A Phase I Trial Evaluating mFOLFOX6 and Avastin With Nexavar as First-Line Treatment for Metastatic Colorectal Cancer
Condition: Metastatic Colorectal Cancer
MeSH terms: Colorectal Neoplasms
Intervention: sorafenib; bevacizumab; mFOLFOX6 regimen
Intervention description: Sorafenib will be administered daily starting day 1 at 200mg QOD at Dose Level 1; 200mg/day at Dose Level 2; 200mg BID (5 days on/ 2 days off) at Dose Level 3; 200mg BID at Dose Level 4; and 400mg BID at Dose Level 5.; Bevacizumab will be administered as 5mg/kg IV on Day 1 of each treatment cycle.; The mFOLFOX6 regimen will be administered on Day 1 of each treatment cycle. This regimen consists of oxaliplatin 85 mg/m2 IV given over 2 hours, leucovorin 400 mg/m2 IV given over 2 hours, and fluorouracil 400 mg/m2 IV bolus, followed by fluorouracil 1200 mg/m2 per day for 2 days continuous infusion.
Intervention MeSH terms: Bevacizumab; Sorafenib
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 8.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Metastatic Colorectal Cancer

Summary:

      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).
    

Eligibility criteria:

        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.