Folfox-B Study for Patients With Colorectal Liver Metastases
Condition: Colorectal Liver Metastases
MeSH terms: Neoplasm Metastasis; Liver Neoplasms
Intervention: 5-Fluorouracil; Bevacizumab; Leucovorin; Oxaliplatin
Intervention description: 400 mg/m^2 IV over 15 minutes, followed by 2400 mg/m^2 IV Over 46 Hours; 5 mg/kg IV Over 30-90 Minutes On Day 1 Every 14 Days; 400 mg/m^2 IV Over 2 Hours On Day 1 Every 14 Days; 85 mg/m^2 IV Over 2 Hours On Day 1 Every 14 Days
Intervention MeSH terms: Leucovorin; Bevacizumab; Fluorouracil; Oxaliplatin
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 2.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Colorectal Liver Metastases; Oxaliplatin; Eloxatin; Fluorouracil; Leucovorin; Bevacizumab; Anti-VEGF monoclonal antibody; rhuMAb-VEGF; Folfox-B; 5-FU; Avastin

Summary:

      Objective:

        -  To evaluate the efficacy of the use of the combination of oxaliplatin, 5-fluorouracil,
           leucovorin and bevacizumab (FOLFOX-B) in patients with unresectable colorectal liver
           metastases, with the objective to downstage hepatic disease and enable complete
           resection of residual disease.

      Primary Objective:

        -  To evaluate the resection rate in patients with initially unresectable hepatic
           colorectal metastases downstaged with FOLFOX-B. Complete resection of all liver lesions
           is the goal.

      Secondary Objectives:

        -  To evaluate the probability of complete response, partial response or stable disease.

        -  To evaluate the proportion of patients who are resected, and the proportion of patients
           achieving an R0 resection (among those receiving surgery).

        -  To correlate survival with downstaging and resection based on metastatic colorectal
           prognostic score.

        -  To evaluate the disease-free survival and overall survival.

        -  To evaluate the positron emission tomography response rate.

        -  To explore correlations of clinical response with telomerase and hTERT expression.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Patients must have hepatic colorectal metastasis confirmed by percutaneous or
             intraoperative hepatic tumor biopsy.

          2. Patients must have radiological evidence of measurable liver metastasis with helical
             CT scan (1 cm or greater in greatest transverse dimension).

          3. Patients with synchronous disease and resectable intact primary tumors are eligible.

          4. Colorectal liver metastases will be determined to be unresectable by a surgeon with
             expertise in hepatic surgery (equal to or greater than 10 resections performed in a
             year). A patient is defined as unresectable when distribution and extent of disease
             preclude margin negative resection (tumor contact with or involvement of all three
             major hepatic veins or portal confluence or a combination of involvement of main
             branches of portal veins and hepatic veins), but two adjacent hepatic segments with
             adequate vascular inflow and outflow are relatively spared (contain 4 or fewer
             lesions).

          5. Performance status: Zubrod 0 or 1.

          6. Patients with a prior history of non-colorectal cancer may be included if there is no
             evidence of malignancy for at least 5 years from last treatment and no evidence of
             recurrence. In addition, patients with completely resected non-melanoma skin cancer or
             cervical carcinoma in-situ may be included.

          7. Radiological baseline studies shall be completed within 21 days of protocol
             registration.

          8. Laboratory data as follows (within 21 days of protocol registration): Adequate bone
             marrow as evidenced by; Hemoglobin greater than or equal to 9.0 g %; White blood cell
             count greater than or equal to 3,000 cells/mm; Platelet count greater than or equal to
             100,000 cells/mm(3); Absolute neutrophil count greater than or equal to 1500/mm(3).

          9. Continued from inclusion # 9: Laboratory data as follows (within 21 days of protocol
             registration): Adequate renal function as evidenced by; Creatinine less than or equal
             to 1.5 mg/dL or estimated creatinine clearance greater than or equal to 60 cc/min;
             Urinalysis: less than or equal to trace proteinuria. If greater than trace proteinuria
             exists, a 24- hour urine collection for assessment of protein must demonstrate less
             than 500 mg of protein/24 hours.

         10. Continued from inclusion #10: Laboratory data as follows (within 21 days of protocol
             registration): Adequate hepatic function as evidenced by; Total Bilirubin less than or
             equal to 2.0 mg %; Alanine aminotransferase less than or equal to 280 IU/L; Aspartate
             aminotransferase less than or equal to 230 IU/L; International normalized ratio less
             than or equal to 2.0.

         11. Women must not be pregnant or lactating. Women of childbearing potential must have a
             negative Beta-HCG serum pregnancy test and to refrain from breast-feeding, as
             specified in the informed consent given the unknown risk of teratogenicity of agents
             in the study. Patients of childbearing potential agree to use an effective form of
             contraception during the study and for 90 days following the last dose of study
             medication.

         12. Age greater than or equal to 18 years.

         13. Coumadin, 1 mg, for patency of central venous catheter or therapeutic doses of
             coumadin (INR less than or equal to 3) permitted.

         14. Patients or their legally authorized representative must agree to participate, be able
             to read, understand and provide informed consent to participate in the trial.

         15. Patients must be recovered from both acute and late effects of any prior surgery,
             radiotherapy or other antineoplastic therapy.

        Exclusion Criteria:

          1. Patients with surgically resectable colorectal liver metastases.

          2. Patients with evidence of unresectable extrahepatic disease.

          3. Patients with CNS metastases.

          4. Patients with diffusely distributed bilateral hepatic metastases without sparing of
             two adjacent hepatic segments.

          5. Patients who have previously undergone chemotherapy treatment for metastatic disease.

          6. Patients who developed metastatic disease less than or equal to 6 months from adjuvant
             chemotherapy for stage II or stage III colorectal cancer.

          7. Patients who have ever received bevacizumab.

          8. Previous or concurrent treatment of hepatic metastatic disease with resection,
             radiotherapy, radiofrequency ablation, cryotherapy/other ablative techniques, or
             hepatic artery infusion chemotherapy.

          9. Patients who underwent a major invasive surgical procedure or open biopsy within 28
             days prior to registration.

         10. Patients who underwent colonoscopy, core biopsy, or fine needle aspiration within 7
             days prior to registration.

         11. Patients who had an arterial thromboembolic event, including transient ischemic attack
             (TIA), cerebrovascular accident (CVA), unstable angina, or myocardial infarction (MI)
             within 12 months of registration. Patients must not have greater than or equal to
             Grade 2 peripheral vascular disease.

         12. Patients with uncontrolled intercurrent illness including, but not limited to, ongoing
             or active infection, cardiac disease NYHA class III or IV, unstable angina pectoris,
             unstable cardiac arrhythmia or tachycardia (heart rate greater than or equal to 100
             beats per minute), poorly controlled hypertension (systolic blood pressure greater
             than or equal to 200 mmHg or diastolic blood pressure greater than or equal to 100
             mmHg) or psychiatric illness/social situations that would limit compliance with study
             requirements are excluded.

         13. Patients with preexisting chronic hepatic disease (chronic active hepatitis B or C,
             cirrhosis), which would preclude surgical resection of metastases.

         14. Patients with known hypersensitivity to any of the components of oxaliplatin,
             5-fluorouracil, leucovorin or bevacizumab (AVASTIN™).

         15. Patients who have received chemotherapy within 30 days of the first scheduled day of
             protocol treatment.

         16. Patients who received radiotherapy within 4 weeks of trial entry.

         17. Patients who are receiving concurrent investigational therapy or who have received
             investigational therapy within 30 days of the first scheduled day of protocol
             treatment (investigational therapy is defined as treatment for which there is
             currently no regulatory authority approved indication).

         18. Peripheral neuropathy greater than or equal to Grade 2.

         19. Patients with an active infection or with a fever greater than or equal to 38.5
             degrees C within 3 days of the first scheduled day of protocol treatment.

         20. Patients with known autoimmune disease including HIV.