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Phase I Trial of FOLFIRI in Combination With Sorafenib and Bevacizumab in Patients With Advanced Gastrointestinal Malignancies

Phase 1
18 Years
Open (Enrolling)
Recurrent Colon Cancer, Recurrent Rectal Cancer, Stage IVA Colon Cancer, Stage IVA Rectal Cancer, Stage IVB Colon Cancer, Stage IVB Rectal Cancer

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Trial Information

Phase I Trial of FOLFIRI in Combination With Sorafenib and Bevacizumab in Patients With Advanced Gastrointestinal Malignancies


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.

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

- 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

- 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

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

- 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

- 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

Type of Study:


Study Design:

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

MTD of sorafenib tosylate in combination with FOLFIRI and bevacizumab, determined according to incidence of DLT graded using NCI CTCAE version 4.0

Outcome Time Frame:

2 weeks

Safety Issue:


Principal Investigator

Joleen Hubbard

Investigator Role:

Principal Investigator

Investigator Affiliation:

Mayo Clinic


United States: Food and Drug Administration

Study ID:




Start Date:

August 2011

Completion Date:

Related Keywords:

  • Recurrent Colon Cancer
  • Recurrent Rectal Cancer
  • Stage IVA Colon Cancer
  • Stage IVA Rectal Cancer
  • Stage IVB Colon Cancer
  • Stage IVB Rectal Cancer
  • Colonic Neoplasms
  • Rectal Neoplasms



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