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A Phase I Study Of The Antiangiogenic Agent Bevacizumab In Combination With 5-Fluourouracil And External Beam Radiation Therapy In Rectal Cancer

Phase 1
18 Years
Not Enrolling
Adenocarcinoma of the Rectum, Stage II Rectal Cancer, Stage III Rectal Cancer

Thank you

Trial Information

A Phase I Study Of The Antiangiogenic Agent Bevacizumab In Combination With 5-Fluourouracil And External Beam Radiation Therapy In Rectal Cancer


I. To determine the maximum tolerated dose (MTD) of a vascular endothelial growth factor
(VEGF) neutralizing antibody, bevacizumab, when administered concurrently with
5-fluorouracil (5-FU) and external beam radiation therapy (EBRT) in patients with clinical
stage T3 or T4 rectal cancer prior to surgery.

II. To obtain preliminary data of the pathological response rate after preoperative therapy.

III. To obtain preliminary data regarding progression free survival, local control, and
overall survival.

IV. To obtain preliminary data of the changes in the angiogenic profile of rectal cancer
induced by this therapy.

OUTLINE: This is a multicenter, dose-escalation study of bevacizumab.

Patients receive bevacizumab IV over 30-90 minutes on day 1 (courses 1-4). Beginning with
course 2, patients also receive fluorouracil IV continuously on days 1-14 and undergo
external beam radiotherapy on days 1-5 and 8-12. Treatment repeats every 2 weeks for 4
courses in the absence of disease progression or unacceptable toxicity.

Patients undergo surgery 7 weeks after completion of chemoradiotherapy.

Cohorts of 6 patients receive escalating doses of bevacizumab until the maximum tolerated
dose (MTD) is determined. The MTD is defined as the dose preceding that at which at least 2
of 6 patients experience dose-limiting toxicity. Once the MTD is determined, 20 additional
patients are treated at the MTD.

Patients are followed every 3 months for 2 years, every 6 months for 3 years, and then
annually for 2 years.

Inclusion Criteria:

- Histologically confirmed primary adenocarcinoma of the rectum that begins within 15
cm of the anal verge as determined by sigmoidoscopy and/or colonoscopy

- Clinical T3 or T4 tumors as determined by the following features:

- Tethered or fixed tumor on physical exam

- cT3, cT4, or N+ disease must be confirmed by an endorectal ultrasound or surface
coil MRI

- There must be no evidence of metastatic disease as confirmed by physical examination,
chest radiograph, and abdominal/pelvic CT scan

- ECOG performance status 0, 1, 2 (Karnofsky >= 70%)

- Life expectancy of greater than 2 years

- Leukocytes >= 3,000/ul

- Absolute neutrophil count >= 1,500/ul

- Platelets >= 100,000/ul

- Total bilirubin within normal institutional limits

- AST(SGOT)/ALT(SGPT) < 2.5 X institutional upper limit of normal

- Creatinine within normal institutional limits OR creatinine clearance >= 60
mL/min/1.73 m^2 for patients with creatinine levels above institutional normal

- The effects of bevacizumab on the developing human fetus are unknown; for this reason
and because radiation therapy and 5-FU agents as well as other therapeutic agents
used in this trial are known to be teratogenic, women of child-bearing potential and
men must agree to use adequate contraception (hormonal or barrier method of birth
control) prior to study entry and for the duration of study participation; 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 the willingness to sign a written informed consent document

- Patients with no known HIV or HIV risk factors will be eligible for this study
without HIV testing

Exclusion Criteria:

- Patients with a "concurrently active" second malignancy other than non- melanoma skin
cancers or in situ cervical cancer are excluded; patients are not considered to have
a "concurrently active" malignancy if they have completed therapy and considered by
their physician to be at less than 30% risk of relapse at a minimum of 5 years after
all therapy

- Prior Treatment:

- No prior treatment for this malignancy

- No prior history of pelvic irradiation

- No prior history of 5-FU-based therapy for any malignancy

- No prior treatment with bevacizumab

- Patients must not be receiving any other investigational agents

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition bevacizumab or other agents used in study

- Bevacizumab - Specific exclusion criteria:

- History or evidence upon physical examination of CNS disease (e.g., primary
brain tumor, seizures not controlled with standard medical therapy, any brain
metastases, or history of stroke

- Serious, non-healing wound, ulcer, or bone fracture

- Clinically significant cardiovascular disease (e.g., uncontrolled hypertension,
history of myocardial infarction, unstable angina within 12 months), New York
Heart Association (NYHA) Grade II or greater congestive heart failure, serious
cardiac arrhythmia requiring medication, or Grade II or greater peripheral
vascular disease within 1 year prior to Day 0

- Major surgical procedure, open biopsy, or significant traumatic injury within 28
days prior to Day 0, or anticipation of need for major surgical procedure during
the course of the study; biopsies (other than rectal cancer) within 7 days prior
to Day 0; placement of a vascular access device within 7 days prior to Day 0

- Arterial thromboembolic events within previous 12 months including transient
ischemic attack, cerebrovascular accident, unstable angina, myocardial
infarction, or clinically significant peripheral vascular disease. Vascular
surgery, stenting or angioplasty within previous 12 months; no history of venous
thromboembolic events that require continuation of therapeutic dose of

- Current or recent (within 10 days prior to Day 0) use of full-dose oral or
parenteral anticoagulants or thrombolytic agents (except as required to maintain
patency of preexisting, permanent indwelling IV catheters; for subjects
receiving warfarin, international normalized ratio [INR] of < 1.5; appropriate
use of heparin should be discussed with the Medical Monitor)

- Chronic, daily treatment with aspirin (> 325 mg/day) or nonsteroidal anti-
inflammatory medications (of the kind known to inhibit platelet function at
doses used to treat chronic inflammatory diseases)

- Presence of bleeding diathesis or coagulopathy

- Active infection requiring parenteral antibiotics on Day 0

- Proteinuria at baseline or clinically significant impairment of renal function

- Subjects unexpectedly discovered to have >= 1+ proteinuria during screening
should undergo a 24-hour urine collection, which must be an adequate collection
and must demonstrate < 1 gram protein/24 hr to allow participation in the study

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements

- Pregnant women are excluded from this study because bevacizumab, radiation therapy,
and 5-FU have potential for teratogenic or abortifacient effects; because there is an
unknown but potential risk for adverse events in nursing infants secondary to
treatment of the mother with bevacizumab, breastfeeding should be discontinued if the
mother is treated with bevacizumab; these potential risks may also apply to other
agents used in this study

Type of Study:


Study Design:

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

Outcome Measure:

Maximum tolerated dose of bevacizumab when administered concurrently with 5-fluorouracil (5-FU) and external beam radiation therapy (EBRT) in patients with cT3 and T4 rectal cancer prior to surgery

Outcome Time Frame:

29 days

Safety Issue:


Principal Investigator

Christopher Willett

Investigator Role:

Principal Investigator

Investigator Affiliation:

Duke University


United States: Food and Drug Administration

Study ID:




Start Date:

August 2002

Completion Date:

Related Keywords:

  • Adenocarcinoma of the Rectum
  • Stage II Rectal Cancer
  • Stage III Rectal Cancer
  • Adenocarcinoma
  • Adenocarcinoma, Mucinous
  • Rectal Neoplasms



Massachusetts General Hospital Cancer Center Boston, Massachusetts  02114
Duke University Medical Center Durham, North Carolina  27710