A Randomized Pilot Study of the Activation of the Hemostatic Pathway by FOLFIRI + Bevacizumab With or Without Dalteparin in First Line Treatment of Advanced Colorectal Cancer
- Patients with histologically or cytologically confirmed metastatic or recurrent
colorectal tumors with no previous treatment for advanced disease.
- Age > 18 years (as no dosing or toxicity data are currently available on the use of
5-FU/CPT11 + bevacizumab + dalterparin in patients <18 years of age).
- SWOG performance status 0-1.
- Patients must have adequate organ and marrow function as defined below, with tests
performed no more than seven days prior to the first study drug
administration:leukocytes >3.0, absolute neutrophil count >1,500/ml,platelets > 100 X
109 L ,total bilirubin < upper normal institutional limits,AST(SGOT)/ALT(SGPT) < 2.5
X institutional upper limit of normal ( or < 5x the upper normal institutional limits
in the case of liver metastases,alkaline phosphatase < 2.5 X institutional upper
limit of normal ( or < 5x the upper normal institutional limits in the case of liver
metastases or < 10x the upper normal institutional limits in the case of bone
disease, Serum creatinine < 1.6 mg/dL OR Calculated creatinine clearance > 40
mL/min/1.73 m2, PT, PTT, within normal range, Urine protein/creatinine ratio < 1.0
- At least one measurable lesion according to the RECIST criteria which has not been
irradiated (i.e. newly arising lesions in previously irradiated areas are accepted).
Ascites, pleural effusion, and bone metastases are not considered measurable.
Minimum indicator lesion size: > 10 mm measured by spiral CT or >20mm measured by
- The effects of chemotherapy on the developing human fetus at the recommended
therapeutic dose are unknown. For this reason, women of child-bearing potential and
men must agree to use adequate contraception (hormonal or barrier method of birth
control) prior to study entry, for the duration of study participation and 30 days
from the date of the last study drug administration (postmenopausal woman must have
been amenorrheic for at least 12 months to be considered of non-childbearing
potential). Should a woman become pregnant or suspect she is pregnant while
participating in this study, she should inform her treating physician immediately.
- Ability to understand and willingness to sign a written informed consent prior to
study-specific screening procedures, with the understanding that the patient has the
right to withdraw from the study at any time, without prejudice.
- Have a negative serum pregnancy test within 7 days prior to initiation of
chemotherapy (female patients of childbearing potential).
- Life expectancy of at least 12 weeks.
- Fully recovered from any surgical procedure
- Lactating woman unwilling to stop breast feeding for the duration of study
participation and 30 days from the date of the last study drug administration
- History of allergy to any of the chemotherapeutics or antiemetics appropriate for
administration in conjunction with protocol-directed chemotherapy.
- Prior unanticipated severe reaction to fluoropyrimidine therapy, known
hypersensitivity to 5-fluorouracil, or known DPD deficiency.
- Serious, uncontrolled, intercurrent infection(s) or illnesses including, but not
limited to ongoing or active infection, symptomatic congestive heart failure, or
unstable angina pectoris, or cardiac arrhythmia.
- Treatment for other carcinomas within the last five years, except cured non-melanoma
skin and treated in-situ cervical cancer.
- Current, recent (within 4 weeks of first infusion on this study) or planned
participation in an investigational drug study.
- Patients with documented DIC (disseminated intravascular coagulation).
- Patients with a previous history of a bleeding diathesis or significant bleeding
episode such as gastrointestinal bleeding or a CNS hemorrhage.
- Clinically significant cardiac disease (e.g. congestive heart failure, symptomatic
coronary artery disease and cardiac arrhythmias not well controlled with medication)
within the last 12 months.
- Presence of central nervous system or brain mets.
- Major surgery, open biopsy, or significant traumatic injury within 28 days prior to
Day 1, or anticipation of need for major surgical procedure during the course of the
- Unwillingness to participate or inability to comply with the protocol for the
duration of the study.
- Minor surgical proceures, fine needle aspirations or core biopsies within 7 days
prior to Day 1.
- Blood pressure > 150/100 mmHg.
- Ustable angina.
- New York Heart Association (NYHA) Grade II or greater congestive heart failure.
- History of myocardial infarction or stroke within 6 months.
- Clinically significant peripheral vascular disease.
- Evidence of bleeding diathesis or coagulopathy.
- History of abdominal fistula, gastrointestinal perforation or intraabdominal abscess
within 28 days prior to Day 0.
- Serious, non-healing wound, ulcer or bone fracture.
- Carcinoma of any histology in close proximity to a major vessel, lung cavitation or
history of hemoptysis.
- Completion of previous chemotherapy regimen < four weeks prior to the start of study
treatment (within six weeks of study treatment for mitomycin C and nitrosureas), or
with related toxicities unresolved prior to the start of study treatment.
- Patients who are taking anti coagulation therapy such as coumadin or low molecular
- Patients who have an allergy against heparin.
- Medical, social or psychological factors which would interfere with consent and
- Known defective hemostasis, e.g. thrombocytopenia.
- Patients receiving Hormone Replacement Therapy.