Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outline
Published Results
Trial Contact Information
Registry Information

Alternate Title

Bevacizumab, Fluorouracil, and External-Beam Radiation Therapy in Treating Patients With Stage II or Stage III Rectal Cancer

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase I	Treatment	Closed	18 and over	NCI	DFCI-02025 NCI-5642, NCT00052559, 5642

Objectives

1. Determine the maximum tolerated dose of neoadjuvant bevacizumab when administered with fluorouracil and external beam radiotherapy in patients with stage II or III rectal cancer.
2. Determine the progression-free survival, local control, and overall survival of patients treated with this regimen.
3. Determine the pathological response rate of patients treated with this regimen.
4. Determine, preliminarily, the changes in the angiogenic profile of this disease in these patients induced by this regimen.

Entry Criteria

Disease Characteristics:

• Histologically confirmed adenocarcinoma of the rectum
  • Begins within 15 cm of the anal verge by sigmoidoscopy and/or colonoscopy
• Stage II or III disease
  • Clinical T3 or T4 tumors, as indicated by the following:
    • Tethered or fixed tumor on physical exam
    • cT3, cT4, or N+ disease by endorectal ultrasound or surface coil MRI
• No evidence of metastatic disease by physical examination, chest radiograph, and abdominal/pelvic CT scan
• No primary brain tumor or brain metastases

Prior/Concurrent Therapy:

Biologic therapy

• No prior bevacizumab

Chemotherapy

• No prior fluorouracil-based therapy for any malignancy
• No other concurrent chemotherapy

Endocrine therapy

• No concurrent hormonal therapy except the following:
  • Steroids for adrenal failure or allergic reactions
  • Hormones for non-disease-related conditions (e.g., insulin for diabetes)
  • Intermittent dexamethasone as an antiemetic

Radiotherapy

• No prior pelvic radiotherapy

Surgery

• More than 6 months since prior vascular surgery, stenting, or angioplasty
• More than 28 days since prior major surgery or open biopsy
• More than 7 days since prior biopsy (except rectal cancer)
• More than 7 days since prior placement of vascular access device
• No other concurrent planned major surgery

Other

• More than 10 days since prior full-dose oral or parenteral anticoagulants or thrombolytic agents (except to maintain patency of preexisting, permanent indwelling IV catheters)
• No prior treatment for this malignancy
• No concurrent full-dose oral or parenteral anticoagulants or thrombolytic agents (except to maintain patency of preexisting, permanent indwelling IV catheters)
• No concurrent chronic aspirin use (more than 325 mg/day)
• No concurrent nonsteroidal anti-inflammatory medications (of the kind known to inhibit platelet function at doses used to treat chronic inflammatory diseases)
• No other concurrent investigational agents

Patient Characteristics:

Age

• 18 and over

Performance status

• ECOG 0-2

  OR

• Karnofsky 70-100%

Life expectancy

• More than 2 years

Hematopoietic

• WBC at least 3,000/mm³
• Absolute neutrophil count at least 1,500/mm³
• Platelet count at least 100,000/mm³
• No bleeding diathesis or coagulopathy

Hepatic

• Bilirubin normal
• AST/ALT less than 2.5 times upper limit of normal
• INR less than 1.5*

 [Note: *For patients receiving warfarin]

Renal

• Creatinine normal

  OR

• Creatinine clearance at least 60 mL/min
• No proteinuria

  OR

• Protein less than 1 g on 24-hour urine collection

Cardiovascular

• No history of stroke
• No history of deep vein thrombosis
• No clinically significant cardiovascular disease within the past year, including any of the following:
  • Uncontrolled hypertension
  • Myocardial infarction
  • Unstable angina pectoris
• No arterial thromboembolic events within the past 6 months, including any of the following:
  • Transient ischemic attack
  • Cerebrovascular accident
  • Clinically significant peripheral vascular disease
• No history of venous thromboembolic events requiring continuous therapeutic anticoagulation
• No New York Heart Association class II-IV congestive heart failure
• No serious cardiac arrhythmia requiring medication
• No grade II or greater peripheral vascular disease within the past year

Other

• Not pregnant
• Not nursing during and for at least 3-4 months after study participation
• Negative pregnancy test
• Fertile patients must use effective contraception during and for at least 3-4 months after study participation
• No known HIV or HIV risk factors
  • HIV testing not required
• No other concurrent active malignancy except nonmelanoma skin cancer or carcinoma in situ of the cervix
  • Completed therapy and considered to be at less than 30% risk of relapse at least 5 years after all therapy
• No prior allergic reaction attributed to compounds of similar chemical or biological composition to bevacizumab or other study agents
• No serious non-healing wound, ulcer, or bone fracture
• No evidence of CNS disease (e.g., seizures not controlled with standard medical therapy)
• No significant traumatic injury within the past 28 days
• No active infection requiring parenteral antibiotics
• No other concurrent uncontrolled illness
• No concurrent psychiatric illness or social situation that would preclude study compliance

Expected Enrollment

Approximately 4-32 patients will be accrued for this study.

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.

Willett CG, Duda DG, di Tomaso E, et al.: Efficacy, safety, and biomarkers of neoadjuvant bevacizumab, radiation therapy, and fluorouracil in rectal cancer: a multidisciplinary phase II study. J Clin Oncol 27 (18): 3020-6, 2009.[PUBMED Abstract]

Willett CG, Boucher Y, di Tomaso E, et al.: Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer. Nat Med 10 (2): 145-7, 2004.[PUBMED Abstract]

Trial Contact Information

Trial Lead Organizations

Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute

Jeffrey Clark, MD, Protocol chair		Ph: 617-643-3415; 877-726-5130 Email: jclark@partners.org

Registry Information
Official Title		A Phase I Study Of The Antiangiogenic Agent Bevacizumab In Combination With 5-Fluourouracil And External Beam Radiation Therapy In Rectal Cancer
Trial Start Date		2002-06-03
Trial Completion Date		2003-04-19 (estimated)
Registered in ClinicalTrials.gov		NCT00052559
Date Submitted to PDQ		2002-09-05
Information Last Verified		2007-10-07
NCI Grant/Contract Number		CA06516, CA62490

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