Adenocarcinoma of the Rectum, Stage III Rectal Cancer, Stage II Rectal Cancer
Conditions
Brief summary
This phase I trial is studying the side effects and best dose of bevacizumab when given together with fluorouracil and external-beam radiation therapy in treating patients with stage II or stage III rectal cancer. Monoclonal antibodies, such as bevacizumab, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or deliver cancer-killing substances to them. Drugs used in chemotherapy work in different ways to stop tumor cells from dividing so they stop growing or die. Radiation therapy uses high-energy x-rays to damage tumor cells. Combining monoclonal antibody therapy with chemotherapy and radiation therapy may kill more tumor cells.
Detailed description
PRIMARY OBJECTIVES: 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.
Interventions
BIOLOGICALbevacizumab
Given IV
DRUGfluorouracil
Given IV
RADIATIONexternal beam radiation therapy
Undergo external beam radiation therapy
PROCEDUREtherapeutic conventional surgery
Undergo surgery
OTHERlaboratory biomarker analysis
Correlative studies
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| 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 | 29 days |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pathological response rate after preoperative bevacizumab, 5-FU, EBRT, and surgery | Up to 5 years | — |
| Progression-free survival | From protocol entry until documented progression of disease or death from any cause, assessed up to 5 years | The progression-free survival curve will be estimated using the Kaplan-Meier methods. |
| Local control | Up to 5 years | — |
| Overall survival | Up to 5 years | — |
Countries
United States
Outcome results
None listed