Bevacizumab, Erlotinib and 5-Fluorouracil With External Beam Radiation Therapy in Locally Advanced Rectal Cancer

Phase 1

Completed

Conditions: Rectal Cancer
Adenocarcinoma of the Rectum

Interventions: Drug: 5-fluorouracil
Drug: bevacizumab
Drug: erlotinib
Procedure: External beam radiation therapy (EBRT)

Registration Number: NCT00307736

Lead Sponsor: Massachusetts General Hospital

Brief Summary: The purpose of this study is determine the safety of 5-fluorouracil, bevacizumab and erlotinib when administered in combination with external beam radiation therapy(Phase I portion) as well as to begin to collect information about whether this combination treatment is effective in treating(Phase II portion) patients with locally advanced rectal cancer.

Detailed Description: * All participants will receive the following drugs: 5-fluorouracil (5-FU) given as a continuous 24-hour infusion; Bevacizumab given intravenously; erlotinib given orally at home. In the Phase I portion, we are looking for the highest dose of erlotinib that can be given safely in combination with the 5-FU, bevacizumab and radiation therapy. Therefore the dose of erlotinib may not be the same for each participant. The dose will increase until we find the highest dose without causing serious or unmanageable side effects.

* Study treatment is given as an outpatient and consists of 14 day cycles with a total of 3 cycles. Patients will be given all three study drugs and radiation therapy on a monday (unless a monday falls on on a holiday). This will be day 1 of the first treatment cycle. 5-FU is given continuously days 1-14. Bevacizumab is given on day 1. Erlotinib will be given on days 1-14. Radiation therapy will be performed on Days 1-5 and 8-12.

* The following tests and procedures will be performed weekly while participants are receiving study treatment: physical examination, measurement of vital signs, height and weight; performance status; blood work, urine sample.

* At the end of treatment the following tests will be performed: physical examination and measurement of vital signs; performance status; blood work; CT scans of chest, abdomen and pelvis. Patients will also be evaluated for surgery at this time. Patients will be followed every three months for the first three years after surgery, then every 6 months for the next two years.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 32

Inclusion Criteria

Histologically confirmed primary adenocarcinoma of the rectum that begins within 15cm of the anal verge as determined by sigmoidoscopy or colonoscopy
Clinical T3 or T4 tumors as determined by endoscopic ultrasound and/or rectal MRI
ECOG performance status of 0-2
18 years of age or older
Creatinine of < 2.0
Adequate hepatic function
Adequate hematopoietic function
Use of effective means of contraception in subjects of child-bearing potential

Exclusion Criteria

Evidence of metastatic disease as determined by chest/abdominal/pelvic CT or physical exam
Prior chemotherapy or radiation therapy for treatment of colorectal cancer
Prior treatment with 5-FU
Prior treatment with a tyrosine kinase inhibitor, EGFR inhibitor, or VEGF inhibitor
Patients must not be receiving any other investigational agent
Prior malignancy within the last 5 years except for completely excised skin cancer, in situ cervical cancer
Warfarin anticoagulation
Co-existent malignant disease
Current or recent participation in a clinical trial (within 4 weeks from the first day of treatment)
Pregnancy
Blood pressure of >150/100 mmHg
Unstable angina
NYHA Grade II or greater congestive heart failure
History of myocardial infarction within 6 months
History of stroke within 6 months
Clinically significant peripheral vascular disease
Evidence of bleeding diathesis or coagulopathy
Presence of central nervous system or brain metastases
Major surgical procedure, open biopsy, or significant trauma injury within 28 days prior to day 0, anticipation of need for major surgical procedure during the course of the study
Minor surgical procedures, fine needle aspirations or core biopsies within 7 days prior to day 0
Pregnant or lactating
Urine protein:creatinine ratio > or equal to one at screening
History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to day 0]
Serious, non-healing wound, ulcer, or bone fracture

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Chemotherapy and radiation	5-fluorouracil	Continuous infusion 5-fluorouracil 225 mg/M2/d, bevacizumab 5 mg/kg IV q 14 days, erlotinib 50-150 mg orally daily for duration of radiation.
Chemotherapy and radiation	bevacizumab	Continuous infusion 5-fluorouracil 225 mg/M2/d, bevacizumab 5 mg/kg IV q 14 days, erlotinib 50-150 mg orally daily for duration of radiation.
Chemotherapy and radiation	erlotinib	Continuous infusion 5-fluorouracil 225 mg/M2/d, bevacizumab 5 mg/kg IV q 14 days, erlotinib 50-150 mg orally daily for duration of radiation.
Chemotherapy and radiation	External beam radiation therapy (EBRT)	Continuous infusion 5-fluorouracil 225 mg/M2/d, bevacizumab 5 mg/kg IV q 14 days, erlotinib 50-150 mg orally daily for duration of radiation.

Primary Outcome Measures

Name	Time	Method
Maximum Tolerated Dose (MTD) of Erlotinib When Administered in Combination With 5-fluorouracil (5-FU), Bevacizumab, and External Beam Radiation Therapy	3 years	MTD of Erlotinib was determined using a traditional 3 + 3 dose escalation scheme of three dose levels (50,100,150mg). Successive cohorts of 3-6 patients were enrolled into dose escalation cohorts for 14 day cycles. MTD reflects the highest dose of Erlotinib that had ≤1 out of 6 patients with Dose-Limiting Toxicity (DLT) at the highest dose level below the maximally administered dose. The maximally administered dose is the first dose that causes DLT in \>33% of patients. DLT was defined as: Any grade 4 neutropenia, Any grade 3 thrombocytopenia, or Any ≥ grade 3 non-hematologic toxicity that results in greater than 7 days interruption in therapy.

Secondary Outcome Measures

Name	Time	Method
Summary of Grade 3 or Greater Toxicity	3 years	Summary of grade 3 or greater toxicity by grade and type. All adverse events were evaluated using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. Grade 3: Severe or medically significant but not immediately life threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care activities of daily living. Grade 4 Life-threatening consequences; urgent intervention indicated.
Percentage of Participants With Disease-free Survival	1, 2, 3 years	Summary of disease free survival at 1, 2, and 3 years. Disease free survival is the length of time after primary treatment for cancer ends that the participant survives without any clinical signs or symptoms of that cancer. The data is shown of the percentage of participants still in disease free survival at one, two, and three years.
Post-operative Complications After Resection of Rectal Cancers Following Preoperative 5-FU, Bevacizumab, Erlotinib, and External Beam Radiation Therapy.	3 years	Surgical morbidity following R0 resection with one of the following procedures: abdominal perineal resection, low anterior resection, and low anterior resection with coloanal anastomosis.

Trial Locations

Locations (3): Dana-Farber Cancer Institute
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Boston, Massachusetts, United States
Massachusetts General Hospital
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Boston, Massachusetts, United States
Beth Israel Deaconess Medical Center
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Boston, Massachusetts, United States