Pilot Study of Bevacizumab (Avastin) in Patients With Septic Shock

Sepsis is responsible for significant morbidity, mortality, and costs to patients in our
healthcare system. The hospital case mortality rate for severe sepsis (sepsis with acute
organ system dysfunction) is between 30-50%,7-12 with an incidence of approximately 751,000
cases and 215,000 deaths nationally per year. The overall cost of care is estimated at $16.7
billion annually in the US.Despite significant advances in medical science, the overall
mortality rate for severe sepsis has not improved substantially over time.

VEGF signaling and sepsis. VEGF contributes to inflammation and coagulation - the key
elements in sepsis pathophysiology. For example, under in vitro conditions, VEGF induces the
expression of cell adhesion molecules (E-selectin, ICAM-1, and VCAM-1) in endothelial cells
and promotes adhesion of leukocytes. Moreover, VEGF signaling upregulates tissue factor
mRNA, protein and procoagulant activity. Several studies have shown increased circulating
levels of VEGF in patients with sepsis. In one study, maximum VEGF levels were increased in
survivors versus non-survivors in sepsis. In another study of patients with meningococcal
meningitis, elevated VEGF levels were associated with shock and upregulation of IL-1beta,
IL-10, IL-12, complement activation and increased permeability.We have additional human data
on 83 patients demonstrating an association of VEGF with SOFA score, IL-1, and IL-6.
Consistent with its critical role in inflammation, VEGF inhibition using a VEGF trap
resulted in attenuation of plasma interleukin IL-6 and IL-10 levels in a mouse cecal
ligation puncture (CLP) model.

VEGF signaling is an important determinant of sepsis morbidity and mortality in animal
models. We have recently shown that sepsis is associated with a time-dependent increase in
circulating levels of VEGF in animal and human models of sepsis.2 The overexpression of
sFlt-1 as well as the addition of exogenous sFLT-1 (each binds and neutralizes VEGF) in mice
attenuated lipopolysaccharide- and CLP-mediated mediated morbidity (cardiac dysfunction,
vascular permeability and endothelial activation) and mortality in sepsis. Importantly,
these findings have been reproduced and extended by others.6 The striking and reproducible
reduction in morbidity and mortality make a compelling case for further exploration in human
sepsis.

A role for Bevacizumab in treating patients with severe sepsis. There are several advantages
in employing Bevacizumab as a lead agent for inhibiting VEGF signaling in patients with
severe sepsis. First, as a humanized monoclonal antibody, it has a sufficiently long
half-life that it may be given as a single injection in this patient population. Second, it
is already FDA approved for use in patients with certain types of cancer. Thus, there is
extensive knowledge of its pharmacokinetics and pharmacodynamics (at least in the latter
population). Moreover, it should not be difficult to obtain permission for use in septic
patients. Third, its chief side effect, namely hypertension, will not be a major concern in
sepsis, since this condition is associated with hypotension.

Inclusion Criteria:

- Eligible patients are all adult patients, age > 18, who meet the following inclusion
criteria:

1. Evidence of infection a. temperature > 100.4F or < 97.0F of non-environmental
causes, pneumonia as determined by the presence of an infiltrate on chest x-ray,
a non-contaminated urinalysis with > 10 WBC or a urine dip-stick positive for
leukocyte esterase, an abdominal CT scan yielding the diagnosis of an
intra-abdominal etiology, skin/soft tissue infection on clinical exam.

2. Two or more SIRS criteria a. tachycardia (HR>90) b. tachypnea (RR>20) or hypoxia
(oxygen saturation<90%) c. hyperthermia >100.4 F (38C) or hypothermia <96F
(35.5C) d. leukocytosis WBC> 15,000 cells/mm3 or bands>10%]

3. Septic shock a. persistent hypotension (SBP < 90mmHg) after an initial 20-30
cc/kg fluid challenge, or the need for vasopressors for at least 1 hour in order
to maintain a systolic blood pressure >90 mmHG; enrollment within 48 hours of
meeting eligibility criteria.

Exclusion Criteria:

- Disease-Specific Exclusions:

- Inability to obtain written informed consent from the patient or an appropriate
designee General Medical Exclusions

- Life expectancy of less than 12 weeks

- Bevacizumab-Specific Exclusions:

- Inadequately controlled hypertension

- Prior history of hypertensive crisis or hypertensive encephalopathy

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

- History of myocardial infarction or unstable angina within 12 months prior to
Day 1

- History of stroke or transient ischemic attack within 12 months prior to Day 1

- Known CNS malignancy, except for treated brain metastasis

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

- History of hemoptysis within 1 month prior to Day 1

- History of chronic 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 at screening

- Known hypersensitivity to any component of bevacizumab

- Pregnancy or lactation

- Any clotting abnormalities or a history of deep venous thrombosis or pulmonary
embolus.