Dose limiting toxicity at the lowest planned dose level.

This research study is being performed at approximately 3 sites associated with Accelerated Community Oncology Research Network, Inc. (ACORN). Approximately 45 subjects will take part in this study.

In this study, everyone will receive the same dose of mFOLFOX6 and Avastin. There will be five groups of subjects. Each group of subjects will receive a higher dose of Nexavar than the previous group. This will continue until a subject group has a major side effects from the dose they are given. This is so that the sponsor can determine the highest dose of Nexavar that can be used with mFOLFOX6 and AVastin (this is called the maximum tolerated dose or MTD).

This is an investigator-initiated, multicenter, network, Phase 1, open-label, dose-ranging study. The maximum sample size will be 45 patients (up to 30 patients for determining MTD at Phase I, and an additional 15 patients to provide for estimate of progression free survival). All eligible patients will receive the mFOLFOX6 regimen at full dose followed by IV bevacizumab 5mg/kg on Day 1 of each treatment cycle. Treatment cycle length is 2 weeks (Q2W). Sorafenib will be administered daily throughout treatment beginning on day 1.

Dose limiting toxicity will be defined as any grade 4 hematologic event or any grade 3 or 4 non-hematologic event occurring during cycle 1 or 2 that is attributable to sorafenib or the combination. The following events are excluded from this definition: grade 3 nausea and/or vomiting responsive to antiemetics; grade 3 fever or infection; grade 3 diarrhea responsive to antidiarrheal therapy.

Three patients will be enrolled at a dose level and observed for dose-limiting toxicities (DLTs) for 2 cycles of treatment. Dose escalation for sorafenib will depend on the number of patients experiencing DLT(s) as follows:

• If 0/3 patients experience DLT(s), then 3 more patients are treated at the next higher dose.
• If 1/3 patients experiences DLT(s), then 3 more patients are enrolled at that dose. If 1/6 of the patients treated at that dose experiences DLT(s), then the next cohort is treated at the next higher dose. However, if ≥2/6 patients experience DLT(s) at that dose, then the MTD is considered to have been exceeded. At that point, 3 more patients are treated at the next lower dose, unless 6 have already been treated at that lower dose.
• If ≥2/3 patients experience DLT(s) at a dose, then 3 more patients are enrolled at the next lower dose unless 6 patients have already been treated at that dose.

Dose escalation will continue until the MTD is determined or until all dose levels have been completed. The MTD is defined as the dose at which ≤1 of 6 patients experience DLT(s), and above which ≥2 of 6 patients experience DLT(s). If the MTD is at Dose Level 2 (or lower), then the study will be terminated and no further patients will be enrolled.

Once the MTD for sorafenib combined with mFOLFOX6 and bevacizumab has been determined, an additional 15 patients with mCRC will be enrolled into an extension of the Phase 1 study. These patients will be treated at the MTD for sorafenib with the combination therapy to assess PFS and safety of the regimen as first-line therapy in mCRC. All patients will be eligible for indefinite treatment in the absence of disease progression or unacceptable toxicity.

Inclusion Criteria:

• No prior chemotherapy for metastatic disease.

• Histologically proven colorectal carcinoma.

• Measurable disease by RECIST criteria.

• Age: at least 18 years.

• ECOG performance status of 0 or 1 at study entry.

• Adequate bone marrow, liver and renal function at study entry as assessed by the following:

  • Hemoglobin >9.0 g/dL.
  • ANC ≥1500/mm3.
  • Platelet count ≥100,000/mm3.
  • Total bilirubin ≤1.5 times x ULN.
  • ALT and AST ≤2.5 × ULN (≤5 × ULN for patients with liver involvement).
  • Creatinine ≤1.5 × ULN.

• INR <1.5 or a PT/PTT within normal limits. Patients receiving anti-coagulation treatment with an agent such as warfarin or heparin may be allowed to participate after discussion with ACORN. For patients on warfarin, the INR should be measured prior to initiation of sorafenib and monitored at least weekly, or as defined by the local standard of care, until INR is stable.

• Women of childbearing potential must have a negative serum or urine pregnancy test performed within 7 days prior to the start of treatment.

• Women of childbearing potential and men must agree to use adequate contraception (barrier method of birth control) prior to study entry and for the duration of study participation. Patients should use adequate birth control for at least 3 months after the last administration of sorafenib.

• Ability to understand and the willingness to sign a written informed consent. A signed informed consent must be obtained prior to any study specific procedures.

Exclusion Criteria:

• Prior use of bevacizumab.
• Neuropathy ≥ Grade 2 per CTCAE v3.0.
• Diarrhea ≥ Grade 2 per CTCAE v3.0 within 4 weeks of study treatment start.
• ECOG performance status ≥ 2.
• Proteinuria at baseline: patients discovered to have > 2+ proteinuria at baseline should undergo a 24 hour urine collection and must demonstrate < 1 gram of protein in 24 hours to be eligible.
• Active malignancy other than mCRC (except non-melanoma skin cancer; in situ carcinoma of the cervix; in situ carcinoma of the breast) within the last 5 years.
• Treatment with radiotherapy within 2 weeks of enrollment.
• Cardiac disease: Congestive heart failure > Class II NYHA. Patients must not have unstable angina (anginal symptoms at rest) or new onset angina (began within the last 3 months) or myocardial infarction within the past 6 months.
• Known brain metastasis. Patients with neurological symptoms must undergo a CT scan/ MRI of the brain to exclude brain metastasis.
• Cardiac ventricular arrhythmias requiring anti-arrhythmic therapy.
• Uncontrolled hypertension defined as systolic blood pressure > 150 mm Hg or diastolic pressure > 90 mm Hg, despite optimal medical management.
• Known human immunodeficiency virus infection or chronic Hepatitis B or C.
• Active clinically serious infection > Grade 2 per CTCAE v3.0.
• Thrombolic or embolic events such as a cerebrovascular accident including transient ischemic attacks within the past 6 months.
• Pulmonary hemorrhage/bleeding event ≥ Grade 2 per CTCAE v3.0 within 4 weeks of study treatment start.
• Any other hemorrhage/bleeding event ≥ Grade 3 per CTCAE v3.0 within 4 weeks of study treatment start.
• Serious non-healing wound, ulcer, or bone fracture.
• Evidence or history of bleeding diathesis or coagulopathy.
• Major surgery, open biopsy or significant traumatic injury within 4 weeks of study treatment start; fine needle aspiration or central venous line placement for chemotherapy administration within 7 days of study treatment start.
• Use of daily corticosteroids, St. John's Wort, rifampin (rifampicin), phenytoin, carbamazepine, phenobarbital, ketoconazole. Dexamethasone may only be used as an antiemetic or as a premedication for a bevacizumab hypersensitivity reaction during participation in this study.
• Known or suspected allergy to sorafenib or any other agent given in the course of this trial.
• Any condition that impairs patient's ability to swallow whole pills.
• Any malabsorption problem.

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