
5.2.6 Overall Response  
Overall  Response = Complete Response + Clinical Complete Response + Partial Response.  The 
Overall Response Rate (ORR) is the fraction of subjects with an Overall Response after 6 cycles 
of liposomal doxorubicin in combination with bevacizumab. 
5.2.7 Progression-free survival 
As Kaposi’s Sarcoma is a disease in which recurrence is common, progression will be 
determined based on progression from best response.  As in section 5.2.4., progression must be 
documented on two visits at least 1 week apart.  The criteria for progression from best response 
include: 
5.2.7.1 
An increase of 25% or more over best response in the number of lesions and/or the 
size (sum of the products of the largest perpendicular diameters) of the marker 
lesions or 
5.2.7.2 
A change in character from macular to plaque-like or nodular of at least 25% of the 
lesions or 
5.2.7.3 
New visceral sites of involvement or progression of visceral disease or 
5.2.7.4 
The development of new or increasing tumor-associated edema or effusion that lasts 
at least 1 week and interferes with the normal activities 
Progression-free survival is defined as the time interval from the date of enrolment to the date of 
progression from best response. 
 
 
 
5.3 
TOXICITY CRITERIA 
5.3.1 Toxicity Grading 


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This study will utilize the NCI CTC version 3.0 for toxicity and adverse event reporting. (See: 
http://ctep.info.nih.gov).  All appropriate treatment areas should have access to a copy of the 
CTCAE version 3.0.  
5.3.2 Toxicity Attribution 
The Principal Investigator or physician Associate Investigator will document the relationship of 
the protocol intervention to each adverse event by assigning attribution per adverse event at time 
of clinical evaluation. Attribution will be rated as follows: 
5.3.2.1 
Unrelated 
5.3.2.2 
The adverse event is clearly not related to the investigational agents. 
5.3.2.3 
Unlikely Related 
5.3.2.4 
The adverse event is doubtfully related to the investigational agents. 
5.3.2.5 
Possibly Related 
5.3.2.6 
The adverse event may be related to the investigational agents. 
5.3.2.7 
Probably Related 
5.3.2.8 
The adverse event is likely related to the investigational agents. 
5.3.2.9 
Definitely Related 
5.3.2.10 The adverse event is clearly related to the investigational agents. 
5.4 
STATISTICAL CONSIDERATIONS 
5.4.1 Racial/gender make-up 
Subjects from both genders and all racial/ethnic groups are eligible for this study if 
they meet the eligibility criteria outlined in section 2.1.  Outreach efforts will be made 
to extend accrual to a representative population. As a practical matter, it should be 
noted that historically in the US, KS has been relatively rare in females with HIV 
infection.  However, our more recent studies have increasingly accrued female 
immigrants from Africa. 
5.4.2 Age exclusion 
Patients under the age of 18 will be excluded.  This is a pilot clinical study of an 
agent with unknown safety profile in children and adolescents in a disease that is rare 
in children, and for which standard therapies are available.  Anti-angiogenesis therapy 
theoretically could interfere with growth in children and adolescents.  Additionally, 
since the protocol requires several skin biopsies, patient-volunteers should enter the 
protocol with full consent, rather than just assent.   
5.4.3 Sample size and accrual limit 
5.4.3.1 
Primary Outcome 
This is a pilot study. The primary objective is to estimate of the overall response 
rate of the combination of liposomal doxorubicin and bevacizumab after 6 cycles in 
patients with advanced Kaposi’s sarcoma. The ORR will be evaluated in two 
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Cohort 1: Patients who are either: 
5.4.3.1.1 
HIV negative  
5.4.3.1.2 
HIV infected with stable KS despite one year of HAART    with HIV viremic 
control 
5.4.3.1.3 
HIV infected with progressive KS despite four months of HAART with HIV 
viremic control 
Cohort 2: All other patients with advanced AIDS-associated KS 
Ten evaluable patients will be enrolled in each cohort (20 total).  Patients are 
considered evaluable if they (1) have received at least 2 cycles of liposomal 
doxorubicin, OR (2) have come off the protocol for reasons of treatment toxicity.  Up 
to 3 patients in each cohort may be replaced if they come off the study before being 
considered evaluable.  Thus, the accrual ceiling will be 26 patients.  With 10 
evaluable patients in each cohort, the 80% two sided confidence intervals about the 
fraction with any responses are as follows: 
Number of responses      80% CI 
1.                            
 .01-.34 
2.                            
 .05-.45 
3.                             
.12-.55 
4.                            
.19-.65 
5.                             
.27-.73 
6.                             
.35-.81 
7.                             
.45-.88 
8.                             
.55-.95 
9.                             
.66-.99 
Thus, the evaluation of 10 patients in each cohort may allow an estimate with an 80% 
CI width of approximately .33 to .45. The estimates in the two cohorts will be 
compared and if they are similar (p>0.30 by a Fisher’s exact test), they may be 
combined to form a somewhat more precise estimate of the fraction that respond 
within 6 cycles of treatment. 
5.4.3.2 
 Secondary Outcomes 
The following secondary outcomes will be evaluated with the following statistical 
considerations. 
 
5.4.3.2.1 
Assess the toxicity of liposomal doxorubicin combined with bevacizumab in 
patients with advanced KS. 


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Toxicities (including those possibly, probably, and definitely attributed to study 
treatment) will be assessed by grade.  Toxicities will be evaluated both per cycle 
and per patient.    All patients will be considered evaluable for toxicity. 
5.4.3.2.2 
Estimate the complete response rate after 6 cycles of the combination of 
liposomal doxorubicin in combination with bevacizumab in evaluable 
patients with advanced KS. 
The evaluable patients from each cohort will be evaluated separately as 
described in section 5.4.3.1.  The 80% confidence intervals of the estimates of 
complete response rates and the corresponding to the number of response are 
listed in Section 5.4.3.1. 
The estimates in the two cohorts will be compared and if they are similar 
(p>0.30 by a Fisher’s exact test), they may be combined to form a somewhat 
more precise estimate of the fraction that have a complete response within 6 
cycles of treatment. 
5.4.3.2.3 
Estimate the median number of cycles of liposomal doxorubicin in 
combination with bevacizumab required to achieve a partial response in 
patients with advanced KS. 
The median number of cycles required to achieve a partial response will be 
described for evaluable patients in each cohort separately, along with a range of 
number of cycles required. Patients with progressive disease will be excluded 
from this analysis.   
5.4.3.2.4 
Estimate 12-month progression free survival in evaluable patients with 
advanced KS treated with the combination of liposomal doxorubicin and 
bevacizumab followed by 11 cycles of bevacizumab. 
Progression-free survival will be calculated using Kaplan-Meier methodology. 
Separate curves will be formed for evaluable patients in each cohort, and a 
combined curve may also be formed if the two cohorts have similar PFS (which 
will be indicated by having a p-value >0.30 by a two-tailed log rank test). Since 
the number of patients will be small, these results will be considered to provide 
approximate estimates of PFS. The two-sided 80% confidence interval around 
the PFS estimate at one year will be computed, and it will be of interest to 
determine if this interval includes 70%, the result that was found in our previous 
Doxil/IL-12 study. In view of the pilot nature and limited size of this study, this 
will only be done to determine the approximate impact of this treatment with 
regard to PFS in an informal manner. 
5.4.3.2.5 
Evaluate the impact of the combination of liposomal doxorubicin in 
combination with bevacizumab, as well as bevacizumab maintenance on 
CD4 counts. 
The effect that the combination of liposomal doxorubicin and bevacizumab 
followed by maintenance bevacizumab have on CD4 counts will evaluated 
separately in each cohort, as patients in Cohort 2 would be expected to have 
increases in their CD4 counts once on an optimized HAART regimen. CD4 
counts will be evaluated at baseline, on Day 1 of cycles 4,7,11, and 15, as well 


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as 6 months after completing therapy. Changes in CD4 count at each of these 
time points will be calculated by subtracting the baseline value from the 
subsequent time points, and tested for being different than zero using the 
Wilcoxon signed rank test. As these will be considered entirely exploratory 
analyses, there will not be any formal adjustment for multiple comparisons, 
although the findings will be interpreted informally in the context of the number 
of tests performed.  
5.4.3.2.6 
Evaluate the effect of liposomal doxorubicin combined with bevacizumab 
followed by bevacizumab maintenance, on PBMC and saliva KSHV viral 
load.   
We will perform an exploratory analysis of the effect of the combination of 
liposomal doxorubicin and bevacizumab on log10 saliva and PBMC KSHV 
viral load in all patients in Cohort 1 and Cohort 2 combined.   
5.4.3.2.7 
Explore, in a preliminary manner, the short-term effects of bevacizumab 
and intermediate and long term effects of the combination of bevacizumab 
and liposomal doxorubicin on blood flow to cutaneous KS lesions using 
non-invasive imaging techniques. 
Descriptive changes in imaging results from each of the three modalities of 
target lesions will be detailed for each study subject longitudinally at time 
points Cycle 1 Day 1, Cycle 1 Day 8, Cycle 7 Day 1, and Cycle 17 Day 21 (if 
there are persistent lesions).  
5.4.4 Projected Accrual Timeline 
It is anticipated that up to 3 years may be required to accrue 20 patients to enroll into this pilot 
trial, with the ceiling set at 26 to allow for replacement of patients. 
5.5 
MULTI-INSTITUTIONAL GUIDELINES  
Not applicable. 
5.6 
DATA AND SAFETY MONITORING PLAN 
Patient data will be collected in a timely manner and reviewed by a physician Associate 
Investigator and/or the Principal Investigator, Robert Yarchoan, for toxicity.  Any toxicity 
≥ Grade 3 will be reviewed by the Principal Investigator.  In the event that an unacceptable 
toxicity occurs, the IRB will be informed and appropriate measures, as outlined in Section 7, will 
be taken.  The Principal Investigator will do the monitoring of this pilot study in an ongoing 
manner, and a Data and Safety Monitoring Board will not be used. 
6. HUMAN SUBJECTS PROTECTIONS 
6.1 
RATIONALE FOR SUBJECT SELECTION 
This protocol is designed for the treatment of all adult subjects with advanced KS. The main 
epidemiologic groups that would be potential subjects are those with HIV-associated KS, 
transplant recipients, and those with classic or endemic KS, who are generally older individuals 
from areas where the prevalence of KSHV infection is high.  KS disproportionately affects men, 
with a male:female ratio that varies between epidemiologic groups.  At the HAMB, most women 
who have participated in our previous KS studies have been immigrants from Africa. 


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Strategies for recruitment will include announcements on ClinicalTrials.gov, letters to referring 
physicians, targeting HIV providers and those who provide primary care to the African 
immigrant community, and AIDS treatment bulletins.   
6.2 
PARTICIPATION OF CHILDREN 
KS is an extremely rare tumor in children, with a different presentation that that seen in adults.  
KS in children generally presents with lymphadenopathy, which likely represents a biologically 
different disease than that seen in adults.  As such, subjects <18 will be excluded from this 
protocol. 
6.3 
EVALUATION OF BENEFITS AND RISKS/DISCOMFORTS 
The investigational nature and objectives of this trial, the procedures and treatments involved and 
their attendant risks and discomforts, potential benefits, and potential alternative therapies will be 
carefully explained to the patient or the patient’s surrogate, and a signed informed consent 
document will be obtained. 
6.3.1 Potential Benefits 
The potential benefit to individual patient-volunteers is that the protocol therapy may result in 
rapid improvement of advanced KS.  It may also provide long-term control of KS without the 
high potential cumulative toxicity due to complications associated with chronic administration of 
standard cytotoxic therapy.  Participation in a clinical study will help researchers better 
understand the pathophysiology of KS, as well as allow for an evaluation of liposomal 
doxorubicin in combination bevacizumab in patients with advanced KS. 
6.3.2 Potential Risks and Discomforts 
There may be no direct benefit to the patient-volunteers on this study.  Potential risks include the 
potential toxicity of the agents. Additionally, the safety of the agents has not evaluated when 
used in combination have not been defined in this population. See Section 8 for potential 
toxicities. Additional risks include the small risk of complications related to cutaneous “punch” 
biopsies, which include infection and pain. 
6.4 
RISK/BENEFITS ANALYSIS 
The risks to individual study subjects are reasonable in relation to the anticipated benefits.  This 
protocol combines a standard FDA approved agent for the treatment of KS with bevacizumab, 
which has strong preclinical rationale, an acceptable toxicity profile and promising clinical 
activity in our previous phase II study, 03-C-0110.  Potential therapeutic benefits include 
limitation of cumulative anthracycline dosing, more rapid tumor regression, and additional 
therapeutic options for patients for difficult to manage KS. The risks include potential additive 
toxicities and additional studies associated with participation in a clinical study.  The major 
alternative for patients with advanced KS is to receive FDA approved agents outside of a clinical 
study.  The comparative risks and benefits are acceptable for an early phase clinical study, when 
compared to the alternatives for patients with advanced KS. 
 
6.5 
SPECIMEN HANDLING GUIDELINES  
It is understood that per the NCI policy regarding the Requirements for the Research Use of 
Stored Human Specimens and Data, prospective NIH IRB approval and continuing IRB 


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oversight must be obtained for research involving identified or coded samples or data where 
investigators can identify the source. This policy applies to research protocols where the 
remaining research activities are limited to data analysis and to the subsequent research use of 
specimens or data previously collected under a now terminated protocol.   The following 
guidelines describe how these principles apply to this specific protocol.   
6.5.1 AIDS Monitoring Laboratory 
Many samples on this study will be processed and stored in the AIDS Monitoring Laboratory 
(AML) run by Science Applications International Corporation (SAIC) in the NCI-Frederick 
facility located with Fort Detrick.  The samples are stored under code, and the information 
linking these unique codes to the patients is kept on the AML database.  The laboratory 
informatics system conforms to NIH Information Technology Security Requirements and NIH 
Protection of Human Research Subjects Guidelines.  All laboratory staff is trained to adhere to 
NIH Information Technology Security Requirements and NIH Protection of Human Research 
Subjects Guidelines.  Computers used to access inventory systems require username and 
password for login. The laboratory database is housed in a secure, protected environment and 
backups are performed routinely.  Access to specimen information, clinical data, and stored 
specimens is limited to approved laboratory staff and the investigator in charge of the study (or 
individuals authorized by the investigator). Clinical testing of all samples will be one in 
accordance to the protocol.  The protocol team will inform the AML staff when tests are to be 
run with the specimens, and the samples used for testing will be tracked by the AML.  This 
information will in turn be shared with the protocol team.  The research nurse on the study will 
be in charge of tracking this information for the protocol team. 
6.5.2 Tracking Samples 
The protocol team will inform the AML staff when tests are to be run with the specimens, and 
the samples used for testing will be tracked by the AML.  This information will in turn be shared 
with the protocol team.  The research nurse on the study will be in charge of tracking this 
information for the protocol team. 
6.5.3 Samples for Planned Collaboration 
6.5.3.1 
KSHV PCR and serology: Some of the specimens are sent to the laboratory of Dr. 
Denise Whitby, also in Science Applications International Corporation (SAIC) in 
the NCI-Frederick facility located with Fort Detrick.  The samples sent are coded 
by the protocol research team and have no patient identifiers.  They are logged in by 
Dr. Whitby’s laboratory and kept in a locked facility.  They are run in batch when 
enough specimens are collected. Records are kept when the specimens are used for 
analysis.  
6.5.3.2 
CD103 and VEGF polymporphisms: Specimens for these correlative studies will 
be processed and stored in the AML as outlined in section 6.5.1. Coded samples 
with no patient identifiers will be analyzed in batches once enough specimens are 
collected. Assays will be performed in the laboratory of Dr. William Figg 
6.5.3.3 
Dll4, PDGF-C and G-CSF IHC: Specimens for these correlative studies will be 
processed and stored in the lab of Dr. Giovanna Tosato, (Building 37, Room 
4134B). The samples sent are coded by the protocol research team and have no 
patient identifiers.  They are logged in by Dr. Tosato’s laboratory and kept in a 


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locked facility.  They are run in batch when enough specimens are collected. 
Records are kept when the specimens are used for analysis. 
6.5.4 Dr. Yarchoan’s Laboratory 
A limited number of samples are sent to Dr. Yarchoan’s laboratory.  This is a locked laboratory, 
and a log is kept of the specimens and when they are utilized. 
6.5.5 Routine Samples 
Many routine samples and a sample of the biopsy specimens are sent to the Clinical Pathology or 
Pathology Departments of the NIH Clinical Center.  These samples will be handled according to 
the procedures of these departments.  
6.5.6 Co-enrollment in 01-C-0038 
If patients have co-enrolled on study 01-C-0038 (Collection of Blood, Bone Marrow, Tumor, or 
Tissue Samples from Patients with HIV Infection, KSHV Infection, Viral-related Pre-Malignant 
Lesions, and/or Cancer), then the samples may also be tested under the specifications of that 
study.  Similarly, if patients have co-enrolled on other studies approved by the NCI IRB that call 
for maintaining and testing the samples, then they may be transferred to those studies. 
6.5.7 Unused Samples 
At the termination of the study, if patients have co-enrolled on study 01-C-0038 (Collection of 
Blood, Bone Marrow, Tumor, or Tissue Samples from Patients with HIV Infection, KSHV 
Infection, Viral-related Pre-Malignant Lesions, and/or Cancer), then the samples will be 
transferred to that study unless the patients request that this not occur.  Also, if patients have co-
enrolled on other studies approved by the NCI IRB that call for maintaining the samples, then 
they will be maintained on those protocols.  Otherwise, the unused samples will be destroyed. 
6.5.8 Lost or Destroyed Samples 
The PI will report any loss or destruction of the samples to the IRB, and any new use of the 
samples, specimens, or data will require prospective IRB approval. 
6.5.9 Non-Invasive Imaging  
Dr. Amir Gandjbakhche will maintain non-invasive images.  Images will be coded with no name 
identification.  Records will be maintained in a locked facility. 
6.6 
CONSENT AND ASSENT PROCESS AND DOCUMENTATION 
Informed written consent will be obtained in all patients on this trial.  There will be no minors 
enrolled < 18 years old, so assent is unnecessary. All potential participants will be provided an 
informed consent form to review prior to their screening visit. The Principal Investigator or a 
physician Associate Investigator will discuss the risks, benefits and alternatives to participation 
in this study, and answer all patient questions regarding study participation. Informed consent 
will be obtained on an IRB approved informed consent form, with signatures obtained from the 
consenting physician, a witness, and the study subject.  The original informed consent will be 
stored in the patient’s official hospital records, with a copy stored in the patient’s research chart, 
and a copy provided to the study subject.  
 


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7. SAFETY REPORTING REQUIREMENTS/ DATA AND SAFETY MONITORING 
PLAN 
7.1 
DEFINITIONS 
7.1.1 Adverse Event 
Any untoward medical occurrence in a human subject, including any abnormal sign (for 
example, abnormal physical exam or laboratory finding), symptom, or disease, temporally 
associated with the subject’s participation in research, whether or not considered related to the 
subject’s participation in the research.  
7.1.2 Suspected adverse reaction 
Suspected adverse reaction means any adverse event for which there is a reasonable possibility 
that the drug caused the adverse event. For the purposes of IND safety reporting, ‘reasonable 
possibility’ means there is evidence to suggest a causal relationship between the drug and the 
adverse event. A suspected adverse reaction implies a lesser degree of certainty about causality 
than adverse reaction, which means any adverse event caused by a drug. 
7.1.3 Unexpected adverse reaction 
An adverse event or suspected adverse reaction is considered “unexpected” if it is not listed in 
the investigator brochure or is not listed at the specificity or severity that has been observed; or, 
if an investigator brochure is not required or available, is not consistent with the risk information 
described in the general investigational plan or elsewhere in the current application. 
"Unexpected”, also refers to adverse events or suspected adverse reactions that are mentioned in 
the investigator brochure as occurring with a class of drugs or as anticipated from the 
pharmacological properties of the drug, but are not specifically mentioned as occurring with the 
particular drug under investigation. 
7.1.4 Serious  
An Unanticipated Problem or Protocol Deviation is serious if it meets the definition of a Serious 
Adverse Event or if it compromises the safety, welfare or rights of subjects or others. 
7.1.5 Serious Adverse Event 
An adverse event or suspected adverse reaction is considered serious if in the view of the 
investigator or the sponsor, it results in any of the following: 
• 
Death, 
• 
A life-threatening adverse drug experience 
• 
Inpatient hospitalization or prolongation of existing hospitalization 
• 
Persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
• 
A congenital anomaly/birth defect. 
• 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. 


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7.1.6 Disability 
 A substantial disruption of a person’s ability to conduct normal life functions. 
7.1.7 Life-threatening adverse drug experience 
Any adverse event or suspected adverse reaction that places the patient or subject, in the view of 
the investigator or sponsor, at immediate risk of death from the reaction as it occurred, i.e., it 
does not include a reaction that had it occurred in a more severe form, might have caused death. 
7.1.8 Protocol Deviation (NIH Definition) 
Any change, divergence, or departure from the IRB-approved research protocol.   
7.1.9 Non-compliance (NIH Definition) 
The failure to comply with applicable NIH Human Research Protections Program (HRPP) 
policies, IRB requirements, or regulatory requirements for the protection of human research 
subjects. 
7.1.10 Unanticipated Problem 
Any incident, experience, or outcome that: 
•  Is unexpected in terms of nature, severity, or frequency in relation to  
(a) the research risks that are described in the IRB-approved research protocol and 
informed consent document; Investigator’s Brochure or other study documents, and 
(b) the characteristics of the subject population being studied; AND 
• Is related or possibly related to participation in the research; AND 
• Suggests that the research places subjects or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized. 
7.2 
NCI-IRB AND CLINICAL DIRECTOR REPORTING 
7.2.1 NCI-IRB and NCI CD Expedited Reporting of Unanticipated Problems and Deaths 
The Protocol PI will report in the NIH Problem Form to the NCI-IRB and NCI Clinical Director: 
• All deaths, except deaths due to progressive disease  
• All Protocol Deviations 
• All Unanticipated Problems 
• All non-compliance 
Reports must be received within 7 days of PI awareness via iRIS. 
7.2.2 NCI-IRB Requirements for PI Reporting at Continuing Review 
The protocol PI will report to the NCI-IRB:  
1. A summary of all protocol deviations in a tabular format to include the date the deviation 
occurred, a brief description of the deviation and any corrective action. 


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2. A summary of any instances of non-compliance 
3. A tabular summary of the following adverse events: 
• 
All Grade 2 unexpected events that are possibly, probably or definitely related to the 
research;  
• 
All Grade 3 and 4 events that are possibly, probably or definitely related to the research;  
• 
All Grade 5 events regardless of attribution;  
• 
All Serious Events regardless of attribution.  
NOTE: Grade 1 events are not required to be reported.  
7.3 
DATA AND SAFETY MONITORING PLAN 
The clinical research team will meet on a regular basis when patients are being actively treated 
on the trial to discuss each patient. Decisions about dose level enrollment and dose escalation if 
applicable will be made based on the toxicity data from prior patients.  
All data will be collected in a timely manner and reviewed by the principal investigator or a lead 
associate investigator. Adverse events will be reported as required above. Any safety concerns, 
new information that might affect either the ethical and or scientific conduct of the trial, or 
protocol deviations will be immediately reported to the IRB using iRIS.  
The principal investigator will review adverse event and response data on each patient to ensure 
safety and data accuracy. The principal investigator will personally conduct or supervise the 
investigation and provide appropriate delegation of responsibilities to other members of the 
research staff. 
8. PHARMACEUTICAL AND INVESTIGATIONAL DEVICE INFORMATION 
8.1 
BEVACIZUMAB 
8.1.1 Study Drug Supply 
8.1.1.1 
CCR/CRADA 
8.1.1.2 
The agent (hereinafter referred to as Agent), bevacizumab, used in this protocol 
is/are provided to the NCI under Cooperative Research and Development 
Agreement (CRADA) 2407 between the Pharmaceutical Company, Genentech, 
(hereinafter referred to as Collaborator(s)) and the NCI HIV and AIDS Malignancy 
Branch.  Therefore, the following obligations/guidelines, in addition to the 
provisions in the “Intellectual Property Option to Collaborator” (http:// 
ctep.cancer.gov/industry) apply to the use of the Agent in this study: 
8.1.1.2.1 
Agent may not be used outside the scope of this protocol, nor can Agent be 
transferred or licensed to any party not participating in the clinical study.  
Collaborator(s) data for Agent are confidential and proprietary to 
Collaborator(s) and should be maintained as such by the investigators. 
8.1.1.2.2 
For a clinical protocol where there is an investigational Agent used in 
combination with (an)other investigational Agent(s), each the subject of 
different CTAs or CRADAs , the access to and use of data by each Collaborator 


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shall be as follows (data pertaining to such combination use shall hereinafter be 
referred to as "Multi-Party Data.): 
8.1.1.2.2.1 
NCI will provide all Collaborators with written notice regarding the existence 
and nature of any agreements governing their collaboration with NIH, the 
design of the proposed combination protocol, and the existence of any 
obligations, which would tend to restrict NCI's participation in the proposed 
combination protocol. 
8.1.1.2.2.2 
Each Collaborator shall agree to permit use of the Multi-Party Data from the 
clinical trial by any other Collaborator to the extent necessary to allow said 
other Collaborator to develop, obtain regulatory approval or commercialize 
its own investigational Agent. 
8.1.1.2.2.3 
Any Collaborator having the right to use the Multi-Party Data from these 
trials must agree in writing prior to the commencement of the trials that it 
will use the Multi-Party Data solely for development, regulatory approval, 
and commercialization of its own investigational Agent. 
8.1.1.2.3 
Clinical Trial Data and Results and Raw Data developed under a Collaborative 
Agreement will be made available exclusively to Collaborator(s), the NCI, and 
the FDA, as appropriate and unless additional disclosure is required by law or 
court order. Additionally, all Clinical Data and Results and Raw Data will be 
collected, used and disclosed consistent with all applicable federal statutes and 
regulations for the protection of human subjects, including, if applicable, the 
Standards for Privacy of Individually Identifiable Health Information set forth 
in 45 C.F.R. Part 164. 
8.1.1.2.4 
When a Collaborator wishes to initiate a data request, the request should first be 
sent to the NCI, who will then notify the appropriate investigators of 
Collaborator's wish to contact them. 
8.1.2 Supplier 
8.1.2.1 
Genentech, Inc. 
8.1.2.2 
Manufacturer – Genentech, Inc. 
8.1.2.3 
Chemical name 
8.1.2.3.1 
Bevacizumab (RhuMAb VEGF; Avastin®) 
8.1.2.3.2 
Recombinant humanized anti-vascular endothelial growth factor monoclonal 
antibody 
8.1.2.3.3 
The bevacizumab to be supplied for this protocol is intended for clinical trial 
use only and is not the commercially available Avastin.  Investigational 
bevacizumab and commercially available Avastin may be produced at separate 
facilities and some difference may exist between the two products, although 
both are required to meet similar product testing criteria and are expected to be 
very similar in safety and activity.  For further details and molecule 
characterization, see the updated bevacizumab Investigator Brochure. 
8.1.2.4 
Mechanism of action: Binds to VEGF  


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8.1.3 Toxicity 
A summary of previously reported adverse events is listed below. 
8.1.3.1 
Infusion related events 
Flushing, tachycardia, hypotension, hypertension, rash, fever, chills. 
8.1.3.2 
Cardiovascular 
Pericardial effusion, hypertension (including hypertensive crisis), hypotension, and 
decrease in cardiac function. 
8.1.3.3 
Hematologic 
Arterial and venous thrombosis/embolism (including pulmonary embolism, 
mesenteric vein thrombosis, ischemic bowel, cerebral vascular accident); 
hemorrhage (including epistaxis, CNS hemorrhage/bleeding, hematemesis, 
hemoptysis, GI bleeding, pulmonary hemorrhage); hemorrhage/bleeding without 
grade 3 or 4 thrombocytopenia, leukopenia. Thrombosis and hemorrhage could 
be life threatening and fatal. 
8.1.3.4 
Constitutional  
Fever, rigors, chills, headache, infection without neutropenia, asthenia. 
8.1.3.5 
Skin/integument   
Rash/desquamation; delay in wound healing.   
8.1.3.6 
Gastrointestinal 
Nausea, colitis, stomatitis/pharyngitis, intestinal obstruction, vomiting.  Rare 
adverse events include bowel peroration, bowel anastomotic dehiscence and the 
possibility of delay in wound healing.  These events have been reported in clinical 
trials using bevacizumab alone or in combination with chemotherapy, and were 
likely related to co-existing factors such as tumor involvement, chemotherapy, 
recent invasive procedures or bowel inflammation.  However, it cannot be excluded 
that bevacizumab contributed to these events.   
8.1.3.7 
Hepatic (rare) 
Reversible and marked elevations of liver function tests (total bilirubin and /or 
transaminase and alkaline phosphatase) have been rarely reported when 
bevacizumab is used in combination with chemotherapy or concurrently with other 
drugs that are potentially hepatotoxic.  The mechanism of such hepatic toxicities is 
unclear.  It is possible that in rare occasion, bevacizumab may potentiate the liver 
side effects of a concurrent medication, although it is unclear at this time whether 
bevacizumab alone can cause LFT derangement. 
8.1.3.8 
Pulmonary 
Pulmonary infiltration, dyspnea  
8.1.3.9 
Renal/Genitourinary  
Proteinuria, nephrotic syndrome   


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8.1.3.10 Musculoskeletal 
Arthralgia, chest pain 
8.1.3.11 Central Nervous System 
Reversible Posterior Leukoencephalopathy Syndrome (RPLS) or similar 
leukoencephalopathy syndrome related to vasogenic edema of the white matter 
have been rarely reported in associated with bevacizumab therapy (<1%).  Clinical 
presentations are variable and may include altered mental status, seizure and 
cortical visual deficit.  HTN is a common risk factor and was present in most 
(though not all) patients on bevacizumab who developed RPLS.  MRI scans are key 
to diagnosis and typically demonstrate vasogenic edema (hyperintensity in T2 and 
FLAIR images and hypointensity in T1 images) predominantly in the white matter 
of the posterior parietal and occipital lobes; less frequently, the anterior 
distributions and the gray matter may also be involved.  RPLS should be in the 
differential diagnosis in patients presenting with unexplained mental status change, 
visual disturbance, seizure or other CNS findings.  RPLS  is potentially reversible, 
but timely correction of the underlying causes, including control of blood pressure 
and interruption of the offending drug, is important in order to prevent progression 
to irreversible tissue damage. 
8.1.4 Formulation and Preparation 
8.1.4.1 
How supplied: Bevacizumab is supplied as a clear to slightly opalescent, sterile 
liquid ready for parenteral administration in vials of two sizes: 
8.1.4.1.1 
Each 100mg (25 mg/mL – 4 mL fill) glass vial contains bevacizumab with 
phosphate, trehalose, polysorbate 20, and Sterile Water for Injection, USP or 
8.1.4.1.2 
Each 1000 mg (25 mg/ml- 40 ml fill) glass vial contains bevacizumab with 
phosphate, trehalose, polysorbate 20, and Sterile Water for Injection, USP. 
8.1.4.2 
Preparation:  Opened vials must be used within 8 hours.  Vials contain no 
preservative and are intended for single use only.  The calculated dose should be 
placed in a sterile, empty IV bag and diluted with a sufficient amount of 0.9% 
Sodium Chloride Injection to obtain a final volume of 100 mL.  Once the 
bevacizumab has been added to the bag with 0.9% Sodium Chloride Injection, the 
solution must be administered within 8 hours.  When the rhuMAb VEGF drug 
product container is empty, 0.9% NS from the primary line should be used to flush 
the secondary set to complete rhuMAb VEGF delivery.  0.9% NS infusion should 
be continued to flush the primary IV set with a volume of fluid at least equal to the 
tubing priming volume, thus insuring complete drug delivery. Note that this flush is 
not included in the infusion times below." 
8.1.5 Stability and Storage 
Bevacizumab is shipped on blue ice by overnight delivery.  On receipt, bevacizumab 
should be stored in the refrigerator (2° to 8° C) and should remain refrigerated until 
just prior to use.  Do not freeze.  Do not shake.  Shelf-life studies of bevacizumab are 
continuing.   Opened vials must be used within 8 hours.  Vials contain no preservative 


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and are intended for single use only.  Once the bevacizumab has been added to a bag 
of sterile saline, the solution must be administered within 8 hours.   
8.1.6 Administration Procedures 
8.1.6.1 
Route: Intravenous 
8.1.6.2 
The initial dose should be administered over a minimum of 90 minutes.  If no 
adverse reactions occur, the second dose should be administered over a minimum of 
60 minutes.  Again, if no adverse reactions occur, the third and subsequent doses 
should be administered over a minimum of 30 minutes.  If infusion-related adverse 
reactions occur, subsequent infusions should be administered over the shortest 
period that is well tolerated. 
8.1.7 Incompatibilities 
Unknown incompatibilities 
8.2 
 LIPOSOMAL DOXORUBICIN 
8.2.1 Commercially available 
8.2.1.1 
FDA indication for use in AIDS-associated KS 
8.2.1.2 
Manufacturer: Ortho Biotech Products, L.P. (Doxil) or Sun Pharmaceutical 
Industries, Ltd. (Lipodox).  Lipodox may be used in place of Doxil if Doxil is not 
available. 
8.2.2 Supplier 
Clinical Center Pharmacy will obtain liposomal doxorubicin from commercial sources. 
8.2.3 Toxicity 
8.2.3.1 
Hematologic effects 
8.2.3.1.1 
Neutropenia is the predominant manifestation of hematologic toxicity. 
8.2.3.1.2 
Thrombocytopenia and anemia occur less frequently. 
8.2.3.2 
Cardiac Effects 
8.2.3.2.1 
Conduction Disorders 
Acute transient abnormal ECG findings (ST-T wave changes, prolongation of QT 
interval, arrhythmias) 
8.2.3.2.2 
Cardiomyopathy 
Subacute chronic cardiotoxicity, resulting in cardiomyopathy, usually occurs within 
1 year after discontinuance of anthracycline treatment, but experience with liposomal 
doxorubicin at high cumulative doses currently is too limited to establish its 
cardiotoxic potential.  Late onset cardiotoxicity occurs with high cumulative doses of 
anthracycline therapy, mainly in those who received the drugs as children.  The 
potential for this complication in the liposomal preparation is not known. 
8.2.3.3 
Gastrointestinal effects 
Stomatitis, esophagitis (mucositis) 


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8.2.3.4 
Dermatologic Effects 
8.2.3.4.1 
Alopecia (less with liposomal preparation than with the conventional 
formulation)  
8.2.3.4.2 
Palmar-plantar erythrodysesthesia  
8.2.3.4.3 
Radiation recall injury 
8.2.3.5 
Infusion-related Reactions 
Flushing, shortness of breath, facial edema, headache, chills, back pain, chest and 
throat tightness, hypotension. 
8.2.3.6 
Local Effects 
Extravasation produces local tissue necrosis, cellulitis, vesication, thrombophlebitis, 
lymphangitis or painful induration. 
8.2.3.7 
Pregnancy 
Liposomal doxorubicin can cause fetal harm.  
8.2.4 Formulation and Preparation 
8.2.4.1 
Formulated in long-circulating pegylated liposomes.  The concentrated product is 
supplied in 10 cc vials containing 2/mg/mL of liposomal doxorubicin. 
8.2.4.2 
The concentrate must be diluted in 250 mL 5% dextrose prior to IV infusion.  
Diluents containing preservatives should not be used, and other drugs should not be 
added to the solution.  If a precipitant forms, the solution should not be used. 
8.2.5 Stability and Storage 
8.2.5.1 
Refrigerate the concentrate at 2-8° C; do not freeze.  The diluted solution should 
also be refrigerated at 2-8° C and used within 24 hours. 
8.2.6 Administration procedures 
8.2.6.1 
The diluted formulation should be administered intravenously, without use of inline 
filters and should not be mixed with other drugs. 
8.2.6.2 
Only use 5% dextrose as diluent and no preservatives. 
8.2.6.3 
Initial infusion rate should be over 30 minutes.  
8.2.7 Incompatibilities 
8.2.7.1 
Liposomal doxorubicin has not been formally evaluated for drug interactions.  
Other myelosuppressive agents may potentiate the myelotoxicity of liposomal 
doxorubicin. 
8.2.7.2 
Phenobarbital may increase elimination of liposomal doxorubicin 
8.2.7.3 
Liposomal doxorubicin may decrease serum phenytoin concentrations 
8.2.7.4 
Streptozocin may inhibit hepatic metabolism of liposomal doxorubicin.


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64.    Musselwhite, L. W., Sheikh, V., Norton, T. D., Rupert, A., et al. Markers of endothelial 
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65.    Pliquett, R. U., Schöfer, H., Asbe-Vollkopf, A., Hauser, I. A., et al. Posttransplant kaposi 
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91, e21-e22. 
 


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10.    APPENDICES 
10.1 APPENDIX 1: SCHEDULE OF EVALUATION 
Study Evaluation 
Screening1 
Cycle 1 
D1, 8, 15 
Subsequent 
Cycles, D1 
Follow-up q3m 
Off 
Study 
Eligibility Checklist 
X 
 
 
 
 
KS Biopsy 
X2 
X2 
 
 
 
Document Extent of Disease 
 
X 
X 
X 
X 
Photography, Target Lesions 
 
X3 
X4 
 
 
History and Physical5 
X 
X 
X 
X 
X 
Toxicity Assessment 
X 
X 
X 
X 
X 
C-reactive protein 
X 
 
 
 
X 
Acute care, hepatic and mineral 
panels, TP, uric acid, CK, LDH 
X 
X 
X 
X 
X 
CBC with Differential, Retic 
X 
X 
X 
X 
X 
PT/PTT 
X 
 
 
 
 
FACS (CD4 and CD8) 
X 
 
X6 
 
 
HIV Western Blot 
X 
 
 
 
 
HIV Viral Load (HIV infected) 
X 
 
X6 
 
 
Hepatitis Serology7 
X 
 
 
 
 
VDRL 
X 
 
 
 
 
TFTs 
 
 
 
 
 
Urine Studies8 
X 
X 
X 
X 
X 
Urine β-hCG (women) 
X 
X9  
X 
 
 
EKG 
X 
 
 
 
 
MUGA 
X 
 
X (cycle7)10 
 
 
CXR 
X 
 
X11  
 
 


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Study Evaluation 
Screening1 
Cycle 1 
D1, 8, 15 
Subsequent 
Cycles, D1 
Follow-up q3m 
Off 
Study 
Additional Imaging as Indicated 
for Staging 
X 
 
 
 
4 Red Top Tubes12 (SAIC) 
 
X 
X 
X 
 
4 Yellow Top13 (SAIC) 
 
X 
X (q3 cycles) 
X 
 
Saliva (DW lab, SAIC) 
 
X 
X (q3cycles) 
X 
 
Non-invasive imaging14 
 
X 
X  
 
 
1. 
Results must be completed within 2 weeks of starting study, with the exception of: a) EKG, MUGA must be within 6 weeks of 
study, b) a positive HIV Western Blot may be documented anytime prior to enrollment, an negative HIV western blot must be 
documented within 2 weeks of starting study 
2. 
In addition to screening biopsy, additional punch biopsies may be required to confirm clinical complete responses, document 
progression on uncertain cases. Optional biopsiesmay be performed for biomarker studies on Day 8. 
3. 
Day 1 only 
4. 
Day 1 cycle 7 (completion of liposomal doxorubicin + bevacizumab) and Day 21 cycle 17 (completion of bevacizumab  
5. 
Includes vital signs, current medications, and Performance Status 
6. 
FACS for CD4/CD8 and HIV viral load on Cycles 4, 7, 11, 15, 18 
7. 
Hepatitis B S Ag, Hepatitis B S Ab, Hepatitis B core Ab., HAV total, HCV Ab 
8. 
Urinalysis, urine protein, urine creatinine. If ≥1+proteinuria on dipstick, then 24 hour urine collection 
9. 
Day 1 only 
10. MUGA on Day 1 cycle 7 (+/- 7 days) after completing scheduled 6 cycles of liposomal doxorubicin. Subjects with EF <50% should 
have a follow-up MUGA 3 months later. Repeat MUGA will be performed if additional liposomal doxorubicin is administered in 
combination with bevacizumab. This will be scheduled 21 (+/- 7) days after 6th or final dose of liposomal doxorubicin 
11. Repeat abnormal imaging q 3 cycles until documentation of complete response. 
12. Red top tubes for cytokine studies, human endoglin/Cd105, and KSHV serology 
13. Yellow-top tubes for PBMC KSHV viral loads 
14. Day 1 Cycle 1, Day 8 Cycle 1, Day 1 cycle 7 (completion of liposomal doxorubicin + bevacizumab) and Day 21 cycle 17 
(completion of bevacizumab) if there are persistent lesions. 


Abbreviated Title: Doxil/Bevacizumab in KS 
Version Date: 01/16/2018 
 
62 
 
10.2 APPENDIX 2: ECOG PERFORMANCE CRITERIA 
 
ECOG Performance Status Scale 
 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence of 
disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able to 
carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all self-
care, but unable to carry out any 
work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but is 
able to care for most of his/her needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any self-
care.  Totally confined to bed or 
chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes progressing 
rapidly. 
5 
Dead. 
0 
Dead. 
 


Abbreviated Title: Doxil/Bevacizumab in KS 
Version Date: 01/16/2018 
 
63 
 
10.3 APPENDIX 3: DESCRIPTION OF NON-INVASIVE IMAGING DEVICES 
1. Laser Doppler Imaging Device 
A Moor Instrument moorLDI-2l-simultaneous two wavelength scan will be used.  The scan 
images at 685-690 and 780 nm. This imager scans a low power laser beam (5mW, 800 micron 
diameter) in a raster pattern over the skin.  There is no contact with the skin.  The scanner is 
produced by Moor Instruments Ltd., 501 Silverside Rd., Suite 66, Wilmington, DE 19803.  The 
scanner is held on a special stand (Moor MS2 stand) made specifically for such devices. 
A very closely related instrument, the moor LDI-VR scanner is approved by the FDA by patient 
use.  This scanner just utilizes one wavelength of light (633 nm). The device that will be used in 
the present study differs from the FDA-approved device in that it also assesses the lesions using 
a second wavelength and that the first wavelength is slightly longer.  The other potential safety 
issue is that the 780 nm wavelength is in the infrared spectrum and would not visible. Thus 
patients and users would not necessarily blink if it shined into their eyes.  However, both lights 
shine on the same spot so patients or users would blink upon seeing the 685 nm wavelength 
(which is visible).  Also, the machine is constructed to minimize the chance of anyone (patient or 
user) looking into the laser light. 
2. Multispectral Imaging 
For multispectral imaging, a charge coupled device (CCD) handheld camera will be used.  This 
uses CCD technology similar to that utilized in most digital cameras.  The lesions will be 
illuminated uniformly by a white light held approximately 30 cm from the patient’s skin.  Using 
optical filters, those wavelengths associated with oxyhemoglobin and deoxyhemoglobin 
absorption spectra will be selected and CCD images will be made.  The camera is a cooled 
Princeton CCD Camera interfaced by cable with a personal computer with associated data 
analysis software.  The camera is low voltage.  The camera will not directly contact the patient 
and will be held 5 cm or more from the patient’s skin (approximately 30 to 50). 
3. Thermal Imaging 
For thermal imaging, infrared-sensitive handheld cameras will be used.  We plan to use a camera 
modified from the BioEar PRISM 2000 Thermal Metabolic Imaging System (10618 Rockley 
Rd., Houston, TX).  The name of the camera is the ThermoVision™ Alert, FLIR Systems, USA. 
This camera is at ambient temperature.  If it becomes available, we will also test a cooled camera 
modified from the ThermaCAM SC3000 (FLIR Systems, 16 Esquire rd., Boston, MA).  Cooling 
has the potential of giving more accurate measurements with less background noise.  If this 
camera is found to be superior and can be made available on a long-term basis, we will switch 
over to its use. 
These cameras use low voltage electricity (12- 13 volts) provided by an AC adapter.  They do 
not touch the patient and will be held more than 5 cm from the patient’s skin (approximately 50 
cm).