Sorafenib Tosylate, Bevacizumab, Irinotecan Hydrochloride, Leucovorin Calcium, and Fluorouracil in Treating Patients With Metastatic Colorectal Cancer

This study is ongoing, but not recruiting participants.
Information provided by (Responsible Party):
National Cancer Institute (NCI) Identifier:
First received: June 25, 2011
Last updated: April 21, 2014
Last verified: December 2013

This phase I trial studies the side effects and best dose of sorafenib tosylate when given together with bevacizumab, irinotecan hydrochloride, leucovorin calcium, and fluorouracil in treating patients with metastatic colorectal cancer. Drugs used in chemotherapy, such as irinotecan hydrochloride, leucovorin calcium, and fluorouracil, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Sorafenib tosylate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Sorafenib tosylate and bevacizumab may also stop the growth of tumor cells by blocking blood flow to the tumor. Giving sorafenib tosylate and bevacizumab together with combination chemotherapy may kill more tumor cells.

Condition Intervention Phase
Recurrent Colon Cancer
Recurrent Rectal Cancer
Stage IVA Colon Cancer
Stage IVA Rectal Cancer
Stage IVB Colon Cancer
Stage IVB Rectal Cancer
Drug: irinotecan hydrochloride
Drug: sorafenib tosylate
Biological: bevacizumab
Drug: leucovorin calcium
Drug: fluorouracil
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase I Trial of FOLFIRI in Combination With Sorafenib and Bevacizumab in Patients With Advanced Gastrointestinal Malignancies

Resource links provided by NLM:

Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • MTD of sorafenib tosylate in combination with FOLFIRI and bevacizumab, determined according to incidence of DLT graded using NCI CTCAE version 4.0 [ Time Frame: 2 weeks ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Toxicity profile of sorafenib tosylate in combination with bevacizumab and FOLFIRI as assessed by NCI CTCAE v 4.0 [ Time Frame: Up to 3 months ] [ Designated as safety issue: Yes ]
    Overall toxicity incidence as well as toxicity profiles by dose level, patient and tumor site will be explored and summarized. Frequency distributions, graphical techniques and other descriptive measures will form the basis of these analyses.

  • Response rate in patients treated with sorafenib tosylate in combination with FOLFIRI and bevacizumab, assessed using RECIST [ Time Frame: Up to 3 months ] [ Designated as safety issue: No ]
    Responses will be summarized by simple descriptive summary statistics delineating complete and partial responses as well as stable and progressive disease in this patient population (overall and by tumor group).

Enrollment: 17
Study Start Date: August 2011
Primary Completion Date: May 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (FOLFIRI and bevacizumab)
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 PO QD or BID on days 3-6 and 10-13*. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.
Drug: irinotecan hydrochloride
Given IV
Other Names:
  • Campto
  • Camptosar
  • CPT-11
  • irinotecan
  • U-101440E
Drug: sorafenib tosylate
Given PO
Other Names:
  • BAY 43-9006
  • BAY 43-9006 Tosylate Salt
  • BAY 54-9085
  • Nexavar
  • SFN
Biological: bevacizumab
Given IV
Other Names:
  • anti-VEGF humanized monoclonal antibody
  • anti-VEGF monoclonal antibody
  • Avastin
  • rhuMAb VEGF
Drug: leucovorin calcium
Given IV
Other Names:
  • CF
  • CFR
  • LV
Drug: fluorouracil
Given IV
Other Names:
  • 5-fluorouracil
  • 5-Fluracil
  • 5-FU

Detailed Description:


I. To determine the maximally tolerated dose of the combination of irinotecan hydrochloride, leucovorin calcium, and fluorouracil (FOLFIRI) plus sorafenib tosylate plus bevacizumab.


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 interavenously (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 (QD) or twice daily (BID) 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.


Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • This trial is intended for gastrointestinal malignancies 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
  • Absolute neutrophil count (ANC) >= 1,500/μL
  • Platelet count (PLT) >= 100,000/μL
  • Hemoglobin (Hgb) >= 9.0 mg/dL
  • Total bilirubin =< upper limit of normal (ULN)
  • Alkaline phosphatase =< 3 x ULN
  • Aspartate aminotransferase (AST) =< 3 x ULN OR AST =< 5 times ULN if liver involvement
  • International Normalized Ratio (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 x ULN
  • Calculated creatinine clearance must be >= 45 mL/min using the Cockcroft-Gault formula
  • Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
  • Ability to provide informed consent
  • Willing to return to Mayo Clinic for follow up
  • Life expectancy >= 84 days (3 months)
  • Women of childbearing potential only: negative pregnancy test done =< 7 days prior to registration

Exclusion Criteria:

  • Known standard therapy for patient's disease that is potentially curative


  • Prior treatment with irinotecan, 5-fluoruracil or bevacizumab is allowed
  • Prior treatment with sorafenib is not allowed

    • Inadequately controlled hypertension (systolic blood pressure of > 150 mm Hg or diastolic pressure > 100 mm Hg on anti-hypertensive medications)
    • Prior history of hypertensive crisis or hypertensive encephalopathy
    • 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
    • Heart failure New York Heart Association classification III or IV
    • Thrombolic or embolic events such as a cerebrovascular accident including transient ischemic attacks =< 6 months prior to registration
    • Any hemorrhage/bleeding event > grade 3 =< 4 weeks prior to registration
    • 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

    • Active or recent hemoptysis (>= ½ teaspoon of bright red blood per episode) =< 30 days prior to registration
    • Serious, non-healing wound, active ulcer, or untreated bone fracture
  • Patients with fractures secondary to metastatic disease are eligible after appropriate radiotherapy

    • Significant vascular disease (e.g., aortic aneurysm or aortic dissection), recent peripheral arterial thrombosis, or symptomatic peripheral vascular disease =< 6 months prior to registration
    • History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess =< 6 months prior to registration
    • 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)
    • Known or suspected allergy or hypersensitivity to any agent given in the course of this trial
    • Any condition that impairs patient's ability to swallow whole pills
    • Any malabsorption problem
    • Any 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

    • Failure to fully recover from acute, reversible effects of prior chemotherapy regardless of interval since last treatment
    • Known brain metastasis
  • Patients with neurological symptoms must undergo a computed tomography (CT) scan/magnetic resonance imaging (MRI) of the brain to exclude brain metastasis

    • Any of the following because this study involves an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown:
  • Pregnant women
  • Nursing women
  • Men or women of childbearing potential who are unwilling to employ adequate contraception

    • Other concurrent chemotherapy, immunotherapy, radiotherapy, or any ancillary therapy considered investigational (utilized for a non-Food and Drug Administration [FDA]-approved indication and in the context of a research investigation)
    • Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm
    • 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
    • Other active malignancy =< 3 years prior to registration; EXCEPTIONS:
  • Non-melanotic skin cancer or carcinoma-in-situ of the cervix
  • If there is a history of prior malignancy, they must not be receiving other specific treatment for their cancer, including hormonal therapy
  Contacts and Locations
Please refer to this study by its identifier: NCT01383343

United States, Arizona
Mayo Clinic in Arizona
Scottsdale, Arizona, United States, 85259
United States, Florida
Mayo Clinic in Florida
Jacksonville, Florida, United States, 32224-9980
United States, Minnesota
Mayo Clinic
Rochester, Minnesota, United States, 55905
Sponsors and Collaborators
Principal Investigator: Joleen Hubbard Mayo Clinic
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI) Identifier: NCT01383343     History of Changes
Other Study ID Numbers: NCI-2011-02595, NCI-2011-02595, CDR0000702751, MC1017, 8877, P30CA015083, U01CA069912
Study First Received: June 25, 2011
Last Updated: April 21, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Colonic Neoplasms
Rectal Neoplasms
Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Antibodies, Monoclonal
Calcium, Dietary
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Bone Density Conservation Agents
Molecular Mechanisms of Pharmacological Action
Antimetabolites, Antineoplastic processed this record on April 22, 2014