PRIMARY OBJECTIVES:
I. To determine the maximally tolerated dose of the combination of irinotecan hydrochloride, leucovorin calcium, and fluorouracil (FOLFIRI) plus sorafenib tosylate plus bevacizumab.
SECONDARY OBJECTIVES:
I. To assess the safety of FOLFIRI plus sorafenib tosylate plus bevacizumab. II. To assess the feasibility of the proposed combination. III. To evaluate the response rate and identify any activity of the proposed combination.
OUTLINE: This is a dose-escalation study of sorafenib tosylate followed by a cohort study.
Patients receive irinotecan hydrochloride IV over 90 minutes on day 1, leucovorin calcium IV over 2 hours on day 1, fluorouracil IV continuously over 46 hours on days 1-2, bevacizumab IV over 30-90 minutes on day 1, and sorafenib tosylate orally (PO) once or twice daily on days 3-6 and 10-13*. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.
NOTE: * Patients may also receive sorafenib tosylate on days 7 and 14.
After completion of study therapy, patients are followed up for 3 months.
Inclusion Criteria:
- Diagnosis of colorectal cancer appropriate for irinotecan-based therapy
- Histologic proof of cancer that is now unresectable
- If prior therapy was received, patients must have shown progressive disease during prior treatment or within 6 months of their most recent therapy
- Measurable disease or non-measurable disease
- No known standard therapy for patient's disease that is potentially curative
- No known brain metastasis
- Patients with neurological symptoms must undergo a CT scan/MRI of the brain to exclude brain metastasis
- ECOG performance status 0 or 1
- Life expectancy ≥ 84 days (3 months)
- ANC ≥ 1,500/μL
- Platelet count ≥ 100,000/μL
- Hemoglobin (Hgb) ≥ 9.0 mg/dL
- Total bilirubin normal
- Alkaline phosphatase ≤ 3 times upper limit of normal (ULN)
- AST ≤ 3 times ULN OR AST ≤ 5 times ULN if liver involvement
- INR < 1.5 unless patients are receiving anti-coagulation therapy; patients receiving anti-coagulation therapy with an agent such as warfarin or heparin are allowed to participate if INR ≤ 3.0
- Urine protein creatinine (UPC) ratio < 1 OR urine dipstick < 2+
- Urine protein must be screened by urine analysis for UPC ratio or by dipstick; for UPC ratio ≥ 1.0, 24-hour urine protein must be obtained and the level should be < 1,000 mg
- Creatinine ≤ 1.5 times ULN
- Calculated creatinine clearance must be ≥ 45 mL/min
- Willing to return to Mayo Clinic for follow up
- Negative pregnancy test
- Not pregnant or nursing
- No men or women of childbearing potential who are unwilling to employ adequate contraception
- No inadequately controlled hypertension (systolic blood pressure of > 150 mm Hg or diastolic pressure > 100 mm Hg on anti-hypertensive medications)
- No history of hypertensive crisis or hypertensive encephalopathy
- No history of myocardial infarction or unstable angina ≤ 6 months prior to registration or congestive heart failure requiring use of ongoing maintenance therapy for life-threatening ventricular arrhythmias
- No New York Heart Association classification III or IV heart failure
- No thrombolic or embolic events such as a cerebrovascular accident including transient ischemic attacks ≤ 6 months prior to registration
- No hemorrhage/bleeding event > grade 3 ≤ 4 weeks prior to registration
- No evidence or history of bleeding diathesis (greater than normal risk of bleeding) or coagulopathy (in the absence of therapeutic anticoagulation)
- Patients on full-dose anticoagulants are eligible provided the patient has been on a stable dose for at least 2 weeks of low molecular weight heparin or warfarin and has an INR in the range of 2-3
- Aspirin doses > 325 mg PO daily are not allowed
- No active or recent hemoptysis (≥ ½ teaspoon of bright red blood per episode) ≤ 30 days prior to registration
- 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 vascular disease (e.g., aortic aneurysm or aortic dissection), recent peripheral arterial thrombosis, or symptomatic peripheral vascular disease ≤ 6 months prior to registration
- No history of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess ≤ 6 months prior to registration
- No known or suspected allergy or hypersensitivity to any agent given in the course of this trial
- No condition that impairs patient's ability to swallow whole pills
- No malabsorption problem
- No co-morbid systemic illnesses or other severe concurrent disease that, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens
- No other active malignancy ≤ 3 years prior to registration
- Non-melanotic skin cancer or carcinoma-in-situ of the cervix allowed
- If there is a history of prior malignancy, they must not be receiving other specific treatment for their cancer, including hormonal therapy
- No other concurrent chemotherapy, immunotherapy, radiotherapy, or any ancillary therapy considered investigational (utilized for a non-FDA-approved indication and in the context of a research investigation)
- Not receiving any other investigational agent which would be considered as a treatment for the primary neoplasm
- No prior treatment with irinotecan or sorafenib tosylate
- Prior treatment with bevacizumab IS allowed unless it was previously discontinued due to adverse events
- No major surgical procedures, open biopsy, or significant traumatic injury ≤ 28 days prior to registration or anticipation of need for major surgical procedure during the course of the study
- Core biopsy or minor surgical procedure, including placement of a vascular access device, ≤ 7 days prior to registration is allowed
- Patients taking cytochrome P450 enzyme-inducing antiepileptic drugs ≤ 4 weeks prior to registration will be excluded (phenytoin, carbamazepine, phenobarbital, rifampin, or St. John wort)
- None of the following prior therapies:
- Chemotherapy ≤ 14 days prior to registration
- Immunotherapy ≤ 28 days prior to registration
- Radiation therapy ≤ 28 days prior to registration
- Radiation to > 25% of bone marrow
- No failure to fully recover from acute, reversible effects of prior chemotherapy regardless of interval since last treatment
Last updated: 12/04/2012
NCT ID: NCT01383343
IRB Number:11-002396
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