Paclitaxel + Bevacizumab (Avastin) for the Treatment of Metastatic or Unresectable Angiosarcoma

Regimen A versus B was chosen at the discretion of the treating physician. Both groups were
analyzed together as far as outcome.

Patients were to receive paclitaxel 200 mg/m2 intravenously over 3 hours every 21 days
(Regimen A) or pactlitaxel 90 mg/m2 weekly x 3 of a 28 day cycle (Regimen B) followed by
bevacizumab 15 mg/kg intravenously over (cycle 1: 90 min; cycle 2: 60 min; cycles 3-6: 30
min) every 21 days x 6 cycles. Maintenance bevacizumab (MB) started after the completion of
combination of paclitaxel and bevacizumab and it was given at a dose of 15 mg/kg
intravenously once every 21 days for a maximum of 8 cycles. Patients were allowed to receive
growth factors. Dose reductions were done based on hematologic and non-hematologic
toxicities.

INCLUSION CRITERIA

- Baseline measurements and evaluations must be obtained within 4 weeks of registration
to the study. Abnormal PET scans will not constitute evaluable disease, unless
verified by computed tomography (CT) scan or other appropriate imaging

- At least 1 objective measurable disease parameter by Response Evaluation Criteria In
Solid Tumors (RECIST) criteria

- Unresectable locally advanced or metastatic angiosarcoma

- ≤ 2 prior chemotherapeutic regimens for angiosarcoma

- No prior paclitaxel, docetaxel, or bevacizumab for angiosarcoma (previous paclitaxel
or docetaxel allowed if not given for angiosarcoma and more than 12 months has elapsed
since last dose)

- No evidence of other active malignancies other than carcinomas in-situ of the cervix
or basal cell carcinoma of the skin within 6 months prior to registration

- If history of deep venous thrombosis or pulmonary embolism, receiving a stable dose of
anticoagulation therapy for at least 2 weeks prior to registration

- Within 7 days prior to registration, use of any anti-platelet drugs, such as
ticlopidine, clopidogrel, and cilostazol. The use of aspirin or other nonsteroidal
anti-inflammatory drugs (NSAID) is allowed

- ECOG performance status 0 to 2

- Patients must have adequate organ function as evidenced by the following laboratory
studies (within 2 weeks prior to registration):

- Serum creatinine ≤ 2.0 mg/dL

- Total bilirubin ≤ 2.0 x upper limit of normal (ULN). If documented hepatic
involvement, can be ≤ 3 x ULN

- Serum glutamic oxaloacetic transaminase (SGOT) or Aspartate aminotransferase (AST) < 2
x ULN. If documented hepatic involvement, can be ≤ 5 x ULN

- Absolute neutrophil count ≥ 1500/mm3 and platelet count > 100,000/mm3

- Platelets ≤ 1.5 x ULN

- International normalized ratio (INR) ≤ 1.5 x ULN

- Partial thromboplastin time (PTT) ≤ 1.5 x ULN

- Left ventricular ejection fraction ≥ 50%

- ≥ 18 years

- Women of childbearing potential must have a negative human chorionic gonadotropin
(hCG) pregnancy test within 2 weeks prior to registration

EXCLUSION CRITERIA

- Life expectancy < 12 weeks

- Current, recent (within 4 weeks of the first infusion of this study), or planned
participation in an another experimental drug study

- Inadequately-controlled hypertension (defined as systolic blood pressure > 150 mmHg
and/or diastolic blood pressure > 100 mmHg)

- History of hypertensive crisis or hypertensive encephalopathy

- New York Heart Association (NYHA) Grade II or greater congestive heart failure

- History of myocardial infarction or unstable angina within 6 months prior to Day 1

- History of stroke or transient ischemic attack within 6 months prior to Day 1

- Known central nervous system (CNS) disease, except for treated brain metastasis.
Treated brain metastases are defined as having no evidence of progression or
hemorrhage after treatment and no ongoing requirement for dexamethasone, as
ascertained by clinical examination and brain imaging (MRI or CT) during the screening
period. Anticonvulsants (stable dose) are allowed. Treatment for brain metastases may
include whole brain radiotherapy (WBRT), radiosurgery (RS; Gamma Knife, LINAC, or
equivalent) or a combination as deemed appropriate by the treating physician. Patients
with CNS metastases treated by neurosurgical resection or brain biopsy performed
within 3 months prior to Day 1 will be excluded.

- Significant vascular disease (eg, aortic aneurysm, requiring surgical repair or recent
peripheral arterial thrombosis) within 6 months prior to Day 1

- History of hemoptysis (≥ 1/2 teaspoon of bright red blood per episode) within 1 month
prior to Day 1

- Evidence of bleeding diathesis or significant coagulopathy (in the absence of
therapeutic anticoagulation)

- Major surgical procedure, open biopsy, or significant traumatic injury within 28 days
prior to Day 1 or anticipation of need for major surgical procedure during the course
of the study

- Core biopsy or other minor surgical procedure, excluding placement of a vascular
access device, within 7 days prior to Day 1

- History of abdominal fistula or gastrointestinal perforation within 6 months prior to
Day 1

- Serious, non-healing wound, active ulcer, or untreated bone fracture

- Proteinuria as demonstrated by a urine protein: creatinine ratio (UPC) ratio ≥ 1.0 at
screening

- Known hypersensitivity to any component of bevacizumab

- Active infection requiring parental antibiotics

- Known human immunodeficiency virus (HIV) infection

- Pregnant or breast feeding

- Inability to comply with study and/or follow-up procedures