Phase II Study of Sorafenib/Avastin® as Salvage Therapy in Patients With Metastatic Colorectal Cancer

Inclusion Criteria:

- Diagnosis of stage IV colorectal cancer (histologic proof is not required)

- Measurable disease

- Spiral CT scan required for both pre- and post-treatment tumor assessments of
lesions measuring 1-2 cm

- Progressive disease during or within 6 months of most recent prior chemotherapy
regimen (bevacizumab, fluoropyrimidine, oxaliplatin, or irinotecan-based treatment)
OR considered ineligible for standard therapy

- Documentation of submission of tumor material for KRAS testing available

- Prior anti-EGFR antibody therapy (e.g., cetuximab or panitumumab) required for
patients with wild-type KRAS tumor

- No known brain metastasis

- Patients with neurological symptoms must undergo a CT scan or MRI of the brain
to exclude brain metastasis

- ECOG performance status 0-1

- Life expectancy ≥ 6 months

- Hemoglobin ≥ 9.0 g/dL

- ANC ≥ 1,500/mm³

- Platelet count ≥ 100,000/mm³

- WBC ≥ 3,400/mm³

- INR < 1.5 (≤ 3.0 if on anti-coagulation therapy [e.g., warfarin or heparin])

- Total bilirubin ≤ 1.5 times upper limit of normal (ULN)

- AST ≤ 2.5 times ULN (≤ 5 times ULN if there is liver involvement)

- Alkaline phosphatase ≤ 3 times ULN

- Creatinine ≤ 1.5 times ULN

- Urine protein:creatinine ratio < 1 OR urine dipstick < 2+ OR urine protein < 1,000 mg
by 24-hour urine collection

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception during and for ≥ 6 months after
completion of study treatment (≥ 2 weeks after completion of treatment with sorafenib
tosylate alone)

- Willing to provide mandatory blood samples for translational research studies

- Able to swallow whole pills

- No inadequately controlled hypertension (i.e., systolic BP > 150 mm Hg or diastolic
BP > 100 mm Hg on anti-hypertensive medications)

- No prior hypertensive crisis or hypertensive encephalopathy

- No myocardial infarction or unstable angina within the past 6 months

- No congestive heart failure requiring use of ongoing maintenance therapy for
life-threatening ventricular arrhythmias

- No thrombolic or embolic events (e.g., cerebrovascular accident, including transient
ischemic attacks) within the past 6 months

- No hemorrhage or bleeding event > grade 3 within the past 4 weeks

- No evidence or history of bleeding diathesis or coagulopathy (in the absence of
therapeutic anticoagulation)

- No greater than normal risk of bleeding

- No active or recent hemoptysis (≥ ½ teaspoon of bright red blood per episode) within
the past 30 days

- No concurrent uncontrolled illness including, but not limited to, any of the
following:

- Ongoing or active infection

- Symptomatic congestive heart failure

- Unstable angina pectoris

- Cardiaca rrhythmia requiring anti-arrhythmic drugs

- Psychiatric illness or social situations that would limit compliance with study
requirements

- No known HIV infection or chronic hepatitis B or C infection

- No serious, non-healing wound, active ulcer, or untreated bone fracture

- Patients with fractures secondary to metastatic disease are eligible after
appropriate radiotherapy

- No significant traumatic injury within the past 4 weeks

- No known or suspected allergy or hypersensitivity to any component of bevacizumab,
sorafenib tosylate, or their excipients or to any other agent given in the course of
this study

- No malabsorption problem

- None of the following within the past 6 months:

- Significant vascular disease (e.g., aortic aneurysm or aortic dissection)

- Peripheral arterial thrombosis

- Symptomatic peripheral vascular disease

- Abdominal fistula

- Gastrointestinal perforation

- Intra-abdominal abscess

- No other active malignancy within the past 3 years except non melanoma skin cancer or
carcinoma in situ of the cervix

- Prior malignancy allowed provided patient is not receiving other specific
treatment for that malignancy (other than hormonal therapy)

- No other concurrent investigational agent for this cancer

- Prior radiotherapy allowed

- No prior sorafenib tosylate

- No prior discontinuation of bevacizumab due to adverse events

- More than 4 weeks since prior and no concurrent participation in any other
experimental drug study

- More than 4 weeks since prior St. John's wort or rifampin

- More than 4 weeks since prior and no concurrent major surgical procedure or open
biopsy

- More than 7 days since prior core biopsy or minor surgical procedure, including
placement of a vascular access device

- No concurrent anticoagulant, except low-dose warfarin or heparin for deep venous
thrombosis prophylaxis