Sorafenib and Bevacizumab in Treating Patients With Metastatic Colorectal Cancer

PRIMARY OBJECTIVES:

I. Evaluate proportion of patients who are progression-free at 3 months (in historic
comparison with results for single-agent bevacizumab in ECOG 3200).

SECONDARY OBJECTIVES:

I. Response rate (RR) II. Overall survival (OS) III. Safety IV. Feasibility

OUTLINE: This is a multicenter study.

Patients receive sorafenib tosylate orally twice daily on days 1-5 and 8-12 and bevacizumab
IV over 30-90 minutes on day 1. Courses repeat every 14 days in the absence of disease
progression or unacceptable toxicity. Blood samples are collected at baseline and then
periodically during study treatment for laboratory biomarker and pharmacogenetic studies.

After completion of study treatment, patients are followed periodically for up to 2 years.

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 Kirsten Rat Sarcoma (KRAS) testing
available

- Prior anti-epidermal growth factor receptor (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

- Eastern Cooperative Oncology Group (ECOG) performance status 0-1

- Life expectancy ≥ 6 months

- Hemoglobin ≥ 9.0 g/dL

- Absolute neutrophil count (ANC) ≥ 1,500/mm³

- Platelet count ≥ 100,000/mm³

- White blood cell count (WBC) ≥ 3,400/mm³

- International normalized ratio (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)

- Aspartate aminotransferase (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

- Cardiac arrhythmia 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